Advanced Treatment-Naïve PD-L1, Carcinoma, Non-Small-Cell Lung, Lung Diseases, Lung Neoplasms, Metastatic Lung Non-Small Cell Carcinoma, PD-L1 Gene Mutation, Pembrolizumab, Sitravatinib, Stage IV Lung Non-Small Cell Cancer AJCC v7
Conditions
Brief summary
This is a multicohort phase 2 study to evaluate the efficacy of pembrolizumab combined with the investigational drug sitravatinib in the frontline treatment of advanced, non-squamous PD-L1 positive NSCLC.
Detailed description
This is a multicohort phase 2 study to evaluate the efficacy of pembrolizumab combined with the investigational drug sitravatinib in the frontline treatment of advanced, non-squamous PD-L1 positive NSCLC. For clinical analysis, there will be two patient cohorts defined by PD-L1 status: Cohort 1 for patients with PD-L1 Tumor Proportion Score (TPS) 1-49% and Cohort 2 for patients with TPS≥50%. The investigators will implement a Simon's two-stage design to evaluate the efficacy of sitravatinib in combination with pembrolizumab for each cohort separately. There will be two groups within each cohort of this study: the main study population (Group A) in which patients will receive pembrolizumab plus sitravatinib beginning on Cycle 1 Day 1 (C1D1), and a pembrolizumab run-in population (Group B) in which patients will receive pembrolizumab alone for 1 dose followed by pembrolizumab plus sitravatinib beginning C2D1. The primary endpoint of the trial is the ORR for patients treated with pembrolizumab plus sitravatinib in the main study population. The purpose of the pembrolizumab run-in population is to obtain tissue and blood samples from these patients to be used as controls for correlative studies and to determine the preliminary efficacy of pembrolizumab alone followed by the combination. Primary Objective (1) The primary objective of this study is to evaluate the efficacy of sitravatinib in combination with pembrolizumab in the front-line treatment of patients with advanced non-squamous PD-L1 positive NSCLC by measuring Objective Response Rate (ORR). Secondary Objectives 1. To evaluate other measures of efficacy including Overall Survival (OS), Progression Free Survival (PFS), Duration of Response (DOR) and Clinical Benefit Rate (CBR) in the first-line setting for patients with advanced, non-squamous, PD-L1 positive NSCLC treated with the combination of sitravatinib and pembrolizumab. 2. To evaluate the toxicity profile and tolerability of sitravatinib/pembrolizumab in advanced, treatment naïve, non-squamous, PD-L1 positive NSCLC. Exploratory Objectives: 1. To evaluate ORR, OS, PFS, DOR, and CBR in patients with advanced, non-squamous, treatment naïve, PD-L1 positive NSCLC who receive pembrolizumab run-in followed by pembrolizumab/sitravatinib combination therapy. 2. To evaluate the CNS activity of sitravatinib/pembrolizumab in patients with advanced, treatment naïve, PD-L1 positive NSCLC by measuring Intracranial Objective Response Rate (iORR) and Intracranial Duration of Response(iDOR) in patients with baseline CNS disease, and Intercranial Progression-Free Survival (iPFS) in all patients. 3. To study correlates of the adaptive and innate immune responses induced by sitravatinib and pembrolizumab treatment in both tumor tissue and peripheral blood. 4. To explore the association between tumor immune contexture and clinical benefit to sitravatinib and pembrolizumab.
Interventions
DRUGSitravatinib
Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1).
DRUGPembrolizumab
All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).
Sponsors
Mirati Therapeutics Inc.
