Phase 2 Study of INCB123667 in Platinum-Resistant Ovarian Cancer With Cyclin E1 Overexpression

Prior treatment

• Clinically significant gastrointestinal abnormality, including the following: a. Hospitalization for or clinical findings consistent with a gastrointestinal obstruction within 3 months of signing the main ICF or radiographic evidence of gastrointestinal obstruction at the time of screening. Gastrointestinal obstruction from an uncomplicated isolated lesion that has resolved following primary resection within 3 months of consent may be considered on a case-by-case basis in consultation with the medical monitor to determine suitability for participation. b. Ascites requiring paracentesis more often than every 4 weeks for symptomatic management. Enrollment of participants with an indwelling peritoneal catheter may be considered in consultation with the medical monitor to determine suitability for participation. c. Abdominal/pelvic fistula that has not been successfully medically managed. d. Requirement for enteral or parenteral nutrition. e. Malabsorption syndromes and prior surgical procedures that might affect the gastrointestinal transit and absorption of orally taken medication. f. Endoscopically determined active gastroduodenal ulcer(s). g. Gastrointestinal bleeding (eg, hematemesis, hematochezia, and melena) within 3 months before the first dose of study drug.
• History of thromboembolism and on therapeutic anticoagulation for less than 2 weeks before the first dose of study drug.
• Toxic effects of prior therapy and/or complications from prior surgical intervention that have not improved to ≤ Grade 1 before the first dose of study drug, with the exception of ≤ Grade 2 alopecia.
• Prior treatment with any CDK2 inhibitor.
• Any prior chemotherapy, biological therapy, or targeted therapy 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 radiation therapy within 14 days before the first dose of study drug.
• Current treatment with another investigational medication or prior treatment with an investigational medication other than the study drug within 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug.
• Current use of prohibited medication as described in Protocol Section 6.6.3.
• Current treatment with any potent CYP3A4/CYP3A5 inhibitor or inducer or prior treatment 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. Note: A washout period of ≥ 5 half-lives or 28 days (whichever is shorter) before the first dose of INCB123667 is required for enrollment into the study for prior treatment with a potent CYP3A4/CYP3A5 inhibitor or inducer.
• Any other infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before the first dose of study drug.
• Women who are pregnant (including women who may possibly be pregnant based on medical interview by investigators in Japan), breastfeeding, or expecting to conceive, starting with the screening visit through 180 days after the last dose of study drug treatment..
• The tumor tests positive for FRα but the participant has not received mirvetuximab soravtansine due to it being unavailable.
• Clinically significant or uncontrolled cardiac disease within 6 months before the first dose of study drug, including but not limited to unstable angina pectoris or acute myocardial infarction, or New York Heart Association Class III or IV cardiac disease, congestive heart failure, and uncontrolled arrhythmia, or other clinically significant heart disease. Participants with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study drug are allowed.
• Significant concurrent, uncontrolled medical condition.

Other illness

• Have endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of these histologies, or low-grade/borderline ovarian cancer.
• History of thromboembolism while on anticoagulation therapy.
• Have primary platinum-refractory disease: either did not respond (CR or PR) to first-line platinum-containing therapy or progressed on or within 3 months after the last dose of the first-line platinum-containing therapy.
• Known history of HBV infection with detectable HBV DNA. In cases of chronic HBV infection with active disease, HBV DNA ≥ 500 IU/mL during screening is exclusionary.
• Known history of HCV infection with detectable HCV RNA. Note: Participants who have completed treatment for HCV and are HCV RNA-negative are eligible.
• Known history of HIV infection
• Known hypersensitivity or severe reaction to any component of study drug or formulation components.
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 3 years before the first dose of study drug.

Lab values

• Participants with laboratory values at screening defined in Protocol Section 5.2 Table 6 . Exclusionary Laboratory Values

Other

• History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful.
• Known active CNS metastases and/or carcinomatous meningitis.

• Ability to comprehend and willingness to sign a written ICF for the study.
• Must have received bevacizumab unless there was a contraindication for its use.
• If the tumor tests positive for FRα, participants must have received mirvetuximab soravtansine unless there is an exception for its use on medical grounds.
• Have had documented disease progression during or after the last line of anticancer therapy prior to study entry.
• Measurable disease per RECIST v1.1 on CT or MRI.
• Ability to take medication orally.
• ECOG performance status of 0 to 1.
• Willingness to avoid pregnancy based on the criteria below. a. Female participants who are WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of study drug and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) and refrain from donating oocytes from screening through 180 days after the last dose of study drug. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed. b. Female participants not considered to be of childbearing potential as defined in Appendix A are eligible.
• Female participants aged 18 years or older at the time of signing the ICF
• Willingness and ability to conform to and comply with all Protocol requirements,
• Histological diagnosis of a high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• Have platinum-resistant disease: a. Participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of a platinum-containing regimen, had a response (CR or PR) or had nonmeasurable disease at the start of the platinum-based therapy, and then progressed between > 3 and ≤ 6 months after the last dose of platinum. b. Participants who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 6 months after the last dose of platinum.
• Willingness to undergo pretreatment biopsy.
• Tumor cyclin E1 expression level must be known based on central IHC testing.
• Tumor FRα expression level must be known based on IHC using a validated assay. If local testing is not available, this will be performed by a dedicated central laboratory.
• Received at least 1 and no more than 4 prior lines of systemic therapy following the initial diagnosis, after which single-agent therapy is considered an appropriate next therapeutic option. Points to consider when determining the number of therapies received: a. Neoadjuvant systemic therapy followed by postoperative adjuvant therapy will be considered as 1 line of therapy. b. Maintenance therapy (eg, bevacizumab or PARP inhibitors) will not be considered as a separate line of therapy. c. Therapy changes due to toxicity in the absence of disease progression will not be considered as a separate line of therapy.