Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma

Study Overview
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Brief Summary
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This is an ongoing Phase 2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with glioblastoma (GBM) enrolled into 5 non-comparative cohorts. Primary study objectives, which vary by cohort due to differences in subject populations, include evaluation of the clinical efficacy as measured by the overall survival (OS) rate at 12 months (Cohort A), progression-free survival (PFS) at 6 months (Cohorts B, B2, and B3), and OS at 6 months (Cohort C). For all cohorts, secondary objectives include evaluation of the safety/tolerability and clinical efficacy of study treatment, and exploratory objectives include evaluation of the neurologic function and correlative biomarkers.

Detailed Description
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Eligible subjects are enrolled in parallel into one of the following 5 cohorts as described below. In each cohort, the first study drug administration for the first subject and the second subject are separated by at least 1 week. Cohort A: Subjects with newly diagnosed unmethylated O^6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) GBM receive durvalumab (10 mg/kg every 2 weeks [Q2W]) + standard radiotherapy. The first 6 subjects are evaluated for dose-limiting toxicity (DLT) for 10 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg. Cohort B: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy. Cohort B2: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W). Cohort B3: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). Cohort C: Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). The first 6 subjects are evaluated for DLTs for 6 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg. The Core Study lasts for up to 12 months; optional extension treatment may be offered to subjects who complete 51 weeks of treatment on the Core Study with stable disease or better and upon agreement between the subject, Investigator, and Sponsor. Subjects are followed on study for 90 days after the last drug administration and off study every 6 months for 3 years from the date of the first dose of study treatment. The primary study endpoints have been met, although some subjects remain in treatment and/or follow-up and data collection is ongoing.

