Study of Narazaciclib (ON 123300) Plus Letrozole in Recurrent Metastatic Low-grade Endometrioid Endometrial Cancer
Study Details
Study Description
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 as second or third line treatment in patients with Recurrent Metastatic Low-grade Endometrioid Endometrial Cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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 as the second or third-line treatment for patients with recurrent metastatic low-grade endometrioid endometrial cancer. Pharmacokinetics and pharmacodynamics will also be assessed.
In Phase 1, eligible patients with documented recurrent metastatic LGEEC will be enrolled to escalating dose cohorts. Cohorts will receive escalating doses of daily 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Escalating daily doses of narazaciclib in combination with letrozole (2.5mg day) Phase 1: Initiating at 160mg per day of narazaciclib, patients will receive escalating doses of narazaciclib (oral capsules/once daily) in combination with 2.5mg of letrozole (oral tablet/once daily). Phase 2: All patients will receive the recommended phase 2 dose (RP2D) of the combination of narazaciclib (oral capsules) and letrozole (oral tablet/QD) |
Drug: Narazaciclib
Clear, hard, capsules, each containing 40 mg or 60 mg of narazaciclib as narazaciclib monolactate, which is a yellow/orange color
Other Names:
Drug: Letrozole 2.5mg
Tablet
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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
Secondary Outcome Measures
- PFS at 16 weeks by Investigator assessment [Measured from first dose until 16-weeks]
Progression or other status determined by RECIST assessment
- 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
- Stable disease (SD) rate [From first dose until occurrence of response or progression, up to 1 year]
Percentage of patients maintaining SD 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
- 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.
Other Outcome Measures
- 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: 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.
- PK: Terminal half-life (T1/2) [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 time required to divide the plasma concentration by two after reaching pseudo-equilibrium
- 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: AUC extrapolated to infinity (AUC0-∞) [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) extrapolated to infinity.
- PK: Clearance (CL) [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)]
A proportionality factor that relates the concentration of drug measured in the body to the rate of elimination
- PK: Volume of distribution at steady state (Vss) [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 apparent volume of distribution at steady state.
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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).
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Have confirmed low-grade, [Federation of Gynecology and Obstetrics (FIGO) Grade 1 or 2] endometrioid endometrial cancer (LGEEC). Mixed tumor histology is allowed if the non-endometrioid component is <5%.
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Recurrent metastatic disease or advanced (Stage IV) disease.
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Have received prior checkpoint inhibitor therapy (single agent or in combination with another anti-cancer therapy) if available for this indication and NOT contraindicated.
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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.
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Have measurable disease outside the radiated field.
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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).
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Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
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Tissue for estrogen/progesterone receptor status and molecular classification (paraffin embedded or fresh biopsy if unavailable).
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Have adequate organ function as indicated by the following:
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Absolute neutrophil count (ANC) ≥1.0×109/L
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Platelets ≥100×109/L
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Hemoglobin ≥9.0 g/dL
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International Normalized Ratio (INR) ≤1.5
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Creatinine clearance ≥60/mL, as estimated by Cockcroft-Gault equation
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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).
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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.
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Have baseline corrected QT (QTc) interval <470 msec.
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Are able to swallow oral medications.
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Have a life expectancy of at least 12 weeks
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Sex and Contraceptive/Barrier Requirements
- 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.
- 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:
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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 exclusion criteria.
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Have received a cyclin-dependent kinase (CDK) 4/6 inhibitor in the past.
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Have any significant medical condition, laboratory abnormality, or psychiatric illness that, in the opinion of the Investigator, would prevent the patient from participating in the study or present an unacceptable risk to the patient.
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Are at risk for Torsades de pointes (TdP): Patients who have a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >470 msec) using Fredericia's QT correction formula, or who have a history of additional risk factors for TdP (eg, heart failure, hypokalemia, family history of Long QT Syndrome), or who are currently taking medications that prolong the QT/QTc interval.
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Have uncontrolled intercurrent or significant medical illness, serious underlying medical condition, abnormal laboratory finding, or psychiatric illness/social situation that might, in the Investigator's or the Sponsor's judgment, prevent the participant from receiving study treatment or being followed in this study, or otherwise renders the participant inappropriate for the study, including but not limited to ongoing or active infection, bleeding, congestive heart failure, unstable angina, cardiac arrhythmia, oxygen-dependent lung disease, and psychiatric illness/social situations that limit participation compliance with study procedures and requirements.
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Are currently taking or within 5 half-lives of taking strong inducers and inhibitors of cytochrome P450 enzyme (CYP)2C8 and CYP3A4.
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Have a recent history of venous thromboembolic events, defined as event occurring <6 months prior to screening and also currently on therapy, known underlying hypercoagulability, or a major thromboembolic event within the past 2 years.
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Have baseline Grade ≥2 diarrhea.
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Have Grade ≥3 hypercalcemia (corrected serum calcium >12.5 mg/dL).
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Are pregnant or nursing mothers.
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Have had major surgery within 14 days prior to screening to allow for postoperative healing of the surgical wound and site(s).
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Have received recent (within 28 days prior to screening) live attenuated vaccines.
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Have active infection, including bacterial or fungal infections or active viral infection or viral load, including any human immunodeficiency virus (HIV), or hepatitis B virus (HBV), hepatitis C virus (HCV), or Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19).
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Currently have or have been treated in the past 2 years, for any other cancer or malignancy, except:
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Non-melanoma skin cancer, including basal cell carcinoma of the skin
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Curatively treated carcinoma in situ of the cervix.
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Have any clinically significant, uncontrolled heart disease, and/or cardiac repolarization abnormality, or a history of any of the following:
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Syncope of cardiovascular etiology
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Ventricular arrhythmia of pathological origin
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Sudden cardiac arrest
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Documented history of congestive heart failure with reduced ejection fraction.
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Have interstitial pneumonia or has severe impairment of lung function defined as:
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Vital capacity and diffusing capacity of the lung for carbon monoxide (DLCO) of ≤50% of the normal predicted values, or
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Oxygen (O2) saturation at rest in ambient environment of ≤88%.
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Have received within the 21 days prior to screening, is currently receiving, or intends to receive during the study any nonstudy anticancer therapy, including but not limited to any of the following:
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Anticancer agent
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Investigational agent
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Surgical intervention
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Radiation intervention, including any radiation therapy (includes radiation to an isolated lesion). (Palliative radiation to lesions that are not target lesions is permissible).
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Have central nervous system metastases or leptomeningeal carcinomatosis.
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Have history of or current/active uveitis.
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Are not candidates for treatment with letrozole
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Onconova Therapeutics, Inc.
Investigators
- Study Chair: Mark S Gelder, MD, Onconova Therapeutics
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 19-02