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

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).

• Eflornithine (Dose Level 1) (Drug), also known as DFMO: Eflornithine 2.3 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Eflornithine (Dose Level 2) (Drug), also known as DFMO: Eflornithine 2.8 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Eflornithine (Dose Level -1) (Drug), also known as DFMO: Eflornithine 1.75 g/m2 administered orally every 8 hours on a 2 weeks on, 2 weeks off schedule
• Temozolomide (Drug), also known as Temodar, TMZ: 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 outcomes

• Assessment of Dose Limiting Toxicities [8 weeks]: Protocol Defined Dose Limiting Toxicities
• Incidence of TEAEs All Grades [From enrollment to the follow-up visit 4 weeks after end of treatment]: All Grades
• Incidence of TEAEs Grade 3+ [From enrollment to the follow-up visit 4 weeks after end of treatment]: Grade 3+
• Incidence of TEAEs Serious [From enrollment to the follow-up visit 4 weeks after end of treatment]: Serious
• Incidence of TEAEs Leading to Discontinuation [From enrollment to the end of treatment]: Leading to Discontinuation
• Vital Signs (Heart and Respiratory Rate) [From enrollment to the follow-up visit 4 weeks after end of treatment]: Change from Baseline in Heart Rate and Respiratory Rate
• Vital Signs (Blood Pressure) [From enrollment to the follow-up visit 4 weeks after end of treatment]: Change from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure
• Incidence of Treatment-Emergent Abnormalities in Clinical Laboratory Tests [From enrollment to the follow-up visit 4 weeks after end of treatment]: Lab abnormalities by CTCAE v5.0 Grade

Secondary outcomes

• Overall Survival [From enrollment to up to 2 years after last dose]: Until death or initiation of new anticancer therapy
• Progression Free Survival [From enrollment to the follow-up visit 4 weeks after end of treatment]: Per RANO Criteria as assessed by MRI
• Overall Response Rate [From enrollment to the follow-up visit 4 weeks after end of treatment]: Per RANO Criteria as assessed by MRI
• Pharmacokinetics Cmax [Baseline to Steady State (2 weeks)]: observed maximum concentration
• Pharmacokinetics Cmin [Baseline to Steady State (2 weeks)]: observed minimum concentration
• Pharmacokinetics Tmax [Baseline to Steady State (2 weeks)]: time of observed maximum concentration
• Pharmacokinetics AUCt [Baseline to Steady State (2 weeks)]: area under the concentration-time curve
• Pharmacokinetics lambdaz [Baseline to Steady State (2 weeks)]: elimination rate constant
• Pharmacokinetics t 1/2 [Baseline to Steady State (2 weeks)]: elimination half life
• QTcF-Concentration Relationship [Baseline to Steady State (2 weeks)]: Assessment of change in QTcF relative to plasma concentration of eflornithine
• Assessment of QTcF [Baseline to Steady State (2 weeks)]: Change from baseline in QTcF

Sex: All, ages: 18 Years to any

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.

• Howard Colman, MD, PhD, Principal investigator, Huntsman Cancer Institute