Details

Details

Title A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination with Radiation Therapy in Newly Diagnosed Adult Subjects with Unmethylated MGMT (tumor O-6-methylguanine DNA methyltransferase) Glioblastoma

IRB BRMY1315

CC 16-134

Hospital Main Campus

Phase Phase 3

Disease Brain, Glioblastoma

Drug Nivolumab, Temozolomide

Description

Description

Primary Objective
  • To compare overall survival (OS) of nivolumab plus radiation therapy (RT + nivolumab) versus temozolomide plus radiation therapy (RT + TMZ) in subjects with newly-diagnosed GBM and unmethylated MGMT tumors after surgical resection.
Secondary Objectives
  • To compare investigator-assessed progression-free survival (PFS) of RT + nivolumab versus RT + TMZ;
  • To estimate the overall survival rate at 24 months (OS[24]) of RT + nivolumab versus RT + TMZ (final analysis only);
Exploratory Objectives
    To evaluate the safety of RT + nivolumab and RT + TMZ treatment arms;
  • To evaluate health-related quality of life using the EQ-5D and the European Organization for Research and Treatment of Care General Cancer Module (QLQ-C30) and brain cancer module (QLQ-BN20);
  • To assess neurologic functioning in the RT + nivolumab and RT + TMZ treatment arms using the Neurologic Assessment in Neuro-Oncology (NANO) Scale;
  • To assess cognition in the RT + nivolumab and RT + TMZ treatment arms using the Cogstate tool;
  • To evaluate the pharmacodynamic activity of nivolumab in the peripheral blood and tumor tissue as measured by flow cytometry, immunohistochemistry, soluble factor analysis, and gene expression (microarray technology, quantitative RT-PCR);
  • To investigate the association between biomarkers in the peripheral blood and tumor tissue such as PD-L1 expression, with safety and efficacy for subjects with newly diagnosed GBM treated with nivolumab;
  • To characterize the PK of nivolumab and explore exposure-response relationships;
  • To characterize the immunogenicity of nivolumab in this setting.
Inclusion Criteria

Inclusion Criteria

  1. Signed Written Informed Consent
    • Written informed consent and HIPAA authorization (applies to covered entities in the US only) obtained from the subject/legal representative prior to performing any protocol-related procedures;
    • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study;
  2. Target Population
    • Newly-diagnosed histologically-confirmed supratentorial glioblastoma (Grade IV malignant glioma by World Health Organization, including gliosarcoma)
      • No treatment for GBM other than surgery;
      • Post-operative baseline MRI within 48 hours (preferably 24 hours) of surgical resection
    • Full recovery from surgical resection
      • No major ongoing safety issues following surgery;
      • ≤ 20 mg prednisone or ≤ 3 mg dexamethasone daily (or equivalent);
    • Centrally confirmed (ie, third-party vendor) unmethylated MGMT;
    • Karnofsky performance status of ≥ 70 (Appendix 2)
    • Eligible for radiation therapy based on NCCN guidelines
    • Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has not been treated) is permitted. If re-enrolled, the subject must be re-consented.
  3. Age and Reproductive Status
    • Males and Females, age ≥ 18 years old;
    • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug
    • Women must not be breastfeeding
    • Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half lives. The terminal half life of nivolumab is up to 25 days. The terminal half-life of temozolomide is 1.2 hours.
    • WOCBP randomized to receive nivolumab should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. WOCBP randomized to receive temozolomide should use an adequate method to avoid pregnancy for 6 weeks (30 days plus the time required for temozolomide to undergo five half lives) after last dose of temozolomide.
    • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half lives. The terminal half-life of nivolumab is up to 25 days.
    • Males randomized to receive nivolumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Males randomized to temozolomide should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.
    • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However WOCBP must still undergo pregnancy testing as described in this section. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as found in the informed consent.
  4. Physical and Laboratory Test Findings
    • WBC ≥ 2,000/μL
    • Neutrophils ≥ 1,500/μL
    • Platelets ≥ 100 x103/μL
    • Hemoglobin ≥ 9.0 g/dL
    • Serum creatinine ≤ 1.5xULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula)
      • Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
      • Male CrCl = (140-age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
    • AST ≤ 3.0 x ULN;
    • ALT ≤ 3.0 x ULN;
    • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who may have a total bilirubin < 3.0 x ULN);
Exclusion Criteria

Exclusion Criteria

  1. Target Disease Exceptions
    • Prior treatment for GBM (other than surgical resection)
    • Recurrent GBM
    • MGMT methylated, partially methylated, or indeterminate GBM
    • Biopsy-only of GBM at surgery, defined as <20% resection
    • Ongoing requirement for supraphysiologic steroid, defined as >20 mg prednisone or > 3 mg dexamethasone daily (or equivalent), due to intracranial mass effect
    • CNS hemorrhage of Grade > 1 on baseline MRI scan, unless subsequently documented to have resolved;
    • Any known metastatic extracranial or leptomeningeal disease
    • Secondary GBM (ie, progression from prior low-grade or anaplastic glioma)
    • Known IDH-mutated tumor (if available; test not required)
  2. Medical History and Concurrent Diseases
    • Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results;
    • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways;
    • Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll;
    • Subjects with a condition requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone or > 3 mg dexamethasone or equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 20 mg daily prednisone or > 3 mg dexamethasone or equivalent, are permitted in the absence of active autoimmune disease.
    • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
    • Subjects with history of life-threatening toxicity, including hypersensitivity reaction, related to prior immunoglobulin treatment for another condition (except those considered unlikely to re-occur, with written approval of BMS medical monitor) or any other study drug component.
    • History or evidence upon physical/neurological examination of other central nervous system condition (eg, seizures, abscess) unrelated to cancer, unless adequately controlled by medication or considered not potentially interfering with protocol treatment;
    • Surgical procedure < 7 days prior to study treatment, vascular access device no restriction;
    • Subjects unable (eg, due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head;
    • History of allergy or hypersensitivity to study drug components;
    • Unable to swallow oral medication or any gastrointestinal disease or surgical procedure that may impact the absorption of study drug;
    • Subjects with prior hypersensitivity to dacarbazine (DTIC).
  3. Physical and Laboratory Test Findings
    • Any positive test for hepatitis B virus or hepatitis C virus
    • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated by local regulation.
  4. Allergies and Adverse Drug Reaction
    • History of allergy or hypersensitivity to study drug components
  5. Other Exclusion Criteria
    • Prisoners or subjects who are involuntarily incarcerated (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.)
    • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness