Endometrioid Endometrial Cancer
Conditions
Keywords
Narazaciclib, ON 123300, letrozole
Brief summary
This study will assess the safety and efficacy of increasing doses of narazaciclib (ON 123300) in combination with the standard daily dose (2.5mg) of letrozole in patients with Recurrent Metastatic Low-grade Endometrioid Endometrial Cancer and other Gynecologic Malignancies.
Detailed description
This is a phase 1/2a, open-label, multicenter study to evaluate the safety, tolerability and efficacy of escalating doses of narazaciclib (ON 123300) in combination with letrozole for patients with recurrent metastatic low-grade endometrioid endometrial cancer and other Gynecologic Malignancies. Pharmacokinetics and pharmacodynamics will also be assessed. In Phase 1, eligible patients will be enrolled to escalating dose cohorts. Cohorts will receive escalating doses of oral narazaciclib starting at 160 mg orally, once daily, in combination with letrozole 2.5 mg orally, once daily, in 28-day cycles in a typical 3 + 3 design. The dose of narazaciclib will be increased in 40 mg/day increments from cohort to cohort until the maximum tolerated dose (MTD) and/or the minimal biologically effective dose (MBED) of narazaciclib orally, once daily, in combination with letrozole 2.5 mg orally, once daily, is reached and the RP2D of the combination is established. Three to 6 patients will be enrolled per dose cohort in phase 1. In Phase 2a, narazaciclib and letrozole at the RP2D established in Phase 1 will be administered to approximately 30 eligible patients with documented recurrent metastatic LGEEC for 28-day cycles. Treatment will continue until disease progression, patient withdrawal, or unacceptable drug-related toxicity.
Interventions
DRUGNarazaciclib
Orange tablets, each containing 40 mg or 120 mg of narazaciclib as narazaciclib monolactate
DRUGLetrozole 2.5mg
Tablet
Sponsors
Traws Pharma, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1: 3+3 dose escalation Phase2: Expansion cohort
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must be 18 years of age, or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing informed consent form (ICF). 2. Phase 1 (Dose escalation cohorts): Have confirmed endometrial or other gynecologic malignancy that is amenable for treatment with hormonal therapy and do not have other standard treatment options. (Patients with endometrioid and other types of uterine cancer as well as ovarian cancers may be enrolled at the Investigator's discretion if hormonal based therapy is considered an appropriate option for the patient). OR Phase 2a (Dose expansion cohort): Have confirmed low-grade (Federation of Gynaecology and Obstetrics \[FIGO\] Grade 1 or 2) endometrioid endometrial cancer (LGEEC). Mixed tumor histology is allowed if the non-endometrioid component is \<5%. 3. Recurrent metastatic disease or advanced (Stage IV) disease. 4. Phase 1 (Dose escalation cohorts): Patients may be enrolled regardless of prior checkpoint inhibitor therapy, at the Investigator's discretion. OR Phase 2a (Dose expansion cohort): Have received prior checkpoint inhibitor therapy (single agent or in combination with another anti-cancer therapy) if available for this indication and NOT contraindicated. 5. Phase 1 (Dose escalation cohorts): Patients may be enrolled who have not received prior therapy for recurrent/metastatic disease, or have received any number of prior lines of therapy for recurrent/metastatic disease, at the Investigator's discretion. OR Phase 2a (Dose expansion cohort): Have received 1 or 2 prior lines of systemic therapy for metastatic disease. Patient has NOT received more than 2 prior lines of systemic therapy for metastatic LGEEC (including checkpoint inhibitor, hormone therapy, or chemotherapy). Prior external beam radiotherapy, brachytherapy, and/or surgery for localized disease is allowed and is not counted as a line of therapy. 6. Phase 1 (Dose escalation cohorts): Have either measurable or non- measurable disease. OR Phase 2a (Dose expansion cohort): Have measurable disease outside the radiated field. 7. Local mismatch repair (MMR) immunohistochemistry (IHC) results available (both deficient mismatch repair (dMMR) and mismatch repair protein (MMRP) deficiency (MMRp) patients are eligible, and will be documented for research purposes). 8. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 9. Tissue for estrogen/progesterone receptor status and molecular classification (paraffin embedded or fresh biopsy if unavailable). 10. Have adequate organ function as indicated by the following: 1. Absolute neutrophil count (ANC) ≥1.0×109/L 2. Platelets ≥100×109/L 3. Hemoglobin ≥9.0 g/dL 4. International Normalized Ratio (INR) ≤1.5 5. Serum creatinine ≤1.5 times ULN, or estimated creatinine clearance (calculated according to normal institutional practice) greater than 50 milliliters (ml)/min 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) below 3.0×the upper limit of normal (ULN) (or ALT and AST ≤5×ULN if liver metastases are present). 7. Total serum bilirubin \<1.5×ULN; or total bilirubin ≤3.0×ULN with direct bilirubin within normal range of the central laboratory in participants with well documented Gilbert's Syndrome. 