Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma

NCT03661723 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 18-2773475-787
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 5

Brief Summary

This research study is studying pembrolizumab and re-irradiation as possible treatments for glioblastoma. The drugs involved in this study are:

• Pembrolizumab
• Radiation
• Bevacizumab, an FDA-approved drug for treating recurrent glioblastoma multiforme (GBM)

Conditions

Glioblastoma

Keywords

Glioblastoma

Outcome Measures

Primary Outcomes (3)

• Objective Response Rate (ORR)

  Per Response Assessment in Neuro-Oncology (RANO) Criteria: * Complete Response (CR): * Disappearance of all enhancing measurable \& non-measurable disease sustained for at least 4 weeks * No new lesions * Stable or improved non-enhancing (T2/FLAIR) lesions * No corticosteroids (or physiologic replacement doses only) * And stable or improved clinically * Partial Response (PR): * \>=50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; * No progression of non-measurable disease * No new lesions * Stable or improved non-enhancing (T2/FLAIR) lesions * Same or lower dose of corticosteroids compared with baseline scan * And stable or improved clinically Overall Response Rate (ORR) = Frequency of CR + PR within a population.

  2 years

• Overall Survival Rate at 6 Months (OS-6)

  6 months

• Overall Survival Rate at 12 Months (OS-12)

  12 months

Secondary Outcomes (5)

• Safety & Tolerability: SAEs Experienced by Participants

  2 years

• Duration of Response

  1 year

• Median Progression Free Survival (PFS)

  2 years

• 6-month Progression Free Survival (PFS-6)

  6 months

• Median Overall Survival (OS)

  Participants were followed for survival until death; survival was followed for a max of 4 years. Other Adverse Events (AEs) were collected from registration through 30 days after last dose (SAEs through 90 days); AEs were followed for a max of 2 years.

Study Arms (4)

Pembrolizumab + Radiation (lead-in)

EXPERIMENTAL

* Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks. (De-escalation dosing frequencies = once every 4 weeks and once every 6 weeks.) * Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks

Drug: Pembrolizumab; Radiation: Re-irradiation

Pembrolizumab + Bevacizumab + Radiation (lead-in)

EXPERIMENTAL

* Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks. (De-escalation dosing frequencies = once every 4 weeks and once every 6 weeks.) * Bevacizumab (15 mg/kg) will be administered intravenously (IV) once every 3 weeks * Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks

Drug: Pembrolizumab; Drug: Bevacizumab; Radiation: Re-irradiation

Pembrolizumab + Radiation

EXPERIMENTAL

* Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks * Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks

Drug: Pembrolizumab; Radiation: Re-irradiation

Pembrolizumab + Bevacizumab + Radiation

EXPERIMENTAL

* Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks * Bevacizumab (15 mg/kg) will be administered intravenously (IV) once every 3 weeks * Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks

Drug: Pembrolizumab; Drug: Bevacizumab; Radiation: Re-irradiation

Interventions

Pembrolizumab DRUG

Pembrolizumab is a drug (an antibody) that may treat cancer by working with the immune system

Also known as: Keytruda

Pembrolizumab + Bevacizumab + Radiation; Pembrolizumab + Bevacizumab + Radiation (lead-in); Pembrolizumab + Radiation; Pembrolizumab + Radiation (lead-in)

Bevacizumab DRUG

Bevacizumab (also known as "Avastin") is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

Also known as: Avastin

Pembrolizumab + Bevacizumab + Radiation; Pembrolizumab + Bevacizumab + Radiation (lead-in)

Re-irradiation RADIATION

Radiotherapy destroys cancer cells using radiation aimed at a cancer from a machine

Pembrolizumab + Bevacizumab + Radiation; Pembrolizumab + Bevacizumab + Radiation (lead-in); Pembrolizumab + Radiation; Pembrolizumab + Radiation (lead-in)

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed World Health Organization (WHO) Grade IV glioblastoma. Patients with original histology of low-grade glioma and subsequent histological diagnosis of GBM are eligible. Other WHO grade IV glial neoplasms such as gliosarcoma are NOT eligible 1.2 Willing and able to provide written informed consent/assent for the trial 1.3 ≥ 18 years of age on day of signing informed consent 1.4 Karnofsky performance status (KPS) ≥ 70 (Appendix A) 1.5 Unequivocal evidence for tumor progression by MRI scan 1.6 MRI within 14 days prior to start of study therapy (with vascular imaging when possible). Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the screening MRI scan and Day 1 dose, a new baseline scan is required 1.7 Measurable disease as per Response Assessment in Neuro-Oncology (RANO) criteria 1.8 Cohort A patients must be at their first or second relapse; Cohort B patients must have progressed on no more than one prior bevacizumab-containing regimen (may have received any # of non-bevacizumab-containing regimens). Patients who were treated with prior bevacizumab but did not progress or experienced significant toxicity, are not eligible 1.9 Previous first line therapy with at least radiotherapy utilizing standard dosing of CNS radiation - for either high-grade or low-grade glial neoplasm 1.10 The following time periods must have elapsed from projected Day 1 dose:
• At least 3 weeks from prior surgical resection
• At least 1 week from stereotactic biopsy
• At least 6 months from completion of prior radiotherapy (patient may still be eligible if s/he has a new area of enhancement outside the 80% isodose line of the original radiation field)
• At least 4 weeks from cytotoxic therapy (at least 23 days for temozolomide, and at least 6 weeks from nitrosoureas)
• At least 1 week from cancer vaccines
• At least 6 weeks from antibodies
• At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies (not including tumor treating fields or cancer vaccines); at least 1 week from NovoTTF (Optune) or other tumor treating fields and cancer vaccines
• Cohort B patients only: Day 1 of bevacizumab on-study must be at least 3 weeks from last dose of prior course of Avastin/bevacizumab.
• Negative urine or serum pregnancy within 72 hours prior to registration from any woman of child-bearing potential (WOCBP), defined as any woman physiologically capable of becoming pregnant. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• WOCBP (defined above) must agree to use a highly effective method of contraception (detailed in protocol eligibility) consistently and correctly as described below during study treatment and for 120 days after study discontinuation.
• Male participants must agree to use at least one of the methods of contraception detailed in protocol eligibility starting with the first dose of study therapy through 120 days after the last dose of therapy.

You may not qualify if:

• Recurrent tumor greater than 6 cm in maximum diameter 2.2 Currently participating or plans to participate in another study of an investigational agent or using an investigational device.
• Tumor primarily localized to the brainstem or spinal cord. 2.4 Presence of multifocal tumor, diffuse leptomeningeal or extracranial disease.
• NOTE: Not all instances of multifocal disease will exclude a potential patient; only patients with multifocal sites of active disease will be excluded. (e.g. A patient with a previously treated lesion that remains stable would not be excluded.)
• Medical History/Conditions/Concomitant Medical Illnesses:
• Diagnosis of immunodeficiency. 2.6 History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. e.g. unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.
• History of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug.
• Evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI scans.
• Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade \> 3 within 6 months of start of study drug.
• Known additional malignancy that is progressing or requires active treatment within 1 year of start of study drug, except for those treated with surgical therapy only (e.g. basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).
• Active autoimmune disease requiring systemic treatment in the past 2 years (e.g. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement for adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a form of systemic treatment.
• History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Active infection requiring systemic therapy. 2.14 Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) and is receiving antiretroviral therapy.
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C \[e.g., hepatitis C virus (HCV) RNA (qualitative) is detected\].
• History of non-healing wounds or ulcers, or bone refractures within 3 months of fracture.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (5)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02214, United States

Location

Columbia University / Herbert Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

Hospital of the University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

pembrolizumab; Bevacizumab; Re-Irradiation

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; Radiotherapy; Therapeutics; Retreatment

Results Point of Contact

• Title: David A. Reardon, MD (Clinical Director, Center for Neuro-Oncology)
• Organization: Dana-Farber Cancer Institute

david_reardon@dfci.harvard.edu

617-632-2166

Study Officials

• David A Reardon, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 5, 2018
• First Posted: September 7, 2018
• Study Start: September 28, 2018
• Primary Completion: December 9, 2021
• Study Completion: August 1, 2024
• Last Updated: September 19, 2024
• Results First Posted: April 7, 2023

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)