Sarah Goldberg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In order to be to be eligible to participate in this study, an individual must meet all of the following criteria: * Histologically or cytologically confirmed non-squamous NSCLC that is metastatic (Stage IV), recurrent, or unresectable locally advanced (Stage IIIB/IIIC) disease, not amenable to treatment with curative intent. * No prior systemic therapy for advanced disease. Prior chemotherapy for local or locally advanced disease is allowed if completed \>6 months prior to trial enrollment. Prior immunotherapy is not allowed. * PD-L1 ≥ 1% using the 22c3 PD-L1 IHC assay or a local assay performed in a CLIA facility * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Life expectancy of at least 3 months. * Measurable disease as per RECIST v1.1 * Adequate bone marrow and organ function demonstrated by: * Absolute neutrophil count \>1,500/mm3 (1.5 × 10\^9/L). * Hemoglobin ≥ 8.0 g/dL not dependent on transfusion support. * Platelet count ≥ 75 × 10\^9/L (≥ 75,000 per mm3). * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN without liver metastases; \< 5.0 x ULN if documented liver metastases * Serum total bilirubin ≤ ULN, or for patients with potential Gilbert's, direct bilirubin ≤ ULN * Calculated creatinine clearance ≥ 40 mL/min, using the Cockcroft-Gault formula. * Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment. * Completed informed consent process, including signing IRB approved informed consent form. * Willing to comply with clinical trial instructions and requirements. * Willing to undergo an on-treatment biopsy with an appropriate biopsy site identified prior to treatment initiation
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: * Symptomatic or untreated brain metastases ≥ 2cm in diameter. Patients with brain lesions that are adequately treated with local therapy (i.e. radiation therapy) and neurologically stable without the need for corticosteroids for at least 2 weeks prior to enrollment are allowed. Patients with brain lesions that are asymptomatic, smaller than 2cm, in non-critical regions of the brain and not requiring corticosteroids for at least 2 weeks prior to enrollment may be eligible after review with the Sponsor Investigator. * Leptomeningeal disease * Known mutations/alterations in EGFR, ROS1, ALK, or BRAF * Any prior treatment with checkpoint inhibitor therapy or other immunotherapy agents * Any prior treatment with therapy having the same mechanism of action as sitravatinib (e.g., tyrosine kinase inhibitor with a similar target profile or bevacizumab/ramucirumab) * Active or prior documented autoimmune disease within the past 2 years (note: patients with type 1 diabetes, vitiligo, Graves' disease, hypothyroidism due to an autoimmune condition only requiring hormone replacement, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded). * Active or prior immunocompromising conditions, including use of immunosuppressive medication within 2 weeks of enrollment. This does not include topical, intranasal or inhaled steroids with minimal systemic absorption or systemic corticosteroids at physiologic doses not to exceed 10mg/day of prednisone or equivalent. Use of higher dose corticosteroids for short/defined course (ie prophylaxis in patients with contrast dye allergy) is also allowed if indicated. * Uncontrolled HIV. Patients with HIV may be eligible if they meet the following criteria: * CD4+ T cell count\>350 cell/uL * No history of AIDS-defining opportunistic infection within the past 12 months * Currently tolerating treatment with ART for at least 4 weeks prior to enrollment, with HIV viral load \<400 copies/mL * Patients on specific ART drugs with possibility for drug-drug interaction with sitravatinib may be excluded (see appendix 5). * Active hepatitis C (HCV) infection. Patients with a history of HCV may be eligible if they have completed curative antiviral treatment with undetectable HCV viral load and liver function tests are otherwise within acceptable limits (as described in Section 4.5.2). Patients with chronic Hepatitis B (HBV) infection are not excluded if liver function is within acceptable limits, but should be evaluated for reactivation risk and started on suppressive antiviral therapy prior to enrollment if appropriate. * History of stroke or transient ischemic attack within the previous 6 months. * History of life threatening venous thromboembolic event (such as hemodynamically significant pulmonary embolism) or any arterial thrombotic event within the previous 6 months. Patients with non-life threatening venous thromboembolic events are not excluded and should be managed with anti-coagulation as per standard institutional practice. * Any of the following cardiac abnormalities: * Unstable angina pectoris within the past 6 months. * Congestive heart failure ≥ NYHA Class 3 within the past 6 months. * Prolonged QTc on electrocardiogram \>500 milliseconds. * Left ventricular ejection fraction (LVEF) \< 40%. * Uncontrolled hypertension (\>150mm Hg or \>100mm Hg diastolic) on multiple observations despite standard of care treatment * Major surgery within 4 weeks of the date of randomization. * History of significant hemoptysis or hemorrhage within 4 weeks of