Details

Details

Title A phase II, multicenter, single-arm study of mpdl3280a in patients with locally advanced or metastatic urothelial bladder cancer

IRB ROCH1814

CC 14-441

Hospital Main Campus

Stage Stage 4

Phase Phase 2

Disease Bladder

Drug MPDL3280A

Description

Description

PRIMARY OBJECTIVE

The primary objective for this study is to evaluate the efficacy of MPDL3280A in patients with locally advanced or metastatic UBC, 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 OBJECTIVES

The secondary objectives for this study are as follows:

  • To evaluate progression-free survival (PFS) and duration of response (DOR) according to RECIST v1.1 as assessed by IRF
  • To evaluate PFS and DOR according to modified RECIST as assessed by the investigator
  • To evaluate ORR, DOR, and PFS according to RECIST v1.1 as assessed by the investigator
  • To evaluate OS and 1-year 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

EXPLORATORY OBJECTIVES

The exploratory objectives for this study are as follows:

  • To further evaluate anti-tumor activity by IHC categories
  • 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

Inclusion Criteria

Inclusion Criteria

  1. Signed Informed Consent Form
  2. Ability to comply with protocol
  3. Age ≥ 18 years
  4. Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2-3) or metastatic (M1, Stage IV) TCC (also termed urothelial cell carcinoma) of the urothelium (including renal pelvis, ureters, urinary bladder, urethra) Patients with mixed histologies are required to have a dominant transitional cell pattern. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2-N3).
  5. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to have sufficient viable tumor content prior to study enrollment; tumor specimens will be evaluated for PD-L1 no fewer than 10 may be eligible following discussion with Medical Monitor. Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core needle biopsy specimens, at least three cores should be submitted for evaluation. Patients who submit specimens from TURBTs will be required to submit an additional specimen obtained at the time of cystectomy/nephroureterectomy or metastatic spread (i.e., sample from a metastatic lesion). An archival specimen, if available, may be submitted. Patients who do not have tissue specimens meeting eligibility requirements may undergo a biopsy sample collection during the screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps biopsy samples for cutaneous, subcutaneous, or mucosal lesions. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. Patients having additional tissue samples from procedures performed at different times during the course of their UBC will be requested (but not required) to also submit these samples for central testing. Tissue samples obtained at multiple times for individual patients will greatly contribute to an improved understanding of the dynamics of PD-L1 expression and relationship with intervening anti-cancer therapy. In situations where multiple specimens were received from different sites or at different times, the highest score will be used for primary and secondary analyses.
  6. ECOG performance status of 0 or 1 (see Appendix 6) Patients with ECOG performance status of 2 are allowed in Cohort 1.
  7. Life expectancy ≥ 12 weeks
  8. Measurable disease, as defined by RECIST v1.1 Previously irradiated lesions should not be counted as target lesions unless there has been demonstrated progression in the lesion since radiotherapy and no other lesions are available for selection as target lesions.
  9. 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
    • ymphocyte count ≥ 300/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 times 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.
      Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
  10. 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

Cohort 1-Specific Inclusion Criteria

  1. No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UBC For patients who received prior adjuvant/neoadjuvant chemotherapy or chemoradiation for UBC, a treatment-free interval ≥ 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment na�ve in the metastatic setting. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment.
  2. Ineligible ("unfit") for cisplatin-based chemotherapy as defined by any one of the following criteria: Impaired renal function (GFR > 30 but < 60 mL/min). GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine. A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies Grade ≥ 2 peripheral neuropathy (i.e., sensory alteration or paresthesias including tingling).

Cohort 2-Specific Inclusion Criteria

  1. Disease progression during or following treatment with at least one platinum-containing regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence. A regimen is defined as patients receiving at least two cycles of a platinum-containing regimen. Patients who have received one cycle of a platinum-containing regimen but discontinued due to Grade 4 hematologic toxicity or Grade 3or 4 non-hematologic toxicity may also be eligible. Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen will be considered as second-line patients. Patients with disease progression following chemoradiotherapy must demonstrate progression outside the prior radiotherapy port. Note: The maximum number of prior therapies for patients in Cohort 2 is unrestricted.
Exclusion Criteria

Exclusion Criteria

Cancer-Specific Exclusion Criteria

  1. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed: Palliative radiotherapy for bone metastases or soft tissue lesions should be completed > 7 days prior to baseline imaging. Hormone-replacement therapy or oral contraceptives.
  2. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
  3. Active or untreated CNS metastases as determined by CT or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
    Patients with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
    Evaluable or measurable disease outside the CNS
    No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
    No history of intracranial or spinal cord hemorrhage
    No evidence of significant vasogenic edema
    No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose allowed
    No stereotactic radiation, whole-brain radiation or neurosurgical resection with 2 weeks prior to Cycle 1, Day 1
    Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study
    Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or surgical resection and ≥ 2 weeks since discontinuation of corticosteroids
  4. Leptomeningeal disease
  5. 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.
  6. 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.
  7. 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 in the study.
  8. Malignancies other than UBC 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, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse, or incidental prostate cancer (T1/T2a, Gleason score ≤ 3 + 4 and PSA < 0.5 ng/mL) undergoing active surveillance and treatment naive)

General Medical Exclusion Criteria

  1. Pregnant and lactating women
  2. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  3. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the MPDL3280A formulation
  4. 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, with polyangiitis, 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.
  5. 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.
  6. Serum albumin < 2.5 g/dL
  7. Positive test for HIV
  8. Patients with active hepatitis B virus (HBV chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C virus (HCV) Patients with past 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 HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  9. Active tuberculosis
  10. 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
  11. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
  12. 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.
  13. 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.
  14. 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
  15. Prior allogeneic stem cell or solid organ transplant
  16. 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 (approximately October to March). 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.
  17. 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

Medication-Related Exclusion Criteria

  1. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies. Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided 6 weeks have elapsed from the last dose and there was no history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 or 4). Prior cancer vaccines and cellular immunotherapy are permitted; patients are encouraged to undergo a fresh pre-treatment sample collection for biopsy to evaluate potential changes in PD-L1 status.
  2. Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin [IL]-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
  3. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial 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, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed.