MEK and MET Inhibition in Colorectal Cancer | NCT02510001

NCT02510001

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Sponsor/Collaborators Module

Name	Class
Queen's University, Belfast	OTHER
Oxford University Hospitals NHS Trust	OTHER
Velindre NHS Trust	OTHER_GOV
University Hospital, Antwerp

Oversight Module

Description Module

Detailed Description

This is a two stage study. Firstly a dose escalation step is used to define the best dose for the drug combination, using the rolling 6 design where up to 6 patients are recruited at each dose level, and increasing the dose of one or other agent according to the side effects of treatment. An initial dose escalation phase was completed where 25 patients were enrolled, using the study treatment combination of PD-0325901 with PF-02341066. Following discontinuation of the MEKi (inihibitor), PD-0325901, the study was updated to include a further dose escalation phase using the new combination study treatment, MEKi, Binimetinib with METi, PF-02341066. The effects of this drug combination will be assessed to define the recommended dose level for the dose expansion phase of the study.

Second the new drug combination is observed in 42-98 patients with bowel cancer for its efficacy and tolerability. Patients who give consent will have their archival tumour samples tested for RAS and c-MET status.

Potential participants will, after giving consent, undergo screening tests to ensure that it is safe for them to take part. These involve a detailed medical history, physical exam, blood tests, ophthalmology exam, ECG and ultrasound and skin biopsies. The size and extent of tumours is also assessed by CT and/or MRI scan.

For the initial dose escalation phase, on assurance that the test results are satisfactory, patients start on PD-0325901 first for one week. On Day -7 a physical exam, ECG and blood test is performed, with a repeat blood test on Day -6. End of first week PD samples of blood are taken to observe the level of PD-0325901. Day 1 PF-02341066 is introduced after further clinical safety assessments. There are further blood samples taken over 24 hours to measure levels of PD-0325901 and PF-02341066 on days 21 and 28 of the first cycle.

For the further dose escalation phase, again assuming that the screening test results are satisfactory, patients start on Day 1 with the combined treatment of PF-02341066 with Binimetinib. A physical exam, ECG and blood test is performed, with a repeat blood test on Day 2. There are further blood samples taken over 24 hours to measure levels of Binimetinib and PF-02341066 on day 21of the first cycle.

Patients have weekly visits when side effects are reviewed and a physical examination is performed. On Day 15 a second skin biopsy is taken along with blood tests to assess liver and renal function. At the end of the first 4 weeks cycle, for the initial dose escalation phase, and at end of 8 weeks for the new combination therapy dose escalation phase, an ophthalmology exam is compared with the baseline assessment.

For subsequent cycles in both the initial dose escalation and further dose escalation phases, visits remain weekly and include safety assessments as per Day 1. Blood levels of PD-0325901 or Binimetinib and PF-02341066 are measured on day 21 of even numbered cycles. In addition the tumour size is checked every second cycle, and the study treatment stopped if the tumour continues to grow.

When patients stop taking the study treatment they will be reviewed after 4 weeks for any side effects and have a physical examination and other safety tests performed.

For patients entering the expansion phase of the trial the procedures are similar, except that there is a pre-screening stage where tumour biopsies are required. Patients will have a sample of their tumour assessed, following consent, to determine their RAS and cMET status. This may involve a fresh biopsy. If suitable, the patient will be entered into the screening for the dose expansion phase and a fresh tumour biopsy may be taken if not already done so. The study schedule is the same as for the escalation phase using Binimetinib with PF-02341066. At the end of treatment a further, optional, tumour biopsy may be taken.

