Clinical Trials /

Phase 2 Study of MEDI4736 in Patients With Glioblastoma

NCT02336165

Description:

This is an open-label, non-randomized, multicenter Phase 2 study of MEDI4736 with three non-comparative cohorts: Cohort A: 37 subjects with newly diagnosed unmethylated MGMT GBM will receive MEDI4736 every 2 weeks in combination with standard radiotherapy. Cohort B: 30 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks as monotherapy. Cohort B2: 32 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks + bevacizumab every 2 weeks (10 mg/kg). Cohort B3: 32 bevacizumab-naïve subjects with recurrent GBM will receive MEDI4736 every 2 weeks + bevacizumab every 2 weeks (3 mg/kg). Cohort C: 17 bevacizumab-refractory subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with continued bevacizumab.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Phase 2 Study of MEDI4736 in Patients With <span class="go-doc-concept go-doc-disease">Glioblastoma</span>

Title

  • Brief Title: Phase 2 Study of MEDI4736 in Patients With Glioblastoma
  • Official Title: Phase 2 Study to Evaluate the Clinical Efficacy and Safety of MEDI4736 in Patients With Glioblastoma (GBM)
  • Clinical Trial IDs

    NCT ID: NCT02336165

    ORG ID: LUD2013-006

    Trial Conditions

    Glioblastoma

    Trial Interventions

    Drug Synonyms Arms
    MEDI4736 Durvalumab Cohort A, Cohort B, Cohort C, Cohort B2, Cohort B3

    Trial Purpose

    This is an open-label, non-randomized, multicenter Phase 2 study of MEDI4736 with three
    non-comparative cohorts:

    Cohort A: 37 subjects with newly diagnosed unmethylated MGMT GBM will receive MEDI4736 every
    2 weeks in combination with standard radiotherapy.

    Cohort B: 30 bevacizumab-nave subjects with recurrent GBM will receive MEDI4736 every 2
    weeks as monotherapy.

    Cohort B2: 32 bevacizumab-nave subjects with recurrent GBM will receive MEDI4736 every 2
    weeks + bevacizumab every 2 weeks (10 mg/kg).

    Cohort B3: 32 bevacizumab-nave subjects with recurrent GBM will receive MEDI4736 every 2
    weeks + bevacizumab every 2 weeks (3 mg/kg).

    Cohort C: 17 bevacizumab-refractory subjects with recurrent GBM will receive MEDI4736 every
    2 weeks in combination with continued bevacizumab.

    Detailed Description

    Under some circumstances, the immune system may control or even eliminate tumors. MEDI4736
    is an experimental antibody that is made in the laboratory. Antibodies stimulating the
    immune system have been developed for treatment of human cancers. The idea behind developing
    this type of experimental drug is that stimulating the immune system could be a different
    way of preventing cancer growth or killing cancer cells.

    This study will also evaluate how much MEDI4736 is in the blood at various times, whether
    the immune system becomes activated following treatment and the effect of treatment on
    cancer.

    In subjects with newly diagnosed GBM (Cohort A), MEDI4736 will be administered with standard
    treatment which includes radiation following surgery. The idea to add MEDI4736 to standard
    radiation is that the radiation will cause cell death and release tumor proteins which will
    increase the immune activity of MEDI4736.

    Subjects with recurrent GBM and who have never been treated with Avastin (Cohort B), will
    receive MEDI4736 alone.

    In Cohorts B2 and B3, subjects with recurrent GBM and who have never been treated with
    Avastin will receive MEDI2736 in combination with standard or low dose Avastin respectively.

    Subjects with recurrent GBM and who have currently progressed on Avastin (Cohort C), will
    continue receiving Avastin in combination with MEDI4736. Avastin is another type of antibody
    that prevents the growth of blood vessels that feed the tumor. Despite Avastin being
    approved by the FDA for cancer based on tumor response, essentially all patients eventually
    progress due to resistance.

    The idea to treat cancer with MEDI4736, with or without Avastin, is to identify alternative
    treatment options for cancer, by stimulating the immune system to prevent cancer growth.

