Study of INCB123667 in Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, dose-escalation and dose-expansion study to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of INCB123667 when administered as monotherapy at the RDE(s) in participants with selected advanced or metastatic solid tumors. Part 1A (dose escalation) will determine the recommended dose of INCB123667 for expansion (RDE) and the maximum tolerated dose (MTD). Part 1B (cohort dose expansion phase) will further explore antitumor activity of INCB123667 as a monotherapy in 6 tumor-specific cohorts at the RDE(s) defined in Part 1A.

Official Title
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A Phase 1, Open-Label, Multicenter Study of INCB123667 as Monotherapy in Participants With Selected Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: INCB0123667


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: France Only : Adults age of at least 18 and up to 99 years. Life expectancy greater than 12 weeks. ECOG performance status score of 0 or 1. Disease progression on prior standard treatment, intolerance to or ineligibility for standard treatment, or no available treatment to improve the disease outcome. Availability of a baseline archival tumor specimen or willingness to undergo a pretreatment and an on-treatment tumor biopsy (core or excisional) as applicable to obtain the specimen. Participants in Part 1B: Disease Group 1 : Ovarian/Fallopian/Primary Peritoneal Cancer Disease Group 2 : Endometrial/Uterine Cancer Disease Group 3: Gastric, GEJ, and esophageal adeno-carcinomas Disease Group 4 : TNBC Disease Group 5: Breast cancer (HR+/HER-) Disease Group 6: Other tumor indications Measurable lesions by CT or MRI based on RECIST v1.1 criteria that are considered nonamenable to surgery or other curative treatments or procedures. Willingness to avoid pregnancy or fathering children. Exclusion Criteria: History of clinically significant or uncontrolled cardiac disease, including recent (within the last 12 months) unstable angina pectoris or acute myocardial infarction, or New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, cardiomyopathy not controlled by medication, or other clinically significant heart disease (ie, ≥ uncontrolled Grade 3 hypertension). History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful. Screening QTcF interval > 450 milliseconds is excluded; in the event that a single QTc is > 450 milliseconds, the participant may enroll if the average QTc for the 3 ECGs is < 450 milliseconds. Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment. Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of the first dose of study drug with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the participant has been disease-free for > 1 year after treatment with curative intent. Specific Lab values Significant concurrent, uncontrolled medical conditions, such as liver disease and gastrointestinal disorders. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting study drug. Prior treatment with any CDK2 inhibitor. Any change in endocrine therapy within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug or any administration of targeted therapy, antibody, or hypomethylating agent to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug. Any major surgery within 28 days before the first dose of study drug. Any prior radiation therapy within 28 days before the first dose of study drug. Undergoing treatment with another investigational medication or having been treated with an investigational medication within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug. Undergoing treatment with any potent CYP3A4/CYP3A5 inhibitor or inducer (University of Washington School of Pharmacy 2020) or having been treated with a potent CYP3A4/CYP3A5 inhibitor or inducer within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug. Known or suspected SARS-CoV-2 infection at the time of enrollment. Active HBV or HCV infection that requires treatment. HBV DNA and HCV RNA must be undetectable. Participants who have cleared a prior HBV infection (defined as HBsAg negative, HBsAg antibody positive, and anti-HBc antibody positive) are eligible for the study. Known history of HIV (HIV 1/2 antibodies). Known hypersensitivity or severe reaction to any component of study drug(s) or formulation components. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment. Current use of certain prohibited medications. Women who are pregnant or breastfeeding. For studies conducted in France, the following participants are excluded: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection or who are unable to express their consent per article L.1121-8 of the French Public Health Code.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1a will be dose escalation using a statistical hybrid design to identify the RDE(s), and the starting dose of INCB123667 will be 50mg QD. Part 1B is a dose expansion portion during which drug will be administered at the RDE(s) defined in Part 1A to 6 Disease Groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a Dose Escalation<br>INCB123667 will be administered at a protocol defined starting regimen once daily (QD) orally in 28-day cycles. Subsequent dose regimens will be determined during study conduct. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 1<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with gynecologic tumors (epithelial ovarian/fallopian/primary peritoneal carcinoma ) will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 2<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with Endometrial/Uterine cancer will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 3<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with gastric, Gastro Esophageal Junction (GEJ), and esophageal adenocarcinomas will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 4<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with Triple Negative Breast Cancer(TNBC) will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 5<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with HR+/HER2- breast cancer who have had disease progression on or been intolerant of a CDK4/6 inhibitor will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|
| Experimental: Phase 1b: Dose Expansion Cohort Disease Group 6<br>INCB123667 will be administered at the recommended dose or doses for expansion (RDE[s]) for advanced or metastatic solid tumors. Participants with other tumor indications with CCNE1 amplification or cyclin E1 over-expression will enroll in this group. | Drug: INCB0123667<br>* 25 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1A : Occurrence of Dose Limiting Toxicities (DLTs) | Toxicities occurring during the first treatment cycle, Part 1a, will define tolerability. DLTs will be assessed for severity by the investigator using CTCAE v5.0 criteria. | Up to Day 28 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE is any Adverse Event (AE) either reported for the first time or worsening of a pre-existing event after first dose of study drug. | Up to 12 months | 
| Number of Participants with Dose Interruptions due to TEAE | Participants will receive dose reductions of INCB123667 according to lab guidelines. Treatment may be delayed for up to 2 weeks to allow for resolution of toxicity. | Up to 12 months | 
| Number of Participants who Undergo Dose Reductions due to TEAE | Participants will receive dose reductions according to lab guidelines. Treatment may be delayed for up to 2 weeks to allow for resolution of toxicity. | Up to 12 months | 
| Number of Participants Discontinue study due to TEAE | TEAE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters: Cmax | Defines as the maximum (peak) plasma drug concentration | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK parameters: tmax | Defined as the time to reach maximum (peak) plasma concentration following drug administration | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK parameters: Ctau | Ctau is defined as concentration at the end of the dosing interval | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK Parameters: AUC | Defined as the area under the plasma concentration-time curve | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK Parameters: CL (or CL/F) | Defined as the apparent total body clearance of the drug from plasma | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK Parameters: Vz (or Vz/F) | Defined as apparent volume of distribution during terminal phase | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| PK Parameters: t1/2 | Defined as Elimination half-life (to be used in one-or noncompartmental model) | Cycle 1 Days 1, 8, and 15; Cycle 2 Days 1 and 8 (each cycle is 28 days) | 
| Objective Response Rate (ORR) | Defined as having a best overall Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1. | Up to 12 months | 
| Disease Control Response (DCR) | Defined as having a best overall response of CR, PR, or Stable Disease (SD) as determined by the investigator by radiographic disease assessment according to RECIST v1.1. | Up to 12 months | 
| Duration of Response (DOR) | Defined as the time from earliest date of disease response (Completed Rresponse or Partial Response) until earliest date of disease progression as determined by the investigator by radiographic disease assessment according to RECIST v1.1 or death due to any cause if occurring sooner than progression. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced solid tumors, metastatic solid tumors, Gynecological Tumors,, GI Tumors,, Breast Cancer,, Tumor Agnostic, cyclin E1 gene, epithelial ovarian carcinoma, fallopian carcinoma, primary peritoneal carcinoma, clear cell ovarian cancer, endometrial adenocarcinoma, uterine carcinosarcoma, uterine papillary serous carcinoma, gastrointestinal tumors, gastric adenocarcinomas, GEJ adenocarcinomas, esophageal adenocarcinomas