After trial participation patients will be offered further care with the trial team or their referring oncology team as appropriate.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Escalation Phase Cohort 1 Dose level 1	Experimental	Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle	Drug: PF-02341066 Drug: PD-0325901
Dose Escalation Phase Cohort 2 Dose level 2	Experimental	Crizotinib 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle	Drug: PF-02341066 Drug: PD-0325901
Dose Escalation Phase Cohort 3 Dose level 3	Experimental	Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day 1, then Day 1-21 every 28 day cycle	Drug: PF-02341066 Drug: PD-0325901
Dose Escalation Phase Cohort 4 Dose level 4	Experimental	Crizotinib 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle	Drug: PF-02341066 Drug: PD-0325901
Dose Escalation Phase Cohort 7 Dose level 5	Experimental	Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration

Interventions

Name	Type	Description	Arm Group Labels	Other Names
PF-02341066	Drug	PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously	Dose Escalation Phase Cohort 1 Dose level 1 Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066	Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.	Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)
Clinical Response to Binimetinib Combined With PF-02341066	To investigate response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase (>=20%) to qualify for Progressive Disease; Overall Response (OR) = CR + PR + SD	Dose Expansion phase: change from baseline and up to 12 months.
Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066	To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment.	Dose Escalation Phase: treatment Cycle 1 28 days

Secondary Outcomes

Measure	Description	Time Frame
Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901.	To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.	Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day - 1, Day 21 and Day 28 of Cycle 1

Eligibility Module

Eligibility Criteria

INCLUSION CRITERIA (Inclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients

Age ≥ 16 years (>18 years in France)
ECOG performance status 0-1 (Appendix 1)
Adequate respiratory function on clinical assessment
Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram┼
Able to give informed consent prior to any screening procedures being performed and be capable of complying with the protocol and its requirements
Haematological and biochemical indices within the ranges shown below:
Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed ),
Neutrophils ≥ 1,500/μl,
Platelet count ≥ 100,000/μl,
AST or ALT ≤ 2.5 x ULN, patient with liver metastases ≤ 5 × ULN,
Alkaline phosphatase ≤ 5 x ULN,
Serum Bilirubin ≤ 1.5 x ULN,
Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault equation, or by EDTA) (Appendix 2)
Able to swallow oral medication
Life expectancy of at least 3 months.

Dose escalation phase:

Patients with any advanced solid tumours
Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option.

Dose expansion phase:

Patients will be eligible for pre-screening for this phase provided that:

They have given informed consent to screening.
They are willing to undergo a biopsy for assessment of tumour RAS mutation status and c-MET assessment.
The Investigator anticipates that they are likely to satisfy the eligibility criteria for the trial. Formal screening should not be performed until the tumour pre-screening result is known.

Eligibility for the trial, in patients passing pre-screening, requires:

Histologically confirmed colorectal adenocarcinoma that is either a) RASMT (KRAS codon 12, 13, 61, 117, 146; NRAS codon 12, 13, 61, 117, 146) or b) RASWT/c-MET mutated/amplified or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy and/or targeted therapies for metastatic disease.
Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-MET mutated or amplified CRC or c) RASWT/c-MET over-expressed CRC.
No evidence for a mutation in BRAF at codon600
Metastases accessible for biopsy on 2-3 occasions
At least one other measurable lesion (according to RECIST v1.1).
Unsuitable for potential curative resection. ┼For non-UK territories: if echocardiogram (ECHO) cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by ECHO in the UK.

EXCLUSION CRITERIA (Exclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients

Unstable ischaemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.
Uncontrolled arterial hypertension despite medical treatment.
Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation.
History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed.
Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases. However, patients treated with stereotactic radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression ≥ 3 months. Patients must be off corticosteroid therapy for ≥ 3 weeks.
Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on Binimetinib treatment
Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
Carcinomatous meningitis or leptomeningeal disease.
History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a requirement for ascitic or pleural taps.
History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of retinal vein thrombosis (e.g. history of hyperviscosity or hypercoagulability syndromes).
History of retinal degenerative disease.
History of Gilbert's syndrome.
Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function.
Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.
Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure.
Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices (see Appendix 5).
Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products before treatment. Patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens.
Resting ECG with QTc > 480msec at 2 or more time points within a 24h period (using Fredericia correction).
Requirement for medication known to prolong QT interval (Appendix 5).
History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free
Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intra-uterine device) in addition to condom plus spermicide for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
Prior exposure to any of a HGF, cMET or a MEK inhibitor.

Contacts/Locations Module

Name	Affiliation	Role
Mark R Middleton	Oxford University Hospital NHS Trust	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Oxford University Hospital NHS Trust		Oxford		OX3 7LE	United Kingdom

References Module

Label	URL
Information about the trial on the Oncology Clinical Trials Office (OCTO) website.	View source

IPD Sharing Statement Module

1 patient in escalation phase dose 5 was registered to the trial on 28Sep2016 but withdrew before dose administration due to unexpected and fast disease progression.

Arm/Group Information

ID	Title	Description
FG000	Dose Escalation Phase Dose 1.	Crizotinib (PF-02341066) 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle
FG001	Dose Escalation Phase Dose 2.	Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle
FG002	Dose Escalation Phase Dose 3.	Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day 1, then Day 1-21 every 28 day cycle
FG003	Dose Escalation Phase Dose 4.	Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle
FG004	Dose Escalation Phase 5.	Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration
FG005	Dose Escalation Phase Dose 5a	Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. Crizotinib (PF-02341066) 250mg OD continuous administration
FG006	Dose Escalation Phase Dose 5 (Interval Dosing)	Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration
FG007	Dose Expansion Phase	Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days PF-02341066 (Crizotinib) 250mg OD Days 1-28 continuously Dosage determined following the recommended Phase II dose identification in the dose escalation phase. PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously Binimetinib: Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG0006 subjects FG0015 subjects FG0026 subjects FG0038 subjects FG0048 subjects FG0057 subjects FG0065 subjects FG00737 subjects
COMPLETED		FG0006 subjects FG0015 subjects FG0026 subjects FG0036 subjects FG004
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0032 subjects FG004

Type	Comment	Reasons
Early disease progression		FG0000 subjects FG0010 subjects FG0020 subjects FG003

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Dose Escalation Phase Dose 1.	Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066

Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.

Evaluable patients are those patients who completed cycle 1 or withdrew early for experiencing a DLT. Four patients withdrew early from the study not for DLTs, consequently 21 patients remained for the dose escalation primary analysis.

Posted

Number

Dose Limiting Toxicities (DLTs)

Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)

ID	Title	Description
OG000	Dose Escalation Phase Cohort 1 Dose Level 1	Crizotinib (PF-02341066) 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle

Adverse Events Module

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	Dose Escalation Phase 1 PF-02341066 and PD-0325901	Dose Escalation Phase 1 - Crizotinib and PD-0325901

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal Infection	Infections and infestations	CTCAE (4.0)	Non-systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal abscess	Infections and infestations	CTCAE (4.0)	Non-systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Heather House	University of Oxford Clinical Trials and Research Governance (CTRG)	01865 572245		heather.house@admin.ox.ac.uk

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 29, 2018	Mar 3, 2020	Prot_003.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jun 9, 2016	Nov 7, 2017	SAP_001.pdf
ICF	No	No	Yes	Informed Consent Form	May 11, 2017	Nov 7, 2017	ICF_002.pdf

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D015179	Colorectal Neoplasms

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site

Intervention Browse Module

ID	Term
D000077547	Crizotinib
C506614	mirdametinib
C581313	binimetinib

ID	Term
D010880	Piperidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D000631	Aminopyridines

Masking Info

Dose Escalation Phase Cohort 13 Dose level 5a

Dose Escalation Phase Cohort 2 Dose level 2

Dose Escalation Phase Cohort 3 Dose level 3

Dose Escalation Phase Cohort 4 Dose level 4

Dose Escalation Phase Cohort 7 Dose level 5

Dose Expansion Phase

EG0001 events1 affected25 at risk

EG0010 events0 affected20 at risk

EG0020 events0 affected36 at risk

EG0001 events1 affected25 at risk

EG0010 events0 affected20 at risk

EG0020 events0 affected36 at risk