Trial Title:
Study of Narazaciclib (ON 123300) Plus Letrozole in Endometrial Cancer and Other Gynecologic Malignancies
NCT ID:
NCT05705505
Condition:
Endometrioid Endometrial Cancer
Conditions: Official terms:
Endometrial Neoplasms
Letrozole
Conditions: Keywords:
Narazaciclib
ON 123300
letrozole
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Phase 1: 3+3 dose escalation Phase2: Expansion cohort
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Narazaciclib
Description:
Orange tablets, each containing 40 mg or 120 mg of narazaciclib as narazaciclib
monolactate
Arm group label:
Escalating daily doses of narazaciclib in combination with letrozole (2.5mg day)
Other name:
ON 123300, HX-301
Intervention type:
Drug
Intervention name:
Letrozole 2.5mg
Description:
Tablet
Arm group label:
Escalating daily doses of narazaciclib in combination with letrozole (2.5mg day)
Other name:
Femara
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.
Criteria for eligibility:
Criteria:
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 exclusion criteria.
2. Have received a cyclin-dependent kinase (CDK) 4/6 inhibitor in the past.
3. 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.
4. 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.
5. 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.
6. Are currently taking or within 5 half-lives of taking strong inducers and inhibitors
of cytochrome P450 enzyme (CYP)2C8 and CYP3A4.
7. 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.
8. Have baseline Grade ≥2 diarrhea.
9. Have Grade ≥3 hypercalcemia (corrected serum calcium >12.5 mg/dL).
10. Are pregnant or nursing mothers.
11. Have had major surgery within 14 days prior to screening to allow for postoperative
healing of the surgical wound and site(s).
12. Have received recent (within 28 days prior to screening) live attenuated vaccines.
13. 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).
14. Currently have or have been treated in the past 2 years, for any other cancer or
malignancy, except:
1. Non-melanoma skin cancer, including basal cell carcinoma of the skin
2. Curatively treated carcinoma in situ of the cervix.
15. Have any clinically significant, uncontrolled heart disease, and/or cardiac
repolarization abnormality, or a history of any of the following:
1. Syncope of cardiovascular etiology
2. Ventricular arrhythmia of pathological origin
3. Sudden cardiac arrest
4. Documented history of congestive heart failure with reduced ejection fraction.
16. Have interstitial pneumonia or has severe impairment of lung function defined as:
1. Vital capacity and diffusing capacity of the lung for carbon monoxide (DLCO) of
≤50% of the normal predicted values, or
2. Oxygen (O2) saturation at rest in ambient environment of ≤88%.
17. 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:
1. Anticancer agent
2. Investigational agent
3. Surgical intervention
4. Radiation intervention, including any radiation therapy (includes radiation to
an isolated lesion). (Palliative radiation, prior to screening, to lesions that
are not target lesions is permissible).
18. Have central nervous system metastases or leptomeningeal carcinomatosis.
19. Have history of or current/active uveitis.
20. Are not candidates for treatment with letrozole
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Arizona Oncology Associates, PC - HOPE
Address:
City:
Tucson
Zip:
85711
Country:
United States
Status:
Recruiting
Contact:
Last name:
Stacey Kimbell, RN
Phone:
520-668-5678
Email:
stacey.kimbell@usoncology.com
Contact backup:
Last name:
Julie Klinker, RN
Phone:
520-269-3821
Email:
julie.klinker@usoncology.com
Investigator:
Last name:
Joseph Buscema, MD
Email:
Principal Investigator
Facility:
Name:
Minnesota Oncology Hematology, P.A.
Address:
City:
Minneapolis
Zip:
55404
Country:
United States
Status:
Recruiting
Contact:
Last name:
Brianna Lenox
Phone:
612-884-6329
Email:
Brianna.Lenox@usoncology.com
Investigator:
Last name:
Timothy G Larson, MD
Email:
Principal Investigator
Facility:
Name:
Perlmutter Cancer Center at NYU Langone Hospital - Long Island
Address:
City:
Mineola
Zip:
11501
Country:
United States
Status:
Recruiting
Contact:
Email:
CT.gov@nyulangone.org
Investigator:
Last name:
Bhavana Pothuri, MD
Email:
Principal Investigator
Facility:
Name:
NYU Langone
Address:
City:
New York
Zip:
10016
Country:
United States
Status:
Recruiting
Contact:
Email:
CT.gov@nyulangone.org
Investigator:
Last name:
Bhavana Pothuri, MD
Email:
Principal Investigator
Facility:
Name:
Willamette Valley Cancer Institute and Research Center
Address:
City:
Eugene
Zip:
97401
Country:
United States
Status:
Recruiting
Contact:
Last name:
Jeanne Schaffer, RN, BSN
Phone:
541-736-3385
Email:
jeanne.schaffer@usoncology.com
Contact backup:
Last name:
Nichole Fisher, RN, BSN
Phone:
541-988-0656
Email:
nichole.fisher@usoncology.com
Investigator:
Last name:
Charles K Anderson, MD
Email:
Principal Investigator
Facility:
Name:
Greenville Health System, Institute for Oncology Clinical Research
Address:
City:
Greenville
Zip:
29605
Country:
United States
Status:
Recruiting
Contact:
Last name:
Fiona Davidson
Phone:
864-455-3600
Email:
Fiona.Davidson@prismahealth.org
Contact backup:
Last name:
Lisa Johnson
Phone:
864-455-3600
Email:
Lisa.Johnson@prismahealth.org
Investigator:
Last name:
W. Jeff Edenfield, MD
Email:
Principal Investigator
Facility:
Name:
Texas Oncology-Baylor Charles A. Sammons Cancer Center
Address:
City:
Dallas
Zip:
75246
Country:
United States
Status:
Recruiting
Contact:
Last name:
Christine Terraciano
Phone:
214-370-1942
Email:
christine.terraciano@usoncology.com
Investigator:
Last name:
Noelle G Cloven, MD
Email:
Principal Investigator
Facility:
Name:
Texas Oncology - Fort Worth Cancer Center
Address:
City:
Fort Worth
Zip:
76104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Nori Sullivan, RN, BSN
Phone:
817-413-1760
Email:
nori.sullivan@usoncology.com
Investigator:
Last name:
Noelle G Cloven, MD
Email:
Principal Investigator
Start date:
March 29, 2023
Completion date:
February 2026
Lead sponsor:
Agency:
Traws Pharma, Inc.
Agency class:
Industry
Source:
Traws Pharma, Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05705505
