Evaluation of Eflornithine Plus Temozolomide in Patients With Newly Diagnosed Glioblastoma

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

Detailed Description
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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 56 weeks in total per patient: Screening Period - A maximum screening duration of 4 weeks. Treatment Period - Up to 48 weeks. Follow-Up Visit - 4 weeks 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).

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

Conditions
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Glioblastoma, IDH-wildtype, Glioblastoma, Glioblastoma Multiforme, Glioblastoma IDH (Isocitrate Dehydrogenase) Wildtype, GBM

Intervention / Treatment
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* Drug: Eflornithine (Dose Level 1)
* Drug: Eflornithine (Dose Level 2)
* Drug: Eflornithine (Dose Level -1)
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of World Health Organization (WHO) G4 classified GBM, IDH-wildtype per WHO 2021 tumor classification. Completed external beam radiation therapy per standard of care. Must have received at least 80% of planned daily doses of TMZ during chemoradiation. 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 for GBM other than temozolomide during external beam radiation therapy. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eflornithine Dose Level 1 + Temozolomide<br> | Drug: Eflornithine (Dose Level 1)<br>* Eflornithine 2.3 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule<br>* Other names: DFMO;Drug: Temozolomide<br>* 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<br>* Other names: TMZ;|
| Experimental: Eflornithine Dose Level 2 + Temozolomide<br> | Drug: Eflornithine (Dose Level 2)<br>* Eflornithine 2.8 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule<br>* Other names: DFMO;Drug: Temozolomide<br>* 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<br>* Other names: TMZ;|
| Experimental: Eflornithine Dose Level -1 + Temozolomide<br> | Drug: Eflornithine (Dose Level -1)<br>* Eflornithine 1.75 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule<br>* Other names: DFMO;Drug: Temozolomide<br>* 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<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Dose Limiting Toxicities | Protocol Defined Dose Limiting Toxicities | 8 weeks | 
| Incidence of TEAEs All Grades | All Grades | 52 weeks | 
| Incidence of TEAEs Grade 3+ | Grade 3+ | 52 weeks | 
| Incidence of TEAEs Serious | Serious | 52 weeks | 
| Incidence of TEAEs Leading to Discontinuation | Leading to Discontinuation | 48 weeks | 
| Vital Signs (Heart and Respiratory Rate) | Change from Baseline in Heart Rate and Respiratory Rate | 52 weeks | 
| Vital Signs (Blood Pressure) | Change from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | 52 weeks | 
| Incidence of Treatment-Emergent Abnormalities in Clinical Laboratory Tests | Lab abnormalities by CTCAE v5.0 Grade | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Per RANO Criteria as assessed by MRI | 52 weeks | 
| Overall Response Rate | Per RANO Criteria as assessed by MRI | 52 weeks | 
| Pharmacokinetics Cmax | observed maximum concentration | Baseline to Steady State (2 weeks) | 
| Pharmacokinetics Cmin | observed minimum concentration | Baseline to Steady State (2 weeks) | 
| Pharmacokinetics Tmax | time of observed maximum concentration | Baseline to Steady State (2 weeks) | 
| Pharmacokinetics AUCt | area under the concentration-time curve | Baseline to Steady State (2 weeks) | 
| Pharmacokinetics lambdaz | elimination rate constant | Baseline to Steady State (2 weeks) | 
| Pharmacokinetics t 1/2 | elimination half life | Baseline to Steady State (2 weeks) | 
| QTcF-Concentration Relationship | Assessment of change in QTcF relative to plasma concentration of eflornithine | Baseline to Steady State (2 weeks) | 
| Assessment of QTcF | Change from baseline in QTcF | Baseline to Steady State (2 weeks) |