Carboplatin/Nab-Paclitaxel and Pembrolizumab in NSCLC | NCT02382406

Name	Class
Hoosier Cancer Research Network	OTHER
Merck Sharp & Dohme LLC	INDUSTRY
Celgene Corporation	INDUSTRY

Description Module

Detailed Description

OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

Phase I, Cohort 1 Induction Therapy:

Carboplatin AUC 6 IV, Day 1
Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15
pembrolizumab 2 mg/kg IV, Day 1
Cycle length: 21 days; number of cycles: 4

Phase I, Cohort 1 Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 2* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they continue to meet inclusion criteria requirements.

If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional participants will be enrolled.

Phase I, Cohort 2 Induction Therapy (if necessary):

Carboplatin AUC 6 IV, Day 1
Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15
pembrolizumab 2 mg/kg IV, Day 1 (cycle 2-4 only)
Cycle length: 21 days; Number of cycles: 4

Phase I, Cohort 2 Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 2* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 2, Day 1 (C2D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they continue to meet inclusion criteria requirements.

Phase II Induction Therapy:

Carboplatin AUC 6 IV, Day 1
Nab-paclitaxel 100 mg/m^2 IV, Days 1, 8, 15
pembrolizumab 200mg IV, Day 1 of each cycle
Cycle length: 21 days; number of cycles: 4

Phase II Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 200 mg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they meet the requirements.

*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be adjusted.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm A: Phase I Dose Finding Cohort	Experimental	Twelve subjects will be enrolled and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 IV on Day 1, Day 8, and Day 15, pembrolizumab 2* mg/kg IV on Day 1 for 4 cycles. pembrolizumab (Phase I) treatment for Cohort 1 will continue for a maximum duration of 4 21-day cycles Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with MK-3475 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1. If unacceptable toxicity is seen in Phase I Cohort 1, 12 additional participants will be enrolled in Cohort 2 and treated with carboplatin AUC 6 IV on D1, nab-paclitaxel 100 mg/m2 IV on D1, D8, and D15, MK-3475 2*mg/kg IV on D1 starting C2. MK-3475 (Phase 1) treatment for Cohort 2 will continue for a maximum duration of 3 21-day cycles (C2-4 only).	Drug: Carboplatin Drug: Nab-paclitaxel Drug: MK-3475 (Phase I)
Arm B: Phase II Investigational Treatment	Experimental	Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Day 1, Day 8, and Day 15, and pembrolizumab 200mg IV on Day 1 of each cycle. Pembrolizumab Phase II treatment will continue for a maximum duration of 4 cycles (cycle = 21 days). Maintenance Therapy For participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with MK-3475 2* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from C1D1. *As additional data from ongoing trials becomes available, the dose of MK-3475 may be adjusted.	Drug: Carboplatin Drug: Nab-paclitaxel Drug: MK-3475 (Phase II)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Carboplatin	Drug	Carboplatin AUC 6 IV, D1 for 4 cycles (cycle = 21 days)	Arm A: Phase I Dose Finding Cohort Arm B: Phase II Investigational Treatment

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose	To determine the recommended Phase II dose (RP2D) of MK-3475 and evaluate the safety and tolerability of the combination of MK-3475 with carboplatin/nab-paclitaxel for the first line treatment of phase I participants with advanced NSCLC per CTCAE v4.0 criteria by summarizing the number of adverse events experienced by subjects.	Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity.
Phase II: Disease Assessment for Progression-Free Survival (PFS)	To evaluate progression-free survival (PFS) for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria. PFS is defined as the duration of time from date of registration to time of progression or death, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions	From date of registration to time of first documented progression or death, whichever occurs first (estimate 9 months)
Phase II: Objective Response Rate	To evaluate objective response rate for phase II participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	From the start of treatment until progression or death up to 24 months

Secondary Outcomes

Measure	Description	Time Frame
Phase I: Disease Assessment for Progression-Free Survival (PFS)	To evaluate progression-free survival (PFS) and objective response for phase I participants receiving MK-3475 and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC per RECIST 1.1 criteria. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects must be willing and able to provide written informed consent for the trial and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
Subjects must be ≥ 18 years of age.
Individuals with stage IIIB or IV, unresectable non-small cell lung cancer (NSCLC) who have not received prior chemotherapy for Stage IIIB or IV disease, and who are not candidates for curative surgery or radiation therapy.
ECOG performance status (PS) 0-1
Measurable disease by RECIST v1.1 criteria
Prior to registration, all subjects must have archival tissue available. For subjects who have no archival tissue, but have PD-L1 testing results using the Dako 22C3 antibody, subjects will be permitted to enroll without submitting tissue. If the patient has not had prior testing and no acceptable archival tissue is available, subjects must be willing to consent to providing a pre-treatment biopsy for PD-L1 testing. Regardless of PD-L1 testing status, archival tissue will be requested for research testing if available.
Phase II subjects must be willing to consent to providing a mandatory post-treatment core biopsy for research if clinical feasible.
Women are eligible to participate if they are of non-childbearing potential or have documentation of a negative pregnancy test (serum or urine β-hCG) within 3 days of registration. Sexually active pre-menopausal women of childbearing potential must agree to use adequate, highly effective contraceptive measures, starting with the first dose of study drug and for 120 days after the last dose of last study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable, or injectable contraceptives plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year.
Male participants should agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of last study drug.

