Details
Title A PHASE II, MULTICENTER, SINGLE-ARM STUDY OF MPDL3280A IN PATIENTS WITH PD-L1-POSITIVE LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER
IRB GENE 1513
CC 14-081
Hospital Main Campus
Phase Phase 2
Disease Lung, Lymphoma, Other iNHL
Drug MPDL3280A
Description
Primary ObjectivesThe primary objective for this study is to evaluate the efficacy of MPDL3280A in patients with PD-L1- positive locally advanced or metastatic NSCLC, as measured by:
- Independent review facility (IRF)-assessed ORR according to RECIST v1.1
- Investigator-assessed ORR according to modified RECIST
The efficacy analysis will follow a hierarchical fixed-sequence procedure. For details see Section 6.3.
Secondary ObjectivesThe secondary objectives for this study are as follows:
- To evaluate PFS and DOR according to RECIST v1.1 as assessed by IRF and according to modified RECIST as assessed by the investigators
- To evaluate ORR, DOR, and PFS according to RECIST v1.1 as assessed by the investigators
- To evaluate OS
- To evaluate the safety and tolerability of MPDL3280A
- To characterize the pharmacokinetics of MPDL3280A
- To evaluate the incidence and titers of ATAs against MPDL3280A and to explore the potential relationship of the immunogenicity response with pharmacokinetics, safety, and efficacy
The exploratory objectives for this study are as follows:
- IRF-assessed ORR according to modified RECIST
- To evaluate the relationship between tumor biomarkers (including but not limited to PD-L1, PD-1, and others), as defined by IHC or quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and efficacy
- To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival and/or fresh tumor tissue and blood and their association with disease status and/or response to study treatment
- To evaluate the utility of biopsy at the time of apparent disease progression to distinguish apparent increases in tumor volume related to the immunomodulatory activity of MPDL3280A (i.e., pseudoprogression/tumor immune infiltration) from true disease progression
- To evaluate patient-reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) as measured by the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) and the lung cancer module (QLQ-LC13)
Inclusion Criteria
- Signed Informed Consent Form
- Ability to comply with protocol
- Age ≥ 18 years
- Histologically or cytologically documented Stage IIIB (not eligible for definitive chemoradiotherapy), Stage IV, or recurrent NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th edition; Detterbeck et al. 2009); pathological characterization must be sufficient to define patients as having either squamous or non-squamous histology.
- Patients with progressive disease following chemoradiotherapy must demonstrate progression outside the prior radiotherapy port.
- PD-L1-positive tumor status as determined by an IHC assay based on PD-L1 expression on tumor infiltrating immune cells and/or tumor cells performed by a central laboratory
- A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen collected at first diagnosis and/or subsequent tumor recurrence(s), consistent with the patient's diagnosis that has adequate viable tumor cells, or a minimum of 15 unstained, freshly cut, serial sections is required for participation in this study. This specimen must be reviewed by a pathologist and accompanied by the associated pathology report.
- Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage samples are not acceptable. Tumor tissue from bone metastases is not evaluable for tumor PD-L1 expression and is therefore not acceptable. For core needle biopsy specimens, at least three cores should be submitted for evaluation.
- For samples not meeting minimum requirements for size/slide number, contact the Medical Monitor via your site contact with tissue size and tumor, content/number of slides, etc., to determine eligibility.
- If fewer than 15 slides are available at baseline (but no fewer than 10), the patient may still be eligible, upon discussion with the Medical Monitor.
- In patients without an available archival specimen or for those whose initial sample is PD-L1-negative, a fresh biopsy is acceptable for the purposes of testing PD-L1 status. A positive result in any sample biopsy will satisfy this eligibility criterion.
- ECOG performance status of 0 or 1 (see Appendix 6)
- Life expectancy ≥ 12 weeks
- Measurable disease, as defined by RECIST v1.1
- Previously irradiated lesions should not be counted as target lesions.
- Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
- ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
- WBC counts > 2500/μL
- Lymphocyte count ≥ 500/μL
- Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
- Hemoglobin ≥ 9.0 g/dL
- Patients may be transfused or receive erythropoietic treatment to meet this criterion.
- AST, ALT, and alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN), with the following exceptions:
- Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN
- Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN
- Serum bilirubin ≤ 1.5 x ULN
- Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
- INR and aPTT ≤ 1.5 x ULN
- This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
- Creatinine clearance ≥ 30 mL/min
- For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of MPDL3280A
- No prior chemotherapy for locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCL
- For patients who received prior adjuvant/neoadjuvant chemotherapy for resectable stage NSCLC or chemoradiation for locally advanced, non-metastatic NSCLC, a treatment-free interval >6 months between the last treatment administration and the date of recurrence is required.
- Patients with a known sensitizing mutation in the EGFR gene must have experienced disease progression (during or after treatment) or intolerance to treatment with erlotinib, gefitinib, or another EGFR TKI approved for the treatment of EGFR-mutant NSCLC; patients who have received an investigational EGFR TKI may be eligible following discussion with the Medical Monitor.
- Patients with a known ALK fusion oncogene must have experienced disease progression (during or after treatment) or intolerance to treatment with crizotinib or another ALK inhibitor approved for the treatment of NSCLC in patients having an ALK fusion oncogene; patients who have received an investigational ALK inhibitor may be eligible following discussion with the Medical Monitor.
- Disease progression during or following prior platinum-based chemotherapy for locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC
- Patients with disease progression during or following platinum-based adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation for NSCLC are eligible if ≤ 6 months have elapsed between the last treatment administration and the date of recurrence.
- Patients with a known sensitizing mutation in the EGFR gene must also have experienced disease progression (during or after treatment) or intolerance to treatment with erlotinib, gefitinib, or another EGFR TKI approved for the treatment of EGFR-mutant NSCLC; patients who have received an investigational EGFR TKI may be eligible following discussion with the Medical Monitor.
- Patients with a known ALK fusion oncogene must also have experienced disease progression (during or after treatment) or intolerance to treatment with crizotinib or another ALK inhibitor approved for the treatment of NSCLC in patients having an ALK fusion oncogene; patients who have received an investigational ALK inhibitor may be eligible following discussion with the Medical Monitor.
- Note: The maximum number of prior chemotherapies for patients in Cohort 2 is one.
- Disease progression during or following a prior platinum-based chemotherapy regimen and at least one additional progression following a regimen for locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC
- Patients with disease progression during or following platinum-based adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation for NSCLC are eligible if ≤6 months have elapsed between the last treatment administration and the date of recurrence. These patients will also have at least one additional progression on or after an additional regimen.
- Patients with a known sensitizing mutation in the EGFR gene must also have experienced disease progression (during or after treatment) or intolerance to treatment with erlotinib, gefitinib, or another EGFR TKI approved for the treatment of EGFR-mutant NSCLC; patients who have received an investigational EGFR TKI may be eligible following discussion with the Medical Monitor.
- Patients with a known ALK fusion oncogene must also have experienced disease progression (during or after treatment) or intolerance to treatment with crizotinib or another ALK inhibitor approved for the treatment of NSCLC in patients having an ALK fusion oncogene; patients who have received an investigational ALK inhibitor may be eligible following discussion with the Medical Monitor.
- Note: The maximum number of prior therapies for patients in Cohort 3 is unrestricted.
Exclusion Criteria
Cancer-Specific Exclusions- Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
- Hormone-replacement therapy or oral contraceptives
- TKIs approved for treatment of NSCLC discontinued > 7 days prior to Cycle 1, Day 1. The baseline scan must be obtained after discontinuation of prior TKIs.
- Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
- CNS disease, including treated brain metastases
- Leptomeningeal disease
- Uncontrolled tumor-related pain
- Patients requiring pain medication must be on a stable regimen at study entry.
- Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrollment.
- Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
- 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.
- Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
- Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
- Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study
- Malignancies other than NSCLC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
- Pregnant and lactating women
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or any component of the MPDL3280A formulation
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a more comprehensive list of autoimmune diseases)
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
- Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Serum albumin <2.5 g/dL
- Positive test for HIV
- Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
- Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Active tuberculosis
- Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
- Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
- Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
- Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction <50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
- Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
- Prior allogeneic bone marrow transplantation or solid organ transplant
- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
- Influenza vaccination should be given during influenza season only (example: approximately October to March in the Northern Hemisphere). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Patients who have had prior anti-CTLA-4 treatment may be enrolled, provided the following requirements are met:
- Minimum of 6 weeks from the last dose of anti-CTLA-4
- No history of severe immune related adverse effects from anti-CTLA-4 (CTCAE Grade 3 and 4)
- Patients who have had prior anti-CTLA-4 treatment may be enrolled, provided the following requirements are met:
- Treatment with systemic immunostimulatory agents (including but not limited to IFNs,IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
- Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1
- Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor.
- The use of inhaled corticosteroids for COPD, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.