Evaluation of Eflornithine Plus Temozolomide in Patients With Newly Diagnosed Glioblastoma or Astrocytoma

Official title

An Open-label, Phase 1b Study to Evaluate the Safety and Tolerability of Eflornithine Plus Temozolomide in Patients With Newly Diagnosed Glioblastoma or Astrocytoma

Overview

The purpose of this study is to establish the recommended phase 2 dose of eflornithine in combination with temozolomide in patients whose glioblastoma or astrocytoma is newly diagnosed, and to evaluate safety and tolerability of this combination at that dose.

Detailed description

This open label dose escalation and expansion study will be conducted using a standard dose-escalation design with escalating doses of eflornithine plus temozolomide at the approved dose level, followed by an expansion cohort that will further evaluate safety and preliminary efficacy of the combination at the recommended phase 2 dose.

Duration of participation will be up to approximately 104 weeks in total per patient.

Screening Period - A maximum screening duration of 4 weeks.

Treatment Period - Up to approximately 104 weeks.

Follow-Up Visit - 4 weeks from last treatment.

Long-term Survival Follow-Up - up to 2 years from last treatment.

A total of up to 66 patients will be enrolled in a non-randomized fashion (patients may be added to any of the dose levels below the RP2D to a maximum of approximately 20 per dose level with the intent of further characterizing safety and pharmacokinetics).

Interventions

• Drug Eflornithine (Dose Level 1)
  Eflornithine 2.3 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Drug Eflornithine (Dose Level 2)
  Eflornithine 2.8 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Drug Eflornithine (Dose Level -1)
  Eflornithine 1.75 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Drug Temozolomide
  Temozolomide 150 mg/m2 (with option to escalate per USPI maintenance phase instructions) administered orally once daily on a 5 days on, 23 days off schedule

Primary outcome measures

• Assessment of Dose Limiting Toxicities [Time frame: 8 weeks]
• Incidence of TEAEs All Grades [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Incidence of TEAEs Grade 3+ [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Incidence of TEAEs Serious [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Incidence of TEAEs Leading to Discontinuation [Time frame: From enrollment to the end of treatment]
• Vital Signs (Heart and Respiratory Rate) [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Vital Signs (Blood Pressure) [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Incidence of Treatment-Emergent Abnormalities in Clinical Laboratory Tests [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]

Secondary outcome measures (11)

• Overall Survival [Time frame: From enrollment to up to 2 years after last dose]
• Progression Free Survival [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Overall Response Rate [Time frame: From enrollment to the follow-up visit 4 weeks after end of treatment]
• Pharmacokinetics Cmax [Time frame: Baseline to Steady State (2 weeks)]
• Pharmacokinetics Cmin [Time frame: Baseline to Steady State (2 weeks)]
• Pharmacokinetics Tmax [Time frame: Baseline to Steady State (2 weeks)]
• Pharmacokinetics AUCt [Time frame: Baseline to Steady State (2 weeks)]
• Pharmacokinetics lambdaz [Time frame: Baseline to Steady State (2 weeks)]
• Pharmacokinetics t 1/2 [Time frame: Baseline to Steady State (2 weeks)]
• QTcF-Concentration Relationship [Time frame: Baseline to Steady State (2 weeks)]
• Assessment of QTcF [Time frame: Baseline to Steady State (2 weeks)]

Eligibility criteria

Inclusion criteria

• Diagnosis of World Health Organization (WHO) G4 classified GBM, IDH-wildtype (patients with GBM) or G3 astrocytoma (IDH1 or 2 mutant; CDKN2A/B intact) per WHO 2021 tumor classification.
• Completed external beam radiation therapy per standard of care.
• Patients with GBM: Must have received at least 80% of planned daily doses of TMZ during chemoradiation. Patients with astrocytoma: Must have tolerated adjuvant TMZ treatment through at least 2 and not more than 4 cycles.
• Adequate hematologic, renal, hepatic, and other organ function as indicated by hematology and serum chemistry testing.
• Willing to abstain from intercourse or use acceptable contraceptive methods.
• If taking corticosteroids, must be on a stable or decreasing dose.

Exclusion criteria

• Recent history of recurrent or metastatic cancer that could confound response assessments
• Prior systemic chemotherapy other than temozolomide during external beam radiation therapy (for patients with GBM) or adjuvant temozolomide through up to 4 pre-study cycles (for patients with astrocytoma).
• Prior Optune treatment.
• Active infection or serious intercurrent medical illness.
• Poorly controlled seizures.
• Significant cardiac disease within 6 months of enrollment.
• Poorly controlled diabetes.
• Use of another investigational agent within 30 days of enrollment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 8 centers

• University of Alabama at Birmingham — Birmingham
• Henry Ford Hospital — Detroit
• Columbia University Medical Center - Herbert Irving Pavilion — New York
• Duke University — Durham
• The Cleveland Clinic — Cleveland
• Brown University Health/Rhode Island Hospital — Providence
• UT MD Anderson Cancer Center — Houston
• University of Utah, Huntsman Cancer Institute — Salt Lake City

Identifiers

NCT: NCT05879367 · OT-21-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