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

Single-Arm, Open-Label Phase II Efficacy Study of First-in-Class HIF-2 Alpha Inhibitor, PT2385, for Patients With Recurrent Glioblastoma

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Glioblastoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Pharmacogenomic Study; Drug: HIF-2alpha Inhibitor PT2385

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3410
      • UAB Comprehensive Cancer Center
  • California
    • Los Angeles, California, United States, 90095
      • Jonsson Comprehensive Cancer Center at UCLA
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Abrams Cancer Center of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Hillman Cancer Center at University of Pittsburgh Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Pharmacogenomic Study; Correlative studies; Other Names: PHARMACOGENOMIC, Pharmacogenomic Study; Drug: HIF-2alpha Inhibitor PT2385; Given PO; Other Names: HIF-2alpha Inhibitor PT2385, PT2385

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Radiographic Response as Assessed by the RANO Criteria	Tumor radiographic response assessed by Response Assessment in Neuro-Oncology (RANO) criteria.; Complete Response (CR) = no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR) = ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD) = <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD) = ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS (in months) will be estimated using Kaplan-Meier method along with 95% confidence interval. Definition of PFS is date treatment started to the date of progression.	Assessed up to 2 years
Overall Survival	Overall survival (in months) will be estimated using Kaplan-Meier method along with 95% confidence interval.	From the date of treatment start to the date of death occurrence/or censored at the time of last known alive, assessed up to 2 years
Incidence of Grade 3 and Grade 4 Adverse Events	Number of participants experiencing grade 3 and grade 4 adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	Up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (Cmin) for PT2385	Minimum concentration (Cmin) on Day 15 of cycle 1.; Cycle 1, Week 1, Day 1, Pre-dose 1: within 15 minutes prior to dose; Cycle 1, Week 1, Day 1, 6 Hours Post-dose 1: 6 hours +/- 15 minutes post-dose; Cycle 1, Week 3, Day 15, Pre-dose 1: within 30 minutes prior to dose	Day 15 cycle 1
Pharmacokinetics for PT2385 Drug Exposure	Drug exposure levels in 3 groups: Cmin >1000ng/mL; Cmin: 300-1000 ng/mL and Cmin <300ng/mL	Day 15 cycle 1
Determine Association Between Baseline Tumor Acidity and PT2385 (Imaging)	Baseline Tumor acidity was measured using pH-weighted amine chemical exchange saturation transfer (CEST) MRI contrast on the Magnetic Resonance Imaging R^2 = "reversible transverse relaxation rate" (and is proportional to oxygen extraction and thus hypoxia). MTR = MTRasym "the asymmetry in the magnetization transfer ratio at 3ppm from water" (and it is a surrogate of tumor acidity (MTR) pH quantitative measure of the acidity or basicity (pH) of aqueous or other liquid solutions. Lower pH values correspond to solutions which are more acidic in nature, while higher values correspond to solutions which are more basic or alkaline. Exp = exposure Acid = Acidity Perit Tiss = Peritumoral Tissue Enh Tum = Enhancing Tumor DurTx = Duration treatment	At baseline

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI); Peloton Therapeutics, Inc.
• Investigators: Study Chair: Roy Strowd, MD, Wake Forest /ABTC

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 14, 2017
• Primary Completion (ACTUAL): August 31, 2019
• Study Completion (ACTUAL): June 5, 2020

Study Registration Dates

• First Submitted: July 11, 2017
• First Submitted That Met QC Criteria: July 11, 2017
• First Posted (ACTUAL): July 13, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 9, 2022
• Last Update Submitted That Met QC Criteria: May 5, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence
• Other Study ID Numbers: ABTC 1602; UM1CA137443 (U.S. NIH Grant/Contract); IRB00132128 (OTHER: JHM IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No