Study of Letrozole in Recurrent Gliomas

A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination With Standard Therapy in Recurrent High Grade Gliomas

The purpose of this study is to determine the ability of letrozole to penetrate the blood brain barrier and concentrate in gliomas.

Study Overview

• Status: Recruiting
• Conditions: Brain Tumor
• Intervention / Treatment: Drug: Letrozole Oral Tablet; Drug: Temozolomide

Detailed Description

Nine to forty-two (42 patients only if every cohort required expansion) total patients were planned for the main BN-16-01 phase 0/1 study to explore the ability of letrozole to penetrate the blood brain barrier and gliomas. As of November 2023 The BN-16-01 main study has completed active recruitment (20 subjects were accrued) and all safety and pharmacokinetics data have been analyzed with subsequent publications pending. Characterization of the safety and pharmacokinetics of letrozole in combination with standard of care treatments, such as TMZ has been completed for the main study and provides the rationale for initiation of a sub-study.

A new sub-study "Letrozole and Temozolomide" expansion cohort has been opened to accrual. This Phase 1 expansion cohort of letrozole 15mg administered in combination with 50 mg/m2 metronomic temozolomide (TMZ) in patients with high grade gliomas. 19 subjects total (2 historical subjects from the main study and 17 new accruals) will be enrolled into this expansion cohort.

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: UC Cancer Center Clinical Trials Office; Phone Number: 513-584-7698; Email: cancer@uchealth.com

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Recruiting
      • University of Cincinnati
      • Contact: Trisha Wise-Draper, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Radiographically, histologically or cytologically confirmed recurrent brain high grade glioma with plan for resection or biopsy.

   - Inclusion #1 for Sub-study Only: Radiographically, histologically or cytologically confirmed recurrent brain high grade glioma.

2. Age >18 years.
3. ECOG performance status 0 -2 (Karnofsky >60%, see Appendix A).

4. CBC/differential obtained within 28 days prior to registration on study, with adequate bone marrow function defined as follows:

   • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;
   • Platelets ≥ 100,000 cells/mm3;
   • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable).

5. Adequate hepatic function, defined as follows:

   • Total bilirubin < 2 x institutional ULN within 14 days prior to registration;
   • AST or ALT < 3 x institutional ULN within 14 days prior to registration.
6. Adequate renal function, defined as GFR > 30 ml/min or Cr < 1.5.
7. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential.
8. Imaging prior to treatment including MRI of brain (with contrast preferred but not required).
9. Ability to understand and the willingness to sign a written informed consent document.
10. Inclusion #10 for Sub-study Only: Measurable disease per RANO criteria within 28 days of starting treatment on this study.

Exclusion Criteria

1. Patients may not be receiving any other investigational agents.

2. History of allergic reactions attributed to letrozole or other agents used in study.

   Exclusion #2 for Sub-study Only: History of allergic reactions attributed to letrozole or TMZ.

3. Uncontrolled intercurrent illness including, but not limited to, ongoing significant or serious active cardiovascular disease (CHF exacerbation, unstable angina or MI in last 6 months), or infection including the diagnosis of AIDS or active hepatitis B or C infection, or psychiatric illness or medical or personal conditions that in the opinion of the investigator would limit the patient's ability to participate.
4. Patients attempting to conceive, and pregnant or nursing women are excluded from this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letrozole; The BN-16-01 main study treatment starting dose will be 2.5mg administered orally once daily. Daily doses up to 10mg and single doses of 30mg have been shown to be safe in prior studies and therefore we expect that letrozole doses up to 20mg in this study will be safe. The recommended phase II dose (RP2D) will be considered the dose that results in ≥ 2uM letrozole concentration in the tumor or the highest dose achieved (20mg daily for cohort level 7) with < 2/6 patients with DLTs. This dose will be planned for future phase II studies to determine potential efficacy.	Drug: Letrozole Oral Tablet; Administration: Letrozole will be given orally once daily.; Other Names: Femara
Experimental: Letrozole and temozolomide; Phase 1 expansion cohort of letrozole 15mg administered in combination with 50 mg/m2 metronomic temozolomide (TMZ) in patients with high grade gliomas. Letrozole 15mg will be administered orally once daily for a 7-day lead-in period. After 7 days subjects will continue letrozole in combination 50 mg/m2 TMZ administered orally once daily.	Drug: Letrozole Oral Tablet; Administration: Letrozole will be given orally once daily.; Other Names: Femara; Drug: Temozolomide; 50 mg/m2 TMZ administered orally once daily; Other Names: Temodar
Experimental: Previously Received letrozole and temozolomide; Phase 1 expansion cohort of two identified subjects with gliomas who previously participated in the main study UCCI-BN-16-01 who received as physician's choice of treatment 50 mg/m2 TMZ in combination with dosing of 15 mg letrozole.	Drug: Letrozole Oral Tablet; Administration: Letrozole will be given orally once daily.; Other Names: Femara; Drug: Temozolomide; 50 mg/m2 TMZ administered orally once daily; Other Names: Temodar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Letrozole AUC in tumor tissue.	Pharmacokinetic modeling will be used to determine the overall AUC in the tumor tissue to assess for letrozole penetration through blood brain barrier.	5 days
Progression free survival in letrozole and temozolomide combination	Sub-study expansion cohort only: Progression free survival using RANO criteria at 6 months from the start of the combination of 15 mg letrozole and 50 mg/m2 temozolomide.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	The number of patients with treatment related toxicity will be assessed using CTCAE v4.0	The time patients remain on treatment until 30 days after treatment completed
Progression free Survival	Patients will be followed for response using RANO criteria to determine time from start of treatment to progression.	From start of treatment until time of progression assessed up to 1 year
Overall Survival	Patients will be followed from start of treatment until time of death	From start of treatment until time of death assessed up to 1 year

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Investigators: Principal Investigator: Trisha Wise-Draper, MD, PhD, University of Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2017
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: April 10, 2017
• First Submitted That Met QC Criteria: April 17, 2017
• First Posted (Actual): April 20, 2017

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Alkylating; Alkylating Agents; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Temozolomide; Letrozole
• Other Study ID Numbers: UCCI-BN-16-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No