11. Have baseline corrected QT (QTc) interval \<470 msec. 12. Are able to swallow oral medications. 13. Have a life expectancy of at least 12 weeks 14. Sex and Contraceptive/Barrier Requirements a) Are postmenopausal, defined as: i) Patient's last menstrual period occurred more than 12 months prior to screening without any alternative medical cause, and ii) Patient's postmenopausal status is confirmed by screening serum follicle-stimulating hormone concentration of \>40 milli-International unit/ml (mIU/mL); or iii) Patient has undergone surgical sterilization (bilateral oophorectomy and/or hysterectomy) OR b) Must have a negative pregnancy test at screening and upon study entry (Cycle 1 Day 1) if not postmenopausal and c) Contraceptive use must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies if not postmenopausal. Patients under 55 years with intact ovaries will undergo hormonal verification. 15. Are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
1. Phase 1 (Dose escalation cohorts): Cancer other than endometrial or other gynecologic malignancy. OR Phase 2a (Dose expansion cohort): Non-low-grade EEC (not FIGO Grades 1 or 2) or non-endometrioid adenocarcinoma, sarcoma, small cell carcinoma with neuroendocrine differentiation, or non-epithelial cancers as
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities (DLTs) will be tabulated and summarized by cohort | From First dose until end of Cycle 1 (28 days) | Number of DLTs per cohort |
| Phase 2 - Progression-free survival (PFS) at 24 weeks by Investigator assessment | Measured from first dose until 24-weeks | Progression or other status determined by RECIST assessment |
| Treatment-emergent adverse events (TEAEs), including DLTs will be graded by CTCAE v5.0 | From first dose until 30 days after final dose, up to approximately 1 year | Percentage of patients experiencing TEAEs, by system organ class (SOC) and preferred term |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median PFS by Investigator assessment | Measured from first dose until diagnosis of progression including 2 years of follow-up after discontinuation of treatment. | Time from first dose to progression by RECIST assessment. A Kaplan-Meier curve will be provided. |
| Complete response (CR) rate | From first dose until occurrence of response or progression, up to 1 year | Percentage of patients achieving a CR by RECIST |
| Partial response (PR) rate | From first dose until occurrence of response or progression, up to 1 year | Percentage of patients achieving a PR by RECIST |
| Overall response rate (ORR equals CR + PR) | From first dose until occurrence of response or progression, up to 1 year | Percentage of patients achieving a CR or PR by RECIST |
| PFS at 16 weeks by Investigator assessment | Measured from first dose until 16-weeks | Progression or other status determined by RECIST assessment |
| Disease control rate (DCR equals CR+PR+SD) | From first dose until occurrence of response or progression, up to 1 year | Percentage of patients achieving a CR or PR or maintaining SD by RECIST |
| Duration of response (DoR) | From time of response until progression, up to approximately 1 year | Time from definition of response to diagnosis of progression. A Kaplan-Meier curve will be provided. |
| Time to response (TTR) | From first dose until response or progression, up to approximately 1 year. | Time from first dose until definition of response. A Kaplan-Meier curve will be provided. |
| Median overall survival (mOS) | From time of first dose until 2 years after end of treatment (Up to approximately 3 years). | Time from first dose until death from any cause. A Kaplan-Meier curve will be provided. |
| Stable disease (SD) rate | From first dose until occurrence of response or progression, up to 1 year | Percentage of patients maintaining SD by RECIST |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum plasma concentration of drug (Cmax) | Samples will be collected a predose through 24 hours post dose on Days 1 and 8, then pre-dose on Cycle 2 Day 1 and Cycle 3 Day 1 | Highest concentration of drug measured in the PK samples |
| PK: Area under the concentration-time curve (AUC) from time 0 to time of last quantifiable sample (AUC0-t) | Samples will be collected a predose through 24 hours post dose on Days 1 and 8, then pre-dose on Cycle 2 Day 1 and Cycle 3 Day 1 (each cycle is 28 days) | The area under the concentration-time curve from dosing (time 0) to time t. |
| PK: Time to reach Cmax (Tmax) | Samples will be collected a predose through 24 hours post dose on Days 1 and 8, then pre-dose on Cycle 2 Day 1 and Cycle 3 Day 1 (each cycle is 28 days) | Time from dosing until collection of the PK samples with the highest drug concentration. |
| Measurement of tyrosine kinase activity (TKa) levels in serum | Samples will be collected at Screening, Days, 1, 8, 15, 22, 29, then monthly until end of treatment, up to approximately 1 year | Tyrosine kinase 1 (TK1) is a metabolic enzyme fundamentally involved in DNA synthesis that plays a critical role in cell proliferation |
Countries
United States
Contacts
Primary ContactVictor Moyo, MD
Outcome results
None listed