Exclusion Criteria:

Individuals with the presence of symptomatic CNS metastases requiring radiation treatment, surgery, or ongoing use of corticosteroids.
Untreated or brain metastasis causing any symptoms, such as neurologic deficits or headache. Individuals with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline and whole brain radiation or stereotactic radiosurgery completed over 4 weeks prior to registration), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment.
History of solid organ or stem cell transplant requiring immunosuppressive medications.
Any prior adjuvant cytotoxic chemotherapy within 12 months of registration. Subjects who received chemotherapy for earlier stage disease more than 12 months prior to study registration are eligible for this trial.
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
Any radiotherapy within 2 weeks prior to registration (4 weeks for brain radiotherapy as noted above).
Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
History of other invasive malignancy that is currently active and/or has been treated within 12 months of registration. (Notable exceptions include: basal cell carcinoma, squamous cell carcinoma of the skin, localized prostate cancer, in situ carcinomas of the cervix and breast, and superficial bladder cancers [non-muscle-invasive]).
Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or hypersensitivity pneumonitis.
Has a history of pneumonitis that required steroids or current pneumonitis.
Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v 4.0 criteria.
Known significant liver disease including viral, alcoholic, active hepatitis B or C, and/or cirrhosis.
Abnormal liver or renal function as defined as: bilirubin ≥ 1.5 mg/dL; AST or ALT ≥ 2.5 x the ULN; alkaline phosphatase > 2.5 x the ULN, there is no upper limit if bone metastasis is present in the absence of liver metastasis; creatinine > 1.5 mg/dL
Abnormal baseline hematologic or coagulation parameters as defined as: absolute neutrophil count (ANC) <1.5 x 10^9/L; hemoglobin < 9.0 g/dL; platelets < 100 x 10^9/L; International Normalized Ratio (INR) of prothrombin time (PT) ≥ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; Activated Partial Thromboplastin Time (aPTT) ≥ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Has received a live vaccine within 30 days prior to the first dose of study drug.
Known activating EGFR mutation or ALK translocation
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab.

Name	Affiliation	Role
Nisha Mohindra, M.D.	Hoosier Cancer Research Network	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
City of Hope		Duarte	California	91010	United States
Northwestern University, Robert H. Lurie Comprehensive Cancer Center

Label	URL
Hoosier Cancer Research Network Website	View source

Arm/Group Information

ID	Title	Description
FG000	Phase I, Cohort 1	Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Days 1, 8, and 15, and pembrolizumab 2* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.
FG001	Phase I, Cohort 2	Phase I, Cohort 2: Induction Therapy If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in Phase I, Cohort 2. Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nabpaclitaxel 100 mg/m2 given IV on Days 1, 8, and 15. Pembrolizumab 2* mg/kg IV will be given on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles (pembrolizumab given Cycles 2 to 4 only). Phase I, Cohort 2 Maintenance Therapy: For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 2* mg/kg will continue on Day 1 of each 21- day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 2, Day 1.
FG002	Phase II	Induction Therapy Cycles 1-4 Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will continue for a maximum duration of 4 cycles of study treatment. Each cycle starts when all the criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with pembrolizumab. Pembrolizumab should be given with carboplatin and nab-paclitaxel on day 1 of the cycle. Chemotherapies may be withheld for six weeks, while pembrolizumab can be withheld for 12-weeks. If there is a pembrolizumab-specific toxicity requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in chemotherapy beyond 6 weeks require withdrawal from the study treatment. Maintenance Therapy For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 200 mg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1 Day 1.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Phase I, Cohort 1	Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Days 1, 8, and 15, and pembrolizumab 2* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

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

Phase I: Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Recommended Phase II Dose

To determine the recommended Phase II dose (RP2D) of MK-3475 and evaluate the safety and tolerability of the combination of MK-3475 with carboplatin/nab-paclitaxel for the first line treatment of phase I participants with advanced NSCLC per CTCAE v4.0 criteria by summarizing the number of adverse events experienced by subjects.

No subjects had been enrolled to Phase I, cohort 2.

Posted

Count of Participants

Participants

Begin C1D1 and every 2 chemotherapy cycles (6 weeks) thereafter, for up to 2 years or until unacceptable toxicity.

ID	Title	Description
OG000	Phase I, Cohort 1	Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Days 1, 8, and 15, and pembrolizumab 2* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.

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	Phase I, Cohort 1	Phase I, Cohort 1: Induction Therapy Twelve subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m^2 given IV on Days 1, 8, and 15, and pembrolizumab 2* mg/kg IV on Day 1.Treatment will continue for a maximum duration of 4 cycles with cycle length of 21 days. Phase I, Cohort 1 Maintenance Therapy: Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with pembrolizumab 2* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms

ID	Term
D016190	Carboplatin
C520255	130-nm albumin-bound paclitaxel
D000068196	Albumin-Bound Paclitaxel
C582435	pembrolizumab
D017321	Clinical Trials, Phase I as Topic
D017322	Clinical Trials, Phase II as Topic

ID	Term
D056831	Coordination Complexes
D009930	Organic Chemicals
D017239	Paclitaxel
D043823	Taxoids