Symptoms and General Pathology

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Polycystic Ovary Syndrome

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Reproductive Control Agents

Letrozole

Progesterone

Chorionic Gonadotropin

Aromatase Inhibitors

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Hormones

Hormone Antagonists

Progestins

Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7.Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is \>17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination. No supplemental progesterone therapy in luteal phase

Letrrozole 2.5 to 5 mg oral tablet cycle day 3-7. Pelvic ultrasound at cycle day 11 or 12 and repeat if needed until leading follicle is \>17 mm. Ovidrel 250 mcg injected sq. Timed intercourse or intrauterine insemination.Crinone 8% (progesterone) vaginal therapy was provided in luteal phase for 14 days .Administration was started the second day after intrauterine insemination or timed intercourse.

progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.

Progesterone Vaginal Gel 8%

letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction

Letrozole Oral Tablet

pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is \>17 mm in diameter

pelvic ultrasound

ovidrel 250 mcg given when leading follicle size is \> 17 mm in diameter

Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe

Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel

Intrauterine insemination or timed intercourse

Laurel A Stadtmauer, MD, PhD

Aromatase inhibitors such as letrozole are hypothesized to maintain normal hypothalamic/ pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS, may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen levels. Letrozole also may act to increase midluteal P levels presumably by induction of follicles and corpora lutea. The investigators are asking the question whether P supplementation with Crinone (8%) may have an additive beneficial effect on endometrial development in those women taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented to be significantly higher than serum levels after vaginal administration which may lead to higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There have been retrospective studies showing progesterone supplementation seems to benefit both CC and letrozole treatment groups. In fact, this study showed the only pregnancies in the letrozole group were those in women who took P supplementation. However the number of cycles studied was small. There is a place for a randomized controlled trial (RCT) to determine if luteal phase P supplementation with Crinone should be used in all women using letrozole for Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed Intercourse (TI). This is currently not done in all clinical practices.

Approval of the study was obtained from the local IRB. Prospective volunteers had had an infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline evaluation including ultrasound of ovaries and uterus performed as standard of care. If the results of these tests and the remaining Inclusion/Exclusion criteria were met, the study consent was reviewed with participants and signatures were obtained. Participants contacted the clinic at the start of their menses (spontaneous or progesterone-induced) to start the treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12 and repeated if needed to determine response until at least 1 follicle with mean diameter \> 17mm in size was observed. When the appropriate follicle size was reached, participants were randomized into one of the two treatment groups as determined by a randomization table, and Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on day 21, the participant was considered a letrozole failure, the cycle was stopped, and the participant was dropped from the study and was not included in subsequent cycles.

IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the participant was randomized to progesterone (Crinone), the luteal phase was supplemented once daily with vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any pregnancies occurring in either treatment group were followed for delivery outcomes. Information regarding the delivery (induced, vaginal, cesarean section), date of birth, infant measurements (weight and length) and other important information regarding the infant's condition was obtained. Participants were allowed to undergo up to 3 cycles of letrozole as the pregnancy rates for the first 3 cycles have been shown to be similar. The participants were re-randomized each cycle. If the participant was pregnant, Crinone (8%) was continued until 10 weeks gestation in both groups.

Each participant was able to proceed with up to 3 cycles (consecutively, if desired) of OI over the next 6 months and was re-randomized each cycle.

Participants who met criteria were randomized to either Crinone vaginal therapy versus no therapy in the luteal phase of an ovulation induction cycle. Participants who did not achieve a pregnancy were able to participate in up to 3 cycles, and were re-randomized with each cycle.

Data analysis was completed by blinded observer who had access only to participant ID number, cycle number and treatment, and pregnancy outcome

Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole

"Supplementation of the Luteal Phase With Vaginal Progesterone (Crinone 8%) in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction With Letrozole: A Prospective and Randomized Controlled Trial

The primary endpoint of the trial is the Clinical Pregnancy Rate per cycle initiated

The secondary endpoint is the Live Birth Rate per cycle initiated (each cycle is 28 days)

Watson Pharmaceuticals

Eastern Virginia Medical School

Principal Investigator

Nervous System Diseases

Rare Diseases

Recurrence

Glioma

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

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.

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.

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.

Administration: Letrozole will be given orally once daily.

50 mg/m2 TMZ administered orally once daily

UC Cancer Center Clinical Trials Office

Trisha Wise-Draper, MD, PhD

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

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 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

Pharmacokinetic modeling will be used to determine the overall AUC in the tumor tissue to assess for letrozole penetration through blood brain barrier.

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.

The number of patients with treatment related toxicity will be assessed using CTCAE v4.0

Patients will be followed for response using RANO criteria to determine time from start of treatment to progression.

Patients will be followed from start of treatment until time of death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole	NCT03440359	Polycystic Ovar...	Progesterone Va... Letrozole Oral ... pelvic ultrasou... Ovidrel 250 MCG... Intrauterine in...	20 Years - 40 Years	Eastern Virginia Medical School
Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole	NCT03440359	Polycystic Ovar...	Progesterone Va... Letrozole Oral ... pelvic ultrasou... Ovidrel 250 MCG... Intrauterine in...	20 Years - 40 Years	Eastern Virginia Medical School
Study of Letrozole in Recurrent Gliomas	NCT03122197	Brain Tumor	Letrozole Oral ... Temozolomide	18 Years -	University of Cincinnati
Study of Letrozole in Recurrent Gliomas	NCT03122197	Brain Tumor	Letrozole Oral ... Temozolomide	18 Years -	University of Cincinnati

Spots Global Cancer Trial Database for letrozole oral tablet