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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.

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.

Arms

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.

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.

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.

Interventions

Drug: - Letrozole Oral Tablet

Administration: Letrozole will be given orally once daily.

Drug: - Temozolomide

50 mg/m2 TMZ administered orally once daily