Atezolizumab in Patients With NSCLC or Advanced Solid Tumors Having Had Prior Treatment With a PD-1 Inhibitor

Overview

This is a Phase II, two part trial (A and B), open label study of Atezolizumab for patients with non-small cell lung cancer (NSCLC) or an advanced solid tumor that has been previously treated with a PD-1 inhibitor (either nivolumab or pembrolizumab).

Full Title of Study: “A Phase II Study of Atezolizumab in Patients With NSCLC or Advanced Solid Tumors That Have Had Prior Treatment With a PD-1 Inhibitor”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2021

Detailed Description

This is an open-label, multi-center, Phase II study of atezolizumab in patients with NSCLC or advanced solid tumors that have had prior treatment with a PD-1 inhibitor (e.g. nivolumab or pembrolizumab). Arm A consists of patients with advanced NSCLC who received first-line PD-1-monotherapy, who have subsequent disease progression. In Arm A, patients with NSCLC will be randomized 1:1 to either chemotherapy plus atezolizumab at a flat dose of 1200 mg IV every 3 weeks or chemotherapy alone until progression or unacceptable toxicity. Platinum-based standard of care doublet chemotherapy (or triplet if bevacizumab is used) will be given by IV every 3 weeks. Platinum chemotherapy may be cisplatin or carboplatin chosen based on histology and at the discretion of the treating investigator. It should be administered according to the directions in the approved labeling.

Arm B consists of approximately 10-15 patients per disease type (renal cell carcinoma [RCC], triple negative breast cancer [TNBC], small cell lung cancer [SCLC], squamous cell carcinoma of the head and neck [SCCHN], melanoma, microsatellite instability-high [MSI-high] solid tumors {as determined by local testing for MSI/mismatch repair (MMR)}), as well as patients with NSCLC who were treated with a PD-1 antibody in ≥ second-line setting and who have had subsequent disease progression and NSCLC patients who have progressed after pembrolizumab plus chemotherapy in the first-line setting. In Arm B, patients with advanced solid tumors will be treated with an atezolizumab flat dose of 1200 mg IV every 3 weeks until progression or unacceptable toxicity.

Primary Objective

The primary objectives of this study are to:

- Assess the efficacy (overall response rate [ORR]) of combining atezolizumab with standard of care chemotherapy in non-small cell lung cancer (NSCLC) patients who have progressed after prior exposure to anti-PD-1 monotherapy treatment.

- Assess the efficacy (ORR) of atezolizumab in patients with advanced solid tumors who have progressed after prior exposure to anti-PD-1 treatment.

Secondary Objectives

The secondary objectives of this study are to:

- Determine the safety of atezolizumab in patients with NSCLC and other advanced solid tumors.

- Estimate the 6-month disease control rate, progression-free survival (PFS), overall survival (OS) in patients with NSCLC and other advanced solid tumors.

Exploratory Objectives

The exploratory objectives of this study are:

- Correlation of programmed death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) with response to therapy.

- Characterization of the tumor microenvironment by IHC, ribonucleic acid (RNA) sequencing and/or reverse transcription polymerase chain reaction (RT-PCR) and correlation of immune gene signatures with response to therapy.

- In selected patients with paired biopsy samples (pre-anti-PD-1 and pre-atezolizumab; or pre and post-atezolizumab tissue):

- Assessment of immune escape mechanisms, that may include but is not limited to neoantigen profiling and T cell receptor (TCR) sequencing.

- Assessment of tumor mutation burden (TMB) by next-generation sequencing (NGS) and correlation with response to therapy.

Interventions

  • Drug: Atezolizumab
    • In Arm A, patients with NSCLC will be randomized 1:1 to either chemotherapy plus atezolizumab at a flat dose of 1200 mg IV every 3 weeks or chemotherapy alone until progression or unacceptable toxicity.
  • Other: Chemotherapy (Arm A Only)
    • Platinum-based standard of care doublet chemotherapy (or triplet if bevacizumab is used) will be given by IV every 3 weeks. Platinum chemotherapy may be cisplatin or carboplatin chosen based on histology and at the discretion of the treating investigator. It should be administered according to the directions in the approved labeling.

Arms, Groups and Cohorts

  • Experimental: Arm A (Chemo + Atezolizumab)
    • Arm A consists of patients with advanced NSCLC who received first-line PD-1-monotherapy, who have subsequent disease progression. In Arm A, patients with NSCLC will be randomized 1:1 to either chemotherapy plus atezolizumab at a flat dose of 1200 mg IV every 3 weeks or chemotherapy alone until progression or unacceptable toxicity. Platinum-based standard of care doublet chemotherapy (or triplet if bevacizumab is used) will be given by IV every 3 weeks. Platinum chemotherapy may be cisplatin or carboplatin chosen based on histology and at the discretion of the treating investigator. It should be administered according to the directions in the approved labeling.
  • Experimental: Arm B (Atezolizumab Only)
    • Arm B consists of approximately 10-15 patients per disease type (renal cell carcinoma [RCC], triple negative breast cancer [TNBC], small cell lung cancer [SCLC], squamous cell carcinoma of the head and neck [SCCHN], melanoma, microsatellite instability-high [MSI-high] solid tumors {as determined by local testing for MSI/mismatch repair (MMR)}), as well as patients with NSCLC who were treated with a PD-1 antibody in ≥ second-line setting and who have had subsequent disease progression and NSCLC patients who have progressed after pembrolizumab plus chemotherapy in the first-line setting. In Arm B, patients with advanced solid tumors will be treated with an atezolizumab flat dose of 1200 mg IV every 3 weeks until progression or unacceptable toxicity.

Clinical Trial Outcome Measures

Primary Measures

  • Efficacy (overall response rate [ORR]) of combining atezolizumab with standard of care chemotherapy
    • Time Frame: Up to 6 months
    • Assess the efficacy (overall response rate [ORR]) of combining atezolizumab with standard of care chemotherapy in non-small cell lung cancer (NSCLC) patients who have progressed after prior exposure to anti-PD-1 monotherapy treatment.

Secondary Measures

  • The incidence of treatment-emergent adverse events (AEs) as a measure of safety
    • Time Frame: Up to 6 months
    • Determine the safety of atezolizmab in patients with NSCLC and other advanced solid tumors
  • Determine the disease control rate (DCR)
    • Time Frame: Up to 6 months
    • Estimate the 6-month disease control rate (DCR) in patients with NSCLC and other advanced solid tumors.
  • The incidence of serious adverse events (AEs) as a measure of safety,
    • Time Frame: Up to 6 Months
    • Determine the safety of atezolizmab in patients with NSCLC and other advanced solid tumors
  • Determine the progression-free survival (PFS)
    • Time Frame: Up to 6 Months
    • Estimate the progression-free survival (PFS) in patients with NSCLC and other advanced solid tumors.
  • Determine the overall survival (OS)
    • Time Frame: Up to 6 Months
    • Estimate the overall survival (OS) in patients with NSCLC and other advanced solid tumors.

Participating in This Clinical Trial

Inclusion Criteria

1. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 – 1 (Appendix A).

2. Adequate hematologic function defined as:

  • Absolute neutrophil count (ANC) ≥1500/μL
  • Hemoglobin (Hgb) ≥9 g/dL
  • Platelets ≥100,000/µL

3. Adequate liver function defined as:

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the upper limit of normal (ULN)
  • Total bilirubin ≤1.5 x ULN (Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN)

4. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated creatinine clearance ≥50 mL/min as calculated by Cockcroft and Gault Formula (for the solid tumor cohort receiving atezolizumab monotherapy, the threshold can be reduced to a creatinine clearance of ≥30 mL/min.).

5. Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 5 months following last dose of study drug(s). Male patients must also refrain from donating sperm during their participation in the study (Appendix C).

6. Age ≥18 years.

7. Willingness to provide a new pre-treatment tumor biopsy.

8. Willingness and ability to comply with study and follow-up procedures.

9. Ability to understand the nature of this study and give written informed consent.

Inclusion Arm A – Non-small cell lung cancer 1. Advanced squamous or non-squamous NSCLC 2. Disease progression after first-line anti-PD-1 therapy (pembrolizumab) for ≥4 months Inclusion Arm B – Advanced solid tumors

1. Patients with advanced RCC, TNBC, SCLC, SCCHN, melanoma, MSI-high solid tumors, and patients with NSCLC who were treated with PD-1 in the ≥ second-line setting, or NSCLC patients who progressed after pembrolizumab plus chemotherapy in the first-line setting Additional cohorts may be added.

2. MSI-high solid tumors as defined by local testing for MSI/MMR will be included.

3. Previously received and tolerated nivolumab or pembrolizumab therapy (and was the last therapy prior to enrollment).

4. Evidence of disease progression.

Exclusion Criteria

1. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

2. History of any Grade 3 or 4 toxicities to a prior CPI treatment

3. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation

4. Most recent immunotherapy ≤21 days and ≥ Grade 1 immunotherapy-related side effects, with the exception of alopecia.

5. Use of systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) ≤28 days or 5 half-lives (whichever is longer) prior to the first dose of atezolizumab.

6. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF- agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions:

  • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
  • Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

7. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study or within 5 months after the last dose of atezolizumab

8. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.

• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

9. Requirement for use of denosumab during the study. Patients who are receiving denosumab for any reason (including hypercalcemia) must be willing and eligible to receive a bisphosphonate instead while in the study.

10. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.

11. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement.

12. Symptomatic, untreated, or actively progressing CNS metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks prior to study entry and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy. Anticonvulsant therapy at a stable dose is permitted.

13. Prior allogeneic stem cell or solid organ transplantation

14. Pregnant or lactating

15. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

16. Uncontrolled diabetes mellitus. Patients with Type II diabetes are eligible if they require only oral hypoglycemic agents and fasting blood glucose level is ≤120. Patients with Type I diabetes are eligible if HbAlc is ≤7%.

17. Significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina (see Appendix B)

18. History of leptomeningeal disease

19. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)

• Patients with indwelling catheters (e.g., PleurX) are allowed.

20. Uncontrolled or symptomatic hypercalcemia (-1.5 mmol/L ionized calcium or calcium -12 mg/dL or corrected serum calcium -ULN).

21. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix F for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

  • Rash must cover ˂ 10% of body surface area
  • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months

22. Serious active infection within 4 weeks of treatment (including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia), or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.

23. Diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.

24. Active tuberculosis

25. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

26. Has a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results.

27. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Exclusion Arm A – Non-small cell lung cancer

1. Intervening treatment with a regimen other than CPI prior to enrollment in this study.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • SCRI Development Innovations, LLC
  • Collaborator
    • Genentech, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Melissa Johnson, MD, Study Chair, SCRI Development Innovations, LLC
  • Overall Contact(s)
    • Sarah Cannon Development Innovations, 844-710-6157, CANN.InnovationsMedical@sarahcannon.com

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