the date of randomization. * Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments. * Has received a live vaccine within 30 days prior to the first dose of trial treatment. * Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior to the date of randomization. * Breast-feeding or planning to breast-feed during the study or within 30 days following the last dose of sitravatinib and within 5 months following the last dose of pembrolizumab. * Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to 267 days | The Objective Response Rate (ORR): The primary endpoint for this study will be ORR as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in the main study population. Presented are counts of participants in the following RECIST categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | until death or date of last contact, up to 2 years | Overall Survival (OS) in the main study populations (ie groups 1A and 2A) is a secondary endpoint for this study. OS in groups 1B and 2B is an exploratory endpoint. Defined as the time from date of treatment start to death due to any cause |
| Progression Free Survival (PFS) | Until progressive disease, death, or last contact, up to 2 years | Progression Free Survival (PFS) in the main study populations (ie groups 1A and 2A) is a secondary endpoint for this study. PFS in groups 1B and 2B is an exploratory endpoint. Defined as time from first dose to first progressive disease (PD) or death due to any cause in the absence of documented PD. |
| Duration of Response (DOR) | Until progressive disease, death, or last contact, up to 2 years | Duration of Response (DOR) for patients in Group A is a secondary endpoints for this study; DOR for Group B is an exploratory endpoint. Defined as time that measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or to death due to any cause in the absence of documented PD. |
| Clinical Benefit Rate (CBR) | up to 2 years | Clinical Benefit Rate (CBR) in Group A is a secondary endpoints for this study, while CBR in Group B is an exploratory endpoint. Defined as percent of patients documented to have a confirmed Complete Response (CR), confirmed Partial Response (PR), or Stable Disease (SD) documented on at least 1 on-study assessment and including at least 5 weeks on study |
| Number of Participants That Experienced at Least 1 Adverse Event | 2 years | Evaluation of the safety and toxicity profile of the combination of sitravatinib and pembrolizumab in the first-line treatment of patients with non-squamous metastatic NSCLC is a secondary objective in this study. Secondary endpoint is adverse events as per CTCAE v.5. The Safety population is defined as all patients who received any dose of study treatment (i.e., sitravatinib and/or pembrolizumab) and will be used for all safety analyses. Number of participants that experienced at least 1 adverse event. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitravatinib: Group 1A Participants receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1).
Sitravatinib: Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1).
Pembrolizumab: All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1). | 1 |
| Sitravatinib: Group 2A Participants receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1).
Sitravatinib: Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1).
Pembrolizumab: All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1). | 3 |
| Sitravatinib Group 1B Participants with receive Pembrolizumab 200mg intravenous (IV) for one dose alone, beginning on cycle 1 day 1 (C1D1). On Cycle 2 Day 1 (C2D1), participants receive Pembrolizumab 200mg intravenous (IV) once every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily.
Sitravatinib: Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1).
Pembrolizumab: All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1). | 2 |
| Sitravatinib Group 2B Participants with receive Pembrolizumab 200mg intravenous (IV) for one dose alone, beginning on cycle 1 day 1 (C1D1). On Cycle 2 Day 1 (C2D1), participants receive Pembrolizumab 200mg intravenous (IV) once every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily.
Sitravatinib: Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1).
Pembrolizumab: All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1). | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 2 | 0 |
| Overall Study | Lack of Efficacy | 1 | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Sitravatinib: Group 1A | Sitravatinib: Group 2A | Sitravatinib Group 1B | Sitravatinib Group 2B | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 9 Participants |
| Region of Enrollment United States | 1 participants | 3 participants | 2 participants | 3 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 2 / 3 | 2 / 2 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 3 / 3 | 2 / 2 | 3 / 3 |
| serious Total, serious adverse events | 1 / 1 | 2 / 3 | 2 / 2 | 1 / 3 |
Outcome results
Primary
Objective Response Rate (ORR)
The Objective Response Rate (ORR): The primary endpoint for this study will be ORR as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in the main study population. Presented are counts of participants in the following RECIST categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD)
Time frame: up to 267 days
Population: Participants available for assessment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sitravatinib: Group 1A | Objective Response Rate (ORR) | Progressive Disease (PD) | 0 Participants |
| Sitravatinib: Group 1A | Objective Response Rate (ORR) | Stable Disease (SD) | 1 Participants |
| Sitravatinib: Group 1A | Objective Response Rate (ORR) | Partial Response (PR) | 0 Participants |
| Sitravatinib: Group 1A | Objective Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Sitravatinib: Group 2A | Objective Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Sitravatinib: Group 2A | Objective Response Rate (ORR) | Stable Disease (SD) | 2 Participants |
| Sitravatinib: Group 2A | Objective Response Rate (ORR) | Partial Response (PR) | 0 Participants |
| Sitravatinib: Group 2A | Objective Response Rate (ORR) | Progressive Disease (PD) | 0 Participants |
| Sitravatinib: Group 1B | Objective Response Rate (ORR) | Progressive Disease (PD) | 1 Participants |
| Sitravatinib: Group 1B | Objective Response Rate (ORR) | Partial Response (PR) | 1 Participants |
| Sitravatinib: Group 1B | Objective Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Sitravatinib: Group 1B | Objective Response Rate (ORR) | Stable Disease (SD) | 0 Participants |
| Sitravatinib: Group 2B | Objective Response Rate (ORR) | Progressive Disease (PD) | 0 Participants |
| Sitravatinib: Group 2B | Objective Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Sitravatinib: Group 2B | Objective Response Rate (ORR) | Stable Disease (SD) | 2 Participants |
| Sitravatinib: Group 2B | Objective Response Rate (ORR) | Partial Response (PR) | 1 Participants |
Secondary
Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR) in Group A is a secondary endpoints for this study, while CBR in Group B is an exploratory endpoint. Defined as percent of patients documented to have a confirmed Complete Response (CR), confirmed Partial Response (PR), or Stable Disease (SD) documented on at least 1 on-study assessment and including at least 5 weeks on study
Time frame: up to 2 years
Population: Only patients who met the eligibility criteria were analyzed. For paricipants in Group 2A, 2 had confirmed SD and 1 was unevaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitravatinib: Group 1A | Clinical Benefit Rate (CBR) | 100 percentage of participants |
| Sitravatinib: Group 2A | Clinical Benefit Rate (CBR) | 66.7 percentage of participants |
Secondary
Duration of Response (DOR)
Duration of Response (DOR) for patients in Group A is a secondary endpoints for this study; DOR for Group B is an exploratory endpoint. Defined as time that measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or to death due to any cause in the absence of documented PD.
Time frame: Until progressive disease, death, or last contact, up to 2 years
Population: Data for this outcome was not collected as there were no patients that met criteria for CR or PR.
Secondary
Number of Participants That Experienced at Least 1 Adverse Event
Evaluation of the safety and toxicity profile of the combination of sitravatinib and pembrolizumab in the first-line treatment of patients with non-squamous metastatic NSCLC is a secondary objective in this study. Secondary endpoint is adverse events as per CTCAE v.5. The Safety population is defined as all patients who received any dose of study treatment (i.e., sitravatinib and/or pembrolizumab) and will be used for all safety analyses. Number of participants that experienced at least 1 adverse event.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sitravatinib: Group 1A | Number of Participants That Experienced at Least 1 Adverse Event | 1 Participants |
| Sitravatinib: Group 2A | Number of Participants That Experienced at Least 1 Adverse Event | 3 Participants |
| Sitravatinib: Group 1B | Number of Participants That Experienced at Least 1 Adverse Event | 2 Participants |
| Sitravatinib: Group 2B | Number of Participants That Experienced at Least 1 Adverse Event | 3 Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) in the main study populations (ie groups 1A and 2A) is a secondary endpoint for this study. OS in groups 1B and 2B is an exploratory endpoint. Defined as the time from date of treatment start to death due to any cause
Time frame: until death or date of last contact, up to 2 years
Population: Only patients who met the eligibility criteria were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitravatinib: Group 1A | Overall Survival (OS) | 246 days |
| Sitravatinib: Group 2A | Overall Survival (OS) | 210 days |
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS) in the main study populations (ie groups 1A and 2A) is a secondary endpoint for this study. PFS in groups 1B and 2B is an exploratory endpoint. Defined as time from first dose to first progressive disease (PD) or death due to any cause in the absence of documented PD.
Time frame: Until progressive disease, death, or last contact, up to 2 years
Population: Only patients who met the eligibility criteria were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitravatinib: Group 1A | Progression Free Survival (PFS) | 246 days |
| Sitravatinib: Group 2A | Progression Free Survival (PFS) | 210 days |