Trametinib and Navitoclax in Treating Patients With Advan... | NCT02079740

ID	Type	Description	Link
NCI-2014-00461	Registry Identifier	CTRP (Clinical Trial Reporting Program)
13-505
9525	Other Identifier	Dana-Farber Cancer Institute
9525	Other Identifier	CTEP
P30CA006516	U.S. NIH Grant/Contract		View source
P50CA127003	U.S. NIH Grant/Contract		View source
U01CA062490	U.S. NIH Grant/Contract		View source
UM1CA186709	U.S. NIH Grant/Contract		View source

Label	Type	Description	Intervention Names
Treatment (trametinib, navitoclax)	Experimental	Patients receive trametinib PO QD and navitoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14.	Procedure: Biopsy Procedure Procedure: Biospecimen Collection Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Biological: Navitoclax Procedure: Positron Emission Tomography Drug: Trametinib

Name	Type	Description	Arm Group Labels	Other Names
Biopsy Procedure	Procedure	Undergo biopsy	Treatment (trametinib, navitoclax)

Measure	Description	Time Frame
(Phase 1b) Maximal Tolerated Dose of Trametinib and Navitoclax	Dose escalation uses a 3+3 enrollment design per dose level. The occurrence of 1 dose limiting toxicity (DLT) will prompt expansion of a given dose level to 6 participants. The occurrence of 2 DLTs in a given dose level will indicate that the maximal tolerated dose (MTD) has been exceeded, and expansion of the prior dose level to 6 participants will occur, if not already performed. The recommended phase 2 dose (RP2D) will be the highest dose level at which no more than 1 out of 6 participants experiences a DLT. Dose escalation will proceed until the MTD/RP2D have been determined.	Within the first 42 days of treatment
(Phase 1b) Dose-Limiting Toxicities of Trametinib and Navitoclox	Dose-limiting toxicity (DLT) are adverse events (AEs) that are serious enough to prevent an increase in dose level of that treatment. Grading based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CTCAE version 5.0 will be utilized beginning April 1, 2018.	Within the first 42 days of treatment
(Phase 2) Response Rate	Response rate is defined as the number of participants who achieve complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1: CR = Disappearance of target lesion(s). Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm PR = At least a 30% decrease in the sum of the longest diameter(s) of target lesion(s) Participants are considered evaluable for response if they had measurable disease present at baseline, received at least one cycle of therapy, and had their disease re-evaluated at least once after initiating therapy.	Up to 6 months
(Phase 2) Progression-free Survival	Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease (PD) or death, whichever occurs first. PD is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 as at least a 20% increase in the (sum of the) longest diameter(s) of target lesion(s), and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Measure	Description	Time Frame
(Phase 1b) Pharmacokinetic Parameter Cmax for Trametinib and Navitoclax When Administered in Combination	Pharmacokinetic blood draw samples collected for the following parameter and reported as mean values per day: maximum observed plasma drug concentration (Cmax). Schedule A: C1 D7 = pre-nav (0h) then 2h, 4h, 6h, 8h C1 D8 = pre-tram (-1h = 23h post-nav) C1 D21 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav C1 D22 = pre-tram (-1h = 23h post-nav) D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h) Schedule B: C1 D7, D14 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav C1 D8, D15 = pre-tram (-1h = 23h post-nav) D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h) Schedule C: C1 D7, D14 = pre-navitoclax (0h) then 2h, 4h, 6h, 8h C1 D8, D15 = pre-trametinib (-1h = 23h post-navitoclax) D1 of Cycle 2,4,8,12 (single trough) = pre-nav (0h)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patients must have histologically- or cytologically-confirmed diagnosis of KRAS or NRAS mutation-positive malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective; patients must have activating mutations affecting codons 12, 13, 61, or 146 as determined in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab to be eligible for this study
Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm by chest x-ray or as >= 10 mm with CT scan, MRI, or calipers by clinical exam
Participants must have received at least one line of prior systemic chemotherapy and must have experienced documented radiographic progression or intolerance on this therapy
Paired pre-treatment and post-treatment biopsies are required for all patients on Part 1 and first 15 patients in Part 2; participants must have available archival tumor tissue (at least 20 unstained slides); if archival tissue is not available or is found not to contain tumor tissue, a fresh biopsy is required; if a patient is having a tumor biopsy, less than 20 unstained slides are acceptable with approval of the principal investigator (PI); biopsies will only be performed in a given patient if they are not deemed to involve unacceptable risk based on the sites of disease and other concurrent medical conditions
Age >= 18 years
- Because no dosing or adverse event data are currently available on the use of trametinib in combination with navitoclax in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
Eastern Cooperative Oncology Group (ECOG) performance status =< 1
