HIF-2 Alpha Inhibitor PT2385 in Treating Patients With Recurrent Glioblastoma

NCT ID: NCT03216499

Last Updated: 2022-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-14
• Study Completion Date: 2020-06-05

Brief Summary

This phase II trial studies how well HIF-2 alpha inhibitor PT2385 works in treating patients with recurrent glioblastoma. HIF-2 alpha inhibitor PT2385 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the efficacy of hypoxia inducible factor (HIF)-2 alpha inhibitor PT2385 (PT2385) as measured by radiographic response rate (by Response Assessment in Neuro-Oncology, RANO, criteria) in patients with recurrent glioblastoma.

SECONDARY OBJECTIVES:

I. To estimate the efficacy of PT2385 as measured by progression free and overall survival in patients with recurrent glioblastoma.

II. To determine the safety of oral PT2385 in patients with recurrent glioblastoma.

TERTIARY OBJECTIVES:

I. To describe the pharmacokinetic and pharmacodynamic properties of PT2385 in patients with recurrent glioblastoma.

II. To describe baseline intratumoral hypoxia using novel, advanced magnetic resonance (MR)-based neuroimaging sequences in patients with recurrent glioblastoma.

III. To explore genetic polymorphisms involved in the metabolism of PT2385.

OUTLINE:

Patients receive HIF-2 alpha inhibitor PT2385 orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years and every 6 months thereafter.

Conditions

Recurrent Glioblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (HIF-2 alpha inhibitor PT2385)

Patients receive HIF-2 alpha inhibitor PT2385 PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Pharmacological Study

Laboratory Biomarker Analysis

Pharmacogenomic Study

Group Type: EXPERIMENTAL

HIF-2alpha Inhibitor PT2385

Intervention Type: DRUG

Given PO

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacogenomic Study

Intervention Type: OTHER

Correlative studies

Interventions

HIF-2alpha Inhibitor PT2385

Given PO

Intervention Type: DRUG

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Pharmacogenomic Study

Correlative studies

Intervention Type: OTHER

Other Intervention Names

HIF-2alpha Inhibitor PT2385, PT2385; PHARMACOGENOMIC, Pharmacogenomic Study

Eligibility Criteria

Inclusion Criteria

• • Patients must have histologically confirmed glioblastoma that is progressive or recurrent following radiation therapy and temozolomide according to the Response Assessment in Neuro-Oncology (RANO) criteria with:

• New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids
• Increase by >= 25% in the sum of the products of perpendicular diameters between the postradiotherapy scan with the smallest tumor measurement and a scan at least 12 weeks from completion of radiation therapy (RT) + temozolomide (TMZ), on stable or increasing doses of corticosteroids

** Note: clinical deterioration not attributable to concurrent medication or comorbid conditions is sufficient to declare progression on current treatment but not for entry onto a clinical trial for recurrence

• Tumor O(6)-methylguanine-DNA-methyltransferase (MGMT) methylation status must be available; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction, (MSPCR), or quantitative polymerase chain reaction (PCR)) are acceptable
• Patients must have a tumor tissue form indicating availability of archived tissue from a previous surgery for glioblastoma, completed and signed by a pathologist
• Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment
• Patients must be able to undergo MRI of the brain with gadolinium; patients must be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI
• Patients must be in first recurrence of glioblastoma following radiation therapy and temozolomide
• Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
• 12 weeks from the completion of radiation
• 6 weeks from a nitrosourea chemotherapy
• 3 weeks from a non-nitrosourea chemotherapy
• 4 weeks from any investigational (not Food and Drug Administration (FDA)-approved) agents
• 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)

• Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
• Absolute neutrophil count >= 1,500/microliter (mcL)
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT))/ alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 4 x institutional upper limit of normal
• Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73m^2 for patients with creatinine levels above institutional normal
• Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
• Patients must be able to provide written informed consent
• Women of childbearing potential must have a negative serum pregnancy test prior to study start; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 30 days after the last dose of study drug
• Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years
• Patients must be able to swallow tablets

Exclusion Criteria

• • Patients receiving any other investigational agents are ineligible

• Patients must not have received prior anti- Vascular endothelial growth factor (VEGF) therapy including bevacizumab (i.e. patients must be bevacizumab naive)
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to PT2385 are ineligible
• Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of PT2385
• Patients with a history of bleeding diathesis are ineligible
• Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with PT2385
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible due to potential drug-drug interactions with PT2385

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

INDUSTRY

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roy Strowd, MD

Role: STUDY_CHAIR

Wake Forest /ABTC

Locations

UAB Comprehensive Cancer Center

Birmingham, Alabama, United States

Jonsson Comprehensive Cancer Center at UCLA

Los Angeles, California, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, United States

Henry Ford Hospital

Detroit, Michigan, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, United States

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States

Abrams Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

Countries

United States

References

Strowd R, Ellingson B, Raymond C, Yao J, Wen PY, Ahluwalia M, Piotrowski A, Desai A, Clarke JL, Lieberman FS, Desideri S, Nabors LB, Ye X, Grossman S. Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma. J Neurooncol. 2023 Oct;165(1):101-112. doi: 10.1007/s11060-023-04456-7. Epub 2023 Oct 21.

Reference Type: DERIVED

PMID: 37864646 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB00132128

Identifier Type: OTHER

Identifier Source: secondary_id

UM1CA137443

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ABTC 1602

Identifier Type: -

Identifier Source: org_study_id