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

NCT02336165 | Completed Phase 2 Results FDA Drug

• 1 other identifier: LUD2013-006
• Study Type: interventional
• Target: 159
• Locations: 2 countries
• Sites: 8

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.

Conditions

Glioblastoma

Keywords

Glioblastoma; Immunotherapy; T Cell; PD-L1; MEDI4736; Radiation; Radiotherapy; GBM

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Number of Participants With Treatment-emergent Adverse Events

  Up to 15 months

• Median PFS as Estimated Using the Kaplan-Meier Method

  Up to 15 months

• Median OS as Estimated Using the Kaplan-Meier Method

  Up to 36 months

• Number of Subjects With Best Overall Response

  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)

  Up to 12 months

Study Arms (5)

Cohort A

EXPERIMENTAL

Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy.

Drug: Durvalumab; Radiation: Standard radiotherapy

Cohort B

EXPERIMENTAL

Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy.

Drug: Durvalumab

Cohort B2

EXPERIMENTAL

Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W).

Drug: Durvalumab; Biological: Bevacizumab

Cohort B3

EXPERIMENTAL

Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W).

Drug: Durvalumab; Biological: Bevacizumab

Cohort C

EXPERIMENTAL

Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W).

Drug: Durvalumab; Biological: Bevacizumab

Interventions

Durvalumab DRUG

Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.

Also known as: MEDI4736

Cohort A; Cohort B; Cohort B2; Cohort B3; Cohort C

Standard radiotherapy RADIATION

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.

Cohort A

Bevacizumab BIOLOGICAL

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.

Also known as: Avastin

Cohort B2; Cohort B3; Cohort C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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):

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• MedImmune LLC: collaborator
• Cancer Research Institute, New York City: collaborator
• Cure Brain Cancer Foundation, Australia: collaborator

Study Sites (8)

Research Facility

Los Angeles, California, 90095, United States

Location

Research Facility

San Francisco, California, 94143, United States

Location

Research Facility

Baltimore, Maryland, 21287, United States

Location

Research Facility

Boston, Massachusetts, 02114, United States

Location

Research Facility

Boston, Massachusetts, 02215, United States

Location

Research Facility

St Louis, Missouri, 63110, United States

Location

Research Facility

New York, New York, 10065, United States

Location

Research Facility

Melbourne, Australia

Location

Related Publications (1)

• Giesinger JM, Kieffer JM, Fayers PM, Groenvold M, Petersen MA, Scott NW, Sprangers MA, Velikova G, Aaronson NK; EORTC Quality of Life Group. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol. 2016 Jan;69:79-88. doi: 10.1016/j.jclinepi.2015.08.007. Epub 2015 Sep 28.

  PMID: 26327487 BACKGROUND

MeSH Terms

Conditions

Glioblastoma

Interventions

durvalumab; Bevacizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The primary study endpoints have been met; final data will be incorporated upon study completion and availability of the data.

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• David A. Reardon, MD

  Dana-Farber Cancer Institute

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 23, 2014
• First Posted: January 12, 2015
• Study Start: February 26, 2015
• Primary Completion: November 1, 2018
• Study Completion: July 6, 2021
• Last Updated: October 12, 2022
• Results First Posted: October 28, 2019

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); US (7)