Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma
- Conditions
- Glioblastoma
- Interventions
- Registration Number
- NCT02336165
- Lead Sponsor
- Ludwig Institute for Cancer Research
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 159
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort A Standard radiotherapy Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy. Cohort B2 Bevacizumab Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W). Cohort B3 Bevacizumab Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). Cohort C Bevacizumab Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). Cohort B3 Durvalumab Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W). Cohort C Durvalumab Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). Cohort A Durvalumab Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy. Cohort B2 Durvalumab Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W). Cohort B Durvalumab Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy.
- Primary Outcome Measures
Name Time Method Overall Survival Rate at 12 Months (OS-12) as Estimated Using the Kaplan-Meier Method (Cohort A) Up to 12 months 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.
Progression-free Survival Rate at 6 Months (PFS-6) as Estimated Using the Kaplan-Meier Method (Cohorts B, B2, and B3) Up to 6 months 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).
Overall Survival Rate at 6 Months (OS-6) as Estimated Using the Kaplan-Meier Method (Cohort C) Up to 6 months 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Treatment-emergent Adverse Events Up to 15 months 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.
Median OS as Estimated Using the Kaplan-Meier Method Up to 36 months 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.
Number of Subjects With Best Overall Response Up to 15 months 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).
Mean Changes From Baseline in the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) Up to 12 months 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.Mean Changes From Baseline in the EORTC Brain Cancer Quality of Life Questionnaire (EORTC-QLQ-BN-20) Up to 12 months 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.
Median PFS as Estimated Using the Kaplan-Meier Method Up to 15 months 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).
Trial Locations
- Locations (1)
Research Facility
🇦🇺Melbourne, Australia