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Summary

for people ages 18 years and up (full criteria)
at San Francisco, California and other locations
study started

Description

Summary

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.

Official Title

Phase 2 Study to Evaluate the Clinical Efficacy and Safety of MEDI4736 in Patients With Glioblastoma (GBM)

Details

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.

Keywords

Glioblastoma Immunotherapy T Cell PD-L1 MEDI4736 Radiation Radiotherapy GBM Bevacizumab Antibodies, Monoclonal

Eligibility

You can join if…

Open to people ages 18 years and up

Cohort A:

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

Cohorts B, B2, B3 and C:

  1. 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.

  1. 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).
  2. Cohort B, B2, B3: No prior VEGF/VEGFR targeted therapy; Cohort C: No more than one prior bevacizumab regimen.
  3. 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:

  1. Subjects with measurable or non-measurable disease.
  2. Histopathologic confirmation of glioblastoma.
  3. 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.

  1. 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.
  2. . ECOG ≤ 1 or Karnofsky performance status of ≥ 70.
  3. . Adequate hematologic, renal and hepatic function, as defined below:
  4. Absolute Neutrophil Count ≥ 1000/mm3
  5. Platelet count ≥ 100,000/mm3
  6. Total bilirubin ≤ 1.5 x ULN; or if subject has Gilbert syndrome, then total bilirubin ≤ 3 x ULN
  7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN
  8. 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.
  • . Age must be greater than or equal to 18 years at date of consent.
  • . 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.

You CAN'T join if...

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:
  23. 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
  24. 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
  25. History of clinically significant bleeding within 6 months of enrollment
  26. History of arterial thromboembolism within 12 months prior to enrollment
  27. Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications)
  28. Any prior history of hypertensive crisis or hypertensive encephalopathy
  29. 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
  30. Evidence of bleeding diathesis or coagulopathy
  31. History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 6 months prior to study enrollment
  32. Serious, non healing wound, ulcer, or bone fracture

Locations

  • Research Facility
    San Francisco, California, 94143, United States
  • Research Facility
    Los Angeles, California, 90095, United States

Details

Status
in progress, not accepting new patients
Start Date
Sponsor
Ludwig Institute for Cancer Research
ID
NCT02336165
Phase
Phase 2
Lead Scientist
Study Type
Interventional
Last Updated
February 14, 2017