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

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Durvalumab
* Radiation: Standard radiotherapy
* Biological: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria [criteria apply to all cohorts unless otherwise specified]: Cohort A: Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for standard radiation therapy. Cohorts B, B2, B3 and C: First or second recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) per modified Response Assessment in Neuro-oncology (RANO) criteria, 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. Cohorts B, B2, B3 and C: 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). Cohorts B, B2, B3: No prior vascular endothelial growth factor (VEGF)/VEGF receptor targeted therapy; Cohort C: No more than one prior bevacizumab regimen. Cohorts B, B2, B3 and C: 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. Subjects with measurable or non-measurable disease. Histopathologic confirmation of glioblastoma. 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. 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. Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky performance status of ≥ 70. Adequate hematologic, renal and hepatic function, as defined below: Absolute neutrophil count ≥ 1000/mm^3; Platelet count ≥ 100,000/mm^3; Total bilirubin ≤ 1.5 x upper limit of normal (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 ≤ 1.5 x 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 United States) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations. Exclusion Criteria [criteria apply to all cohorts unless otherwise specified]: Primary tumors localized to the brain stem or spinal cord. 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. Prior exposure to durvalumab or other programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. Presence of diffuse leptomeningeal disease or extracranial disease. 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. Known primary immunodeficiency or active human immunodeficiency virus. 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 virus surface antigen or hepatitis C virus ribonucleic acid (hepatitis C virus antibody). History of organ transplant requiring use of immunosuppressive medication. History of active tuberculosis. Significant active systemic illness including infections requiring intravenous antibiotics. Current pneumonitis or interstitial lung disease. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only. History of severe allergic reactions to any unknown allergens or any components of the study drugs. Any prior grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study. Lack of availability for follow-up assessments. Lack of availability for Post Study Follow-up contacts to determine relapse and survival. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin). 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 protocol-specified requirements for contraception. 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. 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. Cohorts B2, B3, and C: Evidence of hemorrhage on the baseline MRI or computed tomography (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 7 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. Subjects must not donate blood while on study and for at least 90 days following the last durvalumab treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy. | Drug: Durvalumab<br>* Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.<br>* Other names: MEDI4736;Radiation: Standard radiotherapy<br>* Focal radiotherapy is administered at 2 Gy given daily 5 days per week for a total of 60 Gy over 30 fractions per local institutional guidelines or local prescribing information. On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.<br>|
| Experimental: Cohort B<br>Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy. | Drug: Durvalumab<br>* Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.<br>* Other names: MEDI4736;|
| Experimental: Cohort B2<br>Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W). | Drug: Durvalumab<br>* Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.<br>* Other names: MEDI4736;Biological: Bevacizumab<br>* Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.<br>* Other names: Avastin;|
| Experimental: Cohort B3<br>Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). | Drug: Durvalumab<br>* Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.<br>* Other names: MEDI4736;Biological: Bevacizumab<br>* Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.<br>* Other names: Avastin;|
| Experimental: Cohort C<br>Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). | Drug: Durvalumab<br>* Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.<br>* Other names: MEDI4736;Biological: Bevacizumab<br>* Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate at 12 Months (OS-12) as Estimated Using the Kaplan-Meier Method (Cohort A) | OS-12 with 90% confidence interval (CI) is the primary endpoint of Cohort A and is the percentage of subjects who remain alive at 12 months, where OS is measured from the time of diagnosis until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up. | Up to 12 months | 
| Progression-free Survival Rate at 6 Months (PFS-6) as Estimated Using the Kaplan-Meier Method (Cohorts B, B2, and B3) | PFS-6 is the primary endpoint of Cohorts B, B2, and B3, and is the percentage of subjects who have not progressed at 6 months, with PFS measured from the date of the first dose of study treatment to the date of earliest disease progression (PD) based on modified Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72). | Up to 6 months | 
| Overall Survival Rate at 6 Months (OS-6) as Estimated Using the Kaplan-Meier Method (Cohort C) | OS-6 is the primary endpoint of Cohort C and is the percentage of subjects who remain alive at 6 months, where OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events | Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, magnetic resonance imaging, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of durvalumab. AEs are considered to be treatment emergent if they occur or worsen in severity after the first dose of study treatment. | Up to 15 months | 
| Median PFS as Estimated Using the Kaplan-Meier Method | PFS is measured from the date of the first dose of study treatment to the date of earliest PD based on modified RANO criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72). | Up to 15 months | 
| Median OS as Estimated Using the Kaplan-Meier Method | All subjects are followed for survival at least every 6 months for up to 3 years following initiation of study treatment. In Cohort A, OS is measured from the date of diagnosis until the recorded date of death or last follow-up. In Cohorts B, B2, B3, and C, OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who remain alive or are lost to follow-up at the time of the analysis are censored on the date of last follow-up. | Up to 36 months | 
| Number of Subjects With Best Overall Response | Radiographic response is assessed by consistent imaging methods every (q) 8 to 9 weeks during study treatment administration. Response is categorized per the modified RANO criteria: complete response (CR) indicates no new lesions and disappearance of all disease sustained for ≥ 4 weeks; partial response (PR) indicates no new lesions, no progression of non-measureable disease, and ≥ 50% decrease from baseline in sum of products of perpendicular diameters of measurable lesions sustained for ≥ 4 weeks; stable disease (SD) indicates non-qualification for CR, PR, or progressive disease (PD); PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72). | Up to 15 months | 
| Mean Changes From Baseline in the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) | Health-related quality of life was measured using the validated EORTC-QLQ-C30. Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All questions are answered using a categorical scale (1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much for symptoms and 1= very poor; 7= excellent for global heath questions). Scores were linearly transformed to 0 to 100 scales so that higher scores represented a higher level of functioning. Overall scores were calculated for each patient for each timepoint (Giesinger J et al Journal of Clinical Epidemiology. 2016 Jan;69:79-88). Mean change from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported. | Up to 12 months | 
| Mean Changes From Baseline in the EORTC Brain Cancer Quality of Life Questionnaire (EORTC-QLQ-BN-20) | Health-related quality of life was measured using an EORTC quality of life questionnaire designed specifically for subjects with brain tumors (BN-20). Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All single questions are answered using a categorical scale (e.g., 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much) and linearly transformed to 0 to 100 scales with higher scores for a symptom scale representing higher level of symptoms. The evaluation of HRQoL at each timepoint was measured by mean changes from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Immunotherapy, T Cell, PD-L1, MEDI4736, Radiation, Radiotherapy, GBM