    Trial Arms

    Name Type Description Interventions
    Cohort A Experimental Approximately 37 subjects with newly diagnosed unmethylated MGMT GBM will receive MEDI4736 every 2 weeks in combination with standard radiotherapy. MEDI4736
    Cohort B Experimental Approximately 30 bevacizumab-nave subjects with recurrent GBM will receive MEDI4736 every 2 weeks as monotherapy. MEDI4736
    Cohort C Experimental Approximately 17 bevacizumab-refractory subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with continued bevacizumab. MEDI4736
    Cohort B2 Experimental Approximately 32 bevacizumab-naive subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with bevacizumab (10 mg/kg). MEDI4736
    Cohort B3 Experimental Approximately 32 bevacizumab-naive subjects with recurrent GBM will receive MEDI4736 every 2 weeks in combination with bevacizumab (3 mg/kg). MEDI4736

    Eligibility Criteria

    Inclusion Criteria:

    Cohort A:

    1. Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for
    standard radiation therapy.

    Cohorts B, B2, B3 and C:

    2. First or second recurrence of GBM by diagnostic biopsy or contrast enhanced MRI per
    modified RANO criteria (122), with last baseline MRI confirmation within 14 days
    prior to Study Day 1.

    NOTE: Recurrence is defined as progression following therapy (i.e., chemotherapy;
    radiation). If the subject had a surgical resection for relapsed disease and no
    anti-tumor therapy was administered for up to 12 weeks, and the subject has further
    evidence of tumor growth or undergoes another resection, this will be considered as
    one episode of recurrence.

    3. On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease
    outside of the radiation field or histopathologic confirmation of unequivocal tumor).

    4. Cohort B, B2, B3: No prior VEGF/VEGFR targeted therapy; Cohort C: No more than one
    prior bevacizumab regimen.

    5. Recovery from any prior treatment clinically significant, related adverse events to
    grade 1 or pretreatment baseline with the exception of alopecia and laboratory
    values listed per inclusion criteria.

    Cohorts A, B, B2, B3 and C:

    6. Subjects with measurable or non-measurable disease.

    7. Histopathologic confirmation of glioblastoma.

    8. At the time of Study Day 1, subjects must be at least 4 weeks since major surgical
    procedure, open biopsy, or significant traumatic injury; there should be no
    anticipation of need for major surgical procedure during the course of the study.

    There should be no core biopsy or other minor surgical procedure, excluding placement
    of a vascular access device, within 7 days prior to Study Day 1.

    9. Subjects who have previously been treated with the Optune device are eligible for the
    study as long as toxicity related to the treatment has resolved to Grade 1 or
    baseline.

    10. ECOG 1 or Karnofsky performance status of 70.

    11. Adequate hematologic, renal and hepatic function, as defined below:

    - Absolute Neutrophil Count 1000/mm3

    - Platelet count 100,000/mm3

    - Total bilirubin 1.5 x ULN; or if subject has Gilbert syndrome, then total
    bilirubin 3 x ULN

    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.0 x ULN

    - Creatinine 1.5x ULN 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 Cohorts B2, B3 and C

    - Urinary protein quantitative value of 30 mg/dL in urinalysis or 1+ on
    dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample.

    12. Age must be greater than or equal to 18 years at date of consent.

    13. Written informed consent and any locally required authorization (e.g., Health
    Insurance Portability and Accountability Act [HIPAA] in the USA) obtained from the
    subject/legal representative prior to performing any protocol-related procedures,
    including screening evaluations.

    Exclusion Criteria:

    All Cohorts

    1. Primary tumors localized to the brainstem or spinal cord.

    2. Locally directed therapies including but not limited to stereotactic radiosurgery,
    re-irradiation, Gliadel, and therapeutics administered by direct injection or
    convection-enhanced delivery within 6 months of start of study treatment.

    3. Prior exposure to MEDI4736 or other anti-PD-1, anti-PD-L1, anti-CTLA4 antibodies.

    4. Presence of diffuse leptomeningeal disease or extracranial disease.

    5. Active, suspected or prior documented autoimmune disease (including inflammatory
    bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and
    Hashimoto's thyroiditis). Subjects with vitiligo, type I diabetes mellitus, residual
    hypothyroidism due to autoimmune condition only requiring hormone replacement,
    psoriasis not requiring systemic treatment, or conditions not expected to recur in
    the absence of an external trigger are permitted to enroll.

    6. Known primary immunodeficiency or active HIV.

    7. Known active or chronic viral hepatitis or history of any type of hepatitis within
    the last 6 months indicated by positive test for hepatitis B surface antigen (HBV
    sAG) or hepatitis C virus ribonucleic acid (HCV antibody).

    8. History of organ transplant requiring use of immunosuppressive medication.

    9. History of active tuberculosis.

    10. Significant active systemic illness including infections requiring intravenous
    antibiotics.

    11. Current pneumonitis or interstitial lung disease.

    12. Other invasive malignancy within 2 years prior to entry into the study, except for
    those treated with surgical therapy only.

    13. History of severe allergic reactions to any unknown allergens or any components of
    the study drugs.

    14. Any prior Grade 3 immune-related adverse event (irAE) or any prior
    corticosteroid-refractory irAE.

    15. Mental impairment that may compromise the ability to give informed consent and comply
    with the requirements of the study.

    16. Lack of availability for follow-up assessments.

    17. Lack of availability for Post Study Follow-up contacts to determine relapse and
    survival.

    18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy
    test (minimum sensitivity 25 IU/L or equivalent units of HCG).

    19. Women of childbearing potential not using a medically acceptable means of
    contraception for the duration of the study and unsterilized males not willing to
    abide by requirements for contraception as stated in Section 5.4.

    20. If a subject previously received another investigational treatment, the last dose of
    investigational treatment was administered within 4 weeks of Day 1 of the study.

    21. Any condition that, in the clinical judgment of the treating physician, is likely to
    prevent the subject from complying with any aspect of the protocol or that may put
    the subject at unacceptable risk.

    22. Cohorts B2, B3 and C:

    - Evidence of hemorrhage on the baseline MRI or CT scan other than those that are
    grade 1 and either post-operative or stable on at least two consecutive scans

    - Current use of warfarin sodium or any other Coumadin-derivative anticoagulant.
    Participant must be off Coumadin-derivative anticoagulants for at least seven
    days prior to starting study drug. Low molecular weight heparin and Factor Xa
    antagonists are allowed

    - History of clinically significant bleeding within 6 months of enrollment

    - History of arterial thromboembolism within 12 months prior to enrollment

    - Inadequately controlled hypertension (defined as systolic blood pressure 150
    and/or diastolic blood pressure > 90 mmHg on antihypertensive medications)

    - Any prior history of hypertensive crisis or hypertensive encephalopathy

    - Clinically significant cardiovascular disease within 12 months prior to
    enrollment (or randomization), including myocardial infarction, unstable angina,
    grade 2 or greater peripheral vascular disease, cerebrovascular accident,
    transient ischemic attack, congestive heart failure, or arrhythmias not
    controlled by outpatient medication, percutaneous transluminal coronary
    angioplasty/stent

    - Evidence of bleeding diathesis or coagulopathy

    - History of abdominal fistula, gastrointestinal perforation, or intra abdominal
    abscess within 6 months prior to study enrollment

    - Serious, non healing wound, ulcer, or bone fracture

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Clinical Efficacy, as judged by survival, is the primary objective of the study for all cohorts but the primary endpoints differ by cohort due to the difference in patient populations.

    Secondary Outcome Measures

    Number of Participants with Adverse Events as a Measure of Safety and Tolerability

    Evaluation of Clinical Efficacy by median Progression-Free Survival, and Overall Survival as well as overall response rate (ORR).

    Pharmacokinetic profile of MEDI4736, including half-life, Tmax, Cmax and other parameters.

    Quality of Life (EORTC QLQ-30/BN20).

    Trial Keywords

    Glioblastoma

    Immunotherapy

    T Cell

    PD-L1

    MEDI4736

    Radiation

    Radiotherapy

    GBM