Life expectancy of greater than 3 months
Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4) grade =< 1 (except alopecia) at the time of enrollment; this requirement to return to =< grade 1 does not apply to immune checkpoint inhibitor related endocrinopathies (e.g. thyroiditis, hypophysitis, etc.) that necessitate hormone replacement therapy including, but not limited to levothyroxine, cortisol, and testosterone; CTCAE v5.0 will be utilized beginning April 1, 2018
Leukocytes >= 3,000/mcL
Absolute neutrophil count (ANC) >= 1,200/mcL (subjects may be treated with hematopoietic growth factors to achieve or maintain this level)
Hemoglobin >= 9 g/dL
Platelets >= 100 x 10^9/L
Albumin >= 2.5 g/dL
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN
Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.2 x institutional ULN
Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
The effects of trametinib and navitoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men with a female partner of child bearing potential must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and up to 4 months following completion of therapy
- Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration)
- Vasectomized male subject or vasectomized partner of female subjects
- Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 1 month after study completion
- Intrauterine device (IUD)
- Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams)
- Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 4 months following completion of therapy
Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; the potential hazard to the fetus should be explained to the patient and partner (as applicable)
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer or any carcinoma in situ and/or patients with indolent second malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements specified above
History of interstitial lung disease or pneumonitis
Any major surgery, extensive radiotherapy (> 15 days of treatment), chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to first dose of study treatment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to first dose of study treatment
Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study drug(s) and during the study
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; exception: patients with brain metastases will be allowed on study if they have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 21 days of stable neurologic function and no evidence of central nervous system (CNS) disease progression as determined by CT or MRI within 21 days prior to the first dose of study drug
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO), or to compounds of similar chemical or biologic composition to navitoclax
Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
- Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed)
- Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
- Because the composition, pharmacokinetics (PK), and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
- Due to the expected dose-limiting toxicity of thrombocytopenia, the following concomitant medications are not allowed during navitoclax administration: Warfarin, clopidogrel (plavix), ibuprofen, tirofiban (aggrastat), and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor
Preclinical studies indicate that navitoclax is metabolized by CYP3A4, is a moderate inhibitor of CYP2C8, and is a strong inhibitor of CYP2C9; therefore, caution should be exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin and warfarin; when possible, investigators should switch to alternative medications or monitor the patients closely (particularly in the case of medications that have a narrow therapeutic window such as warfarin; use of warfarin is specifically prohibited while on study); CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration
- Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Patient instructions and information of possible drug interactions will be given to all patients upon enrollment in this study
History or current evidence/risk of retinal vein occlusion (RVO)
History or evidence of cardiovascular risk including any of the following:
- Left ventricle ejection fraction (LVEF) < LLN
- A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
- History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to enrollment are eligible)
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
- History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
- Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
- Known cardiac metastases
- Patients with intra-cardiac defibrillators
Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Subject has an underlying condition predisposing them to bleeding or currently exhibits signs of clinically significant bleeding
Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug
Subject has a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months)
Pregnant women or nursing mothers; animal reproductive studies have not been conducted with trametinib or navitoclax; therefore, the study drug must not be administered to pregnant women or nursing mothers

Name	Affiliation	Role
Ryan B Corcoran	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Massachusetts General Hospital Cancer Center		Boston	Massachusetts	02114	United States
Dana-Farber Cancer Institute

ID	Title	Description
FG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jul 22, 2022

Arm/Group Information

ID	Title	Description
BG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG001	Cohort 2A = Trametinib 1.5 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG002	Cohort 3A = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG003	Cohort 1B = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG004	Cohort 3B = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG005	Cohort 3C = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG006	Cohort 4C = Trametinib 2 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG007	Cohort 5C = Trametinib 2 mg + Navitoclax 250 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG008	Cohort 6C = Trametinib 2 mg + Navitoclax 300 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \
BG009	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
BG010	Expansion Cohort 2 = GYN Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
BG011	Expansion Cohort 3 = Lung Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
BG012	Expansion Cohort 4 = All Other NRAS Mutation-positive Solid Tumor Types	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
BG013	Total	Total of all reporting groups

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Primary

(Phase 1b) Maximal Tolerated Dose of Trametinib and Navitoclax

Dose escalation uses a 3+3 enrollment design per dose level. The occurrence of 1 dose limiting toxicity (DLT) will prompt expansion of a given dose level to 6 participants. The occurrence of 2 DLTs in a given dose level will indicate that the maximal tolerated dose (MTD) has been exceeded, and expansion of the prior dose level to 6 participants will occur, if not already performed. The recommended phase 2 dose (RP2D) will be the highest dose level at which no more than 1 out of 6 participants experiences a DLT. Dose escalation will proceed until the MTD/RP2D have been determined.

Posted

Number

milligrams per day

Within the first 42 days of treatment

ID	Title	Description
OG000	Treatment (Trametinib, Navitoclax)	Patients receive trametinib PO QD and navitoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14. Biopsy: Undergo biopsy Biospecimen Collection: Undergo collection of blood samples Computed Tomography: Undergo conventional CT or PET/CT Magnetic Resonance Imaging: Undergo MRI Navitoclax: Given PO Positron Emission Tomography: Undergo PET/CT Trametinib: Given PO

Units	Counts
Participants	OG00038

Title

Denominators

Categories

Trametinib on Days 1-14

Title	Measurements
	OG0002

Navitoclax on Days 1-28

Title	Measurements
	OG000250

Primary

(Phase 1b) Dose-Limiting Toxicities of Trametinib and Navitoclox

Dose-limiting toxicity (DLT) are adverse events (AEs) that are serious enough to prevent an increase in dose level of that treatment. Grading based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CTCAE version 5.0 will be utilized beginning April 1, 2018.

In Cohort 3B, 2 of 8 participants were deemed not evaluable for DLT. In Cohort 5C, 2 of 8 participants were deemed not evaluable for DLT.

Posted

Count of Participants

Participants

Within the first 42 days of treatment

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Primary

(Phase 2) Response Rate

Response rate is defined as the number of participants who achieve complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1:

CR = Disappearance of target lesion(s). Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
PR = At least a 30% decrease in the sum of the longest diameter(s) of target lesion(s)

Participants are considered evaluable for response if they had measurable disease present at baseline, received at least one cycle of therapy, and had their disease re-evaluated at least once after initiating therapy.

There were a total of 10 participants in phase 2 that were not evaluable for response because they did not have a restaging scan-- 1 from expansion cohort 1, 6 from expansion cohort 2, 1 from expansion cohort 3, and 2 from expansion cohort 4.

Posted

Count of Participants

Participants

Up to 6 months

ID	Title	Description
OG000	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.

Primary

(Phase 2) Progression-free Survival

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease (PD) or death, whichever occurs first.

PD is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 as at least a 20% increase in the (sum of the) longest diameter(s) of target lesion(s), and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Posted

Mean

Full Range

months

Up to 31 months

ID	Title	Description
OG000	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
OG001	Expansion Cohort 2 = GYN Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.

Primary

(Phase 2) Treatment Emergent Adverse Events

Treatment emergent adverse events (TEAEs) are undesirable events not present prior to study treatment, or an already present event that worsens either in intensity or frequency while on treatment. TEAEs are assessed as grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0. CTCAE criteria version 5.0 will be utilized beginning April 1, 2018. TEAEs are also assessed as possibly, probably, or definitely related to study treatment.

Posted

Count of Participants

Participants

up to 29 months on treatment

ID	Title	Description
OG000	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
OG001	Expansion Cohort 2 = GYN Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.

Secondary

(Phase 1b) Pharmacokinetic Parameter Cmax for Trametinib and Navitoclax When Administered in Combination

Pharmacokinetic blood draw samples collected for the following parameter and reported as mean values per day: maximum observed plasma drug concentration (Cmax).

Schedule A:

C1 D7 = pre-nav (0h) then 2h, 4h, 6h, 8h
C1 D8 = pre-tram (-1h = 23h post-nav)
C1 D21 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D22 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule B:

C1 D7, D14 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D8, D15 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule C:

C1 D7, D14 = pre-navitoclax (0h) then 2h, 4h, 6h, 8h
C1 D8, D15 = pre-trametinib (-1h = 23h post-navitoclax)
D1 of Cycle 2,4,8,12 (single trough) = pre-nav (0h)

No data was collected for this outcome for phase 1 cohorts 1B, 3B, 3C, 4C, 5C or 6C.

Posted

Mean

Full Range

ng/mL

Cycle 1 day 7 and day 21

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Secondary

(Phase 1b) Pharmacokinetic Parameter AUC for Trametinib and Navitoclax When Administered in Combination

Pharmacokinetic blood draw samples collected for the following parameter and reported as mean values per day: area under the concentration time curve from zero (pre-dose) to 24 hours (AUC 0-24).

Schedule A:

C1 D7 = pre-nav (0h) then 2h, 4h, 6h, 8h
C1 D8 = pre-tram (-1h = 23h post-nav)
C1 D21 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D22 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule B:

C1 D7, D14 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D8, D15 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule C:

C1 D7, D14 = pre-navitoclax (0h) then 2h, 4h, 6h, 8h
C1 D8, D15 = pre-trametinib (-1h = 23h post-navitoclax)
D1 of Cycle 2,4,8,12 (single trough) = pre-nav (0h)

No data was collected for this outcome for phase 1 cohorts 1B, 3B, 3C, 4C, 5C or 6C.

Posted

Mean

Full Range

h*ng/mL

Cycle 1 day 7 and day 21

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Secondary

(Phase 1b) Pharmacokinetic Parameter C0 for Trametinib and Navitoclax When Administered in Combination

Pharmacokinetic blood draw samples collected for the following parameter and reported as mean values per day: trough plasma drug concentration (C0).

Schedule A:

C1 D7 = pre-nav (0h) then 2h, 4h, 6h, 8h
C1 D8 = pre-tram (-1h = 23h post-nav)
C1 D21 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D22 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule B:

C1 D7, D14 = pre-tram (-1h); pre-nav (0h); then 2h, 4h, 6h, 8h post-nav
C1 D8, D15 = pre-tram (-1h = 23h post-nav)
D1 of Cycle 2,4,8,12 (single trough) = pre-tram (-1h)

Schedule C:

C1 D7, D14 = pre-navitoclax (0h) then 2h, 4h, 6h, 8h
C1 D8, D15 = pre-trametinib (-1h = 23h post-navitoclax)
D1 of Cycle 2,4,8,12 (single trough) = pre-nav (0h)

Posted

Mean

Full Range

ng/mL

Cycle 1 day 7 and day 21

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Secondary

(Phase 1b) Response Rate

CR = Disappearance of target lesion(s). Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
PR = At least a 30% decrease in the sum of the longest diameter(s) of target lesion(s)

There were a total of 6 participants in phase 1 that were not evaluable for response because they did not have a restaging scan-- 1 from cohort 1A (clinical progression), 3 from cohort 3B, and 2 from cohort 5C.

Posted

Count of Participants

Participants

Up to 4 months

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Secondary

(Phase 2) Pharmacokinetic Parameters for Trametinib and Navitoclax When Administered in Combination at Recommended Phase 2 Dose

Pharmacokinetic (PK) blood draw samples collected for the following parameters:

Maximum observed plasma drug concentration (Cmax)
Area under the concentration time curve from zero (pre-dose) to 24 hours (AUC 0-24)
Pre-dose (trough) drug concentration at the end of the dosing interval (C0)
Half-life (t1/2)

Recommended phase 2 dose (RP2D) schedule:

- Day 1 of cycles 2, 4, 8, 12 = pre-trametinib (-1h)

No data was collected for this outcome in the phase 2 expansion cohorts.

Posted

Day 1 of cycles 2, 4, 8, and 12

ID	Title	Description
OG000	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.
OG001	Expansion Cohort 2 = GYN Cancer

Secondary

(Phase 1b and 2) Percent Change in Levels of Proteins/Messenger Ribonucleic Acids Implicated in Mitogen-activated Protein Kinase Signaling

Paired pre-treatment and on treatment tumor biopsies will be obtained to assess the pharmacodynamic response to therapy (e.g., change in levels of proteins/mRNAs implicated in MAPK signaling). Results will be reported as a mean percent (%) change in MAPK transcripts day 15 vs day 0.

Pre-treatment tumor tissue for analysis will be obtained either from archival tissue remaining from a participant's prior surgery, diagnostic biopsy, or other procedure performed during routine clinical care. Alternatively, study-related pre-treatment biopsies will be obtained between days -21 and -1 of treatment if necessary.

On-treatment biopsies will be obtained after ~2 weeks of Cycle 1 combination dosing:

Phase 1b Schedule A = Day 22 +/- 7 days
Phase 1b Schedule B or C = Day 15 +/- 7 days
Phase 2 RP2D = Day 15 +/- 7 days

Posted

Mean

Standard Error

percentage of change MAPK transcripts

up to 50 days

ID	Title	Description
OG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort 1A = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	3	0	3	3	3
EG001	Cohort 2A = Trametinib 1.5 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	3	0	3	3	3
EG002	Cohort 3A = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	2	3	1	3	3	3
EG003	Cohort 1B = Trametinib 1 mg + Navitoclax 150 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	3	1	3	3	3
EG004	Cohort 3B = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	7	8	1	8	8	8
EG005	Cohort 3C = Trametinib 1.5 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	3	0	3	3	3
EG006	Cohort 4C = Trametinib 2 mg + Navitoclax 200 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	3	1	3	3	3
EG007	Cohort 5C = Trametinib 2 mg + Navitoclax 250 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	6	8	0	8	7	8
EG008	Cohort 6C = Trametinib 2 mg + Navitoclax 300 mg	During Phase 1b dose escalation, participants received trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28 of each cycle until disease progression or unacceptable toxicity. A 7-day lead-in dosing of Navitoclax 150 mg will be evaluated in Cycle 1 for dose levels 3-7 before proceeding to their target doses: Schedule A = 7-day lead-in dosing of navitoclax as a single agent, prior to the initiation of trametinib dosing. Schedule B = 7-day lead-in dosing of navitoclax simultaneous with the initiation of trametinib dosing. Dose levels 1-3 will be enrolled according to Schedule A (i.e., cohorts 1A, 2A, 3A). If significant safety concerns are noted, study will proceed according to Schedule A (i.e., cohorts 4A, 5A, 6A, 7A). If no significant safety concerns are noted, and it is deemed safe to proceed, dosing will return to dose level 1 according to schedule B (i.e., cohort 1B), then proceed directly cohort 3B. If >1 DLT within cohort 1B or 3B, then Schedule B will be abandoned, and study will proceed with cohorts 4A, 5A, 6A, 7A. If cohort 3B is completed with \	3	4	1	4	4	4
EG009	Expansion Cohort 1 = Pancreatic Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.	10	12	1	12	11	12
EG010	Expansion Cohort 2 = GYN Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.	14	25	2	25	22	25
EG011	Expansion Cohort 3 = Lung Cancer	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.	4	6	0	6	5	6
EG012	Expansion Cohort 4 = All Other NRAS Mutation-positive Solid Tumor Types	Phase 2 expansion cohorts use recommended phase 2 dosing (RP2D) determined in Phase 1b. Participants with KRAS or NRAS mutation-positive solid tumors will be enrolled into up to 4 different disease-specific expansion cohorts: Pancreatic Cancer GYN Cancer Lung Cancer all other NRAS mutation-positive solid tumor types exclusive of pancreatic, GYN, and lung cancers Initially 12 participants will be enrolled to each expansion cohort in Stage 1. If no responses are observed in a given cohort among the first 12 patients, then that cohort will be stopped for futility. However, if one or more responses are observed in a given cohort, the cohort will proceed to Stage 2, and an additional 13 patients will be enrolled for a total of 25 patients in that cohort.	6	10	0	10	7	10

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal Pain	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG0030 affected3 at risk EG0041 affected8 at risk EG0051 affected3 at risk EG0060 affected3 at risk EG0070 affected8 at risk EG0080 affected4 at risk EG0090 affected12 at risk EG0100 affected25 at risk EG0110 affected6 at risk EG0121 affected10 at risk
Alkaline phosphatase increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0022 affected3 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Alanine aminotransferase increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Anemia	Blood and lymphatic system disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Anorexia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Aspartate aminotransferase increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0022 affected3 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Bloating	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Blood bilirubin increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Blurred vision	Eye disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0021 affected3 at risk EG003
Bruising	Injury, poisoning and procedural complications	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Bullous dermatitis	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Chills	General disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Constipation	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Creatinine increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dehydration	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Diarrhea	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0002 affected3 at risk EG0013 affected3 at risk EG0023 affected3 at risk EG003
Dizziness	Nervous system disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dry eye	Eye disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dry mouth	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Dysgeusia	Nervous system disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dyspepsia	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dyspnea	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Edema face	General disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Edema limbs	General disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Ejection fraction decreased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Eye disorders other	Eye disorders	CTCAE (5.0)	Systematic Assessment	stye	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Fall	Injury, poisoning and procedural complications	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Fatigue	General disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Fever	General disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Flatulence	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Floaters	Eye disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Flushing	Vascular disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Gastroesophageal reflux disease	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Genital edema	Reproductive system and breast disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
gastrointestinal disorders other specify	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	Hematochezia	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
gastrointestinal disorders other specify	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	Perifissural Bleeding With Bowel Movement	EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Headache	Nervous system disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
hepatobiliary disorders other specify	Hepatobiliary disorders	CTCAE (5.0)	Systematic Assessment	Hepatocellular Injury	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Hyperkalemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Hypertension	Vascular disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Hypoalbuminemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Hypocalcemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Hypokalemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Hypomagnesemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Hyponatremia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Hypophosphatemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Hypotension	Vascular disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Infections and infestations Other, specify	Infections and infestations	CTCAE (5.0)	Systematic Assessment	Oral Thrush	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
INR increased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Localized edema	General disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Lymphedema	Vascular disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Lymphocyte count decreased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Malaise	General disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Mucositis oral	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Nail discoloration	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Nail loss	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Nausea	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0012 affected3 at risk EG0023 affected3 at risk EG003
Neutrophil count decreased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Oral pain	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Papulopustular rash	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Paronychia	Infections and infestations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Periorbital edema	Eye disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Platelet count decreased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0002 affected3 at risk EG0012 affected3 at risk EG0023 affected3 at risk EG003
PPE syndrome	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Rash acneiform	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0002 affected3 at risk EG0011 affected3 at risk EG0022 affected3 at risk EG003
Rash maculo-papular	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0012 affected3 at risk EG0022 affected3 at risk EG003
Dysuria	Renal and urinary disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Sinus tachycardia	Cardiac disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Stomach pain	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Thromboembolic event	Vascular disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Urinary tract infection	Infections and infestations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Vaginal hemorrhage	Reproductive system and breast disorders	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Vomiting	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment		EG0002 affected3 at risk EG0012 affected3 at risk EG0023 affected3 at risk EG003
Weight loss	Investigations	CTCAE (5.0)	Systematic Assessment		EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
White blood cell decreased	Investigations	CTCAE (5.0)	Systematic Assessment		EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Skin and subcutaneous tissue disorders Other, specify	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment	bleeding from tumor	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003

ID	Term
D009385	Neoplastic Processes
D009369	Neoplasms
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D001706	Biopsy
D013048	Specimen Handling
D009682	Magnetic Resonance Spectroscopy
C528561	navitoclax
C560077	trametinib
C561454	omipalisib

ID	Term
D003581	Cytodiagnosis
D003584	Cytological Techniques
D019411	Clinical Laboratory Techniques
D019937	Diagnostic Techniques and Procedures
D003933	Diagnosis
D003949	Diagnostic Techniques, Surgical
D013514	Surgical Procedures, Operative
D008919	Investigative Techniques
D013057	Spectrum Analysis
D002623	Chemistry Techniques, Analytical