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Sitravatinib Plus Pembrolizumab in Patients With Advanced Treatment-Naïve PD-L1+ Non-Squamous NSCLC

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ClinicalTrials.gov Identifier: NCT04925986
Recruitment Status : Not yet recruiting
First Posted : June 14, 2021
Last Update Posted : September 8, 2021
Sponsor:
Collaborator:
Mirati Therapeutics Inc.
Information provided by (Responsible Party):
Sarah Goldberg, Yale University

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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Lung Diseases Lung Neoplasms Metastatic Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 PD-L1 Gene Mutation Advanced Treatment-Naïve PD-L1 Sitravatinib Pembrolizumab Drug: Sitravatinib Drug: Pembrolizumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Trial of Sitravatinib Plus Pembrolizumab in Patients With Advanced Treatment-Naïve PD-L1+ Non-Squamous Non-Small Cell Lung Cancer
Estimated Study Start Date : October 1, 2021
Estimated Primary Completion Date : October 1, 2025
Estimated Study Completion Date : October 1, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group 1A: PD-L1 1-49%, Main Study Population
Participants with PD-L1 Tumor Proportion Score (TPS) 1-49% receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1).
Drug: 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).
Other Name: IND 155305

Drug: Pembrolizumab
All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).
Other Name: Keytruda

Experimental: Group 1B: PD-L1 1-49%, Pembrolizumab run-in population
Participants with PD-L1 Tumor Proportion Score (TPS) 1-49% 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.
Drug: 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).
Other Name: IND 155305

Drug: Pembrolizumab
All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).
Other Name: Keytruda

Experimental: Group 2A: PD-L1 ≥ 50%, Main Study Population
Participants with PD-L1 Tumor Proportion Score (TPS) ≥ 50% receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1).
Drug: 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).
Other Name: IND 155305

Drug: Pembrolizumab
All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).
Other Name: Keytruda

Experimental: Group 2B: PD-L1 ≥ 50%, Pembrolizumab run-in population
Participants with PD-L1 Tumor Proportion Score (TPS) ≥ 50% 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.
Drug: 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).
Other Name: IND 155305

Drug: Pembrolizumab
All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).
Other Name: Keytruda




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 2 years ]
    (1) 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.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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.

  2. Progression Free Survival (PFS) [ Time Frame: 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.

  3. Duration of Response (DOR) [ Time Frame: 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.

  4. Clinical Benefit Rate (CBR) [ Time Frame: 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.

  5. Incidence of Adverse Events as per CTCAE v.5 [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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%.
  • 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.

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.
  • Need for treatment with a proton pump inhibitor (antacids and/or H2 antagonist are permitted).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04925986


Contacts
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Contact: Julie Holub, CCRP 860-304-0546 julie.holub@yale.edu
Contact: Kimberly S. Vasquez, MPH 212-363-0809 kimberly.vasquez@yale.edu

Locations
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United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States, 06510
Contact: Kimberly S. Vasquez, MPH    212-363-0809    kimberly.vasquez@yale.edu   
Smilow Cancer Hospital Care Center at North Haven
North Haven, Connecticut, United States, 06473
Contact: Kimberly S. Vasquez, MPH    212-363-0809    kimberly.vasquez@yale.edu   
Sponsors and Collaborators
Sarah Goldberg
Mirati Therapeutics Inc.
Investigators
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Principal Investigator: Sarah Goldberg, MD MPH Yale University
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Responsible Party: Sarah Goldberg, Associate Professor of Internal Medicine (Medical Oncology), Yale University
ClinicalTrials.gov Identifier: NCT04925986    
Other Study ID Numbers: 2000030093
First Posted: June 14, 2021    Key Record Dates
Last Update Posted: September 8, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Lung Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents