Phase 3 Randomized Open‑Label Study of INCB123667 Versus Investigator’s Choice Chemotherapy Combination in Platinum‑Resistant Ovarian Cancer with Cyclin E1 Overexpression
- Trial ID
- 2025-522748-42-00
- Protocol
- INCB123667-305
- Sponsor
- Incyte Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to compare the efficacy of INCB123667 with investigator’s choice chemotherapy in patients with platinum‑resistant ovarian cancer exhibiting cyclin E1 overexpression, using progression‑free survival and overall survival as co‑primary endpoints, thereby determining the potential for improved disease control and survival outcomes.
Secondary objectives include:
- Comparison of objective response rate between INCB123667 and the chemotherapy comparator.
- Further assessment of efficacy of INCB123667 versus the comparator.
- Evaluation of safety and tolerability of INCB123667 relative to investigator‑selected chemotherapy.
- Assessment of changes in health‑related quality of life in the study population.
Participants
The trial enrolled 158 adult female participants with a histologically confirmed diagnosis of high‑grade serous epithelial ovarian cancer, fallopian tube or primary peritoneal carcinoma that was platinum‑resistant. Eligible individuals were aged 18 years or older (in France up to 99 years) and demonstrated an ECOG performance status of 0 or 1, indicating full activity or restriction to strenuous physical activity. Participants had received between one and four prior lines of systemic therapy, including prior bevacizumab and, when applicable, mirvetuximab soravtansine for FRα‑positive tumors, and exhibited documented disease progression after their most recent anticancer regimen. Inclusion required measurable disease per RECIST v1.1, the ability to ingest oral medication, and provision of archival or fresh tumor tissue for biomarker analysis. Women of childbearing potential had to meet strict pregnancy‑prevention criteria. Selection was based on these clinical and laboratory parameters, without additional lifestyle prerequisites such as specific diet or exercise regimens.
Plans and Procedures
The study is a Phase 3 randomized open‑label trial comparing the oral CDK2/4/6 inhibitor INCB123667 (100 mg tablet) with investigator’s choice of intravenous chemotherapy (paclitaxel, topotecan, gemcitabine, or Caelyx pegylated liposomal doxorubicin) in participants with platinum‑resistant ovarian cancer exhibiting cyclin E1 overexpression. After an initial screening visit to verify eligibility criteria—including measurable disease per RECIST v1.1, ECOG performance status 0‑1, and prior therapy requirements—eligible subjects are randomized on Day 1 and commence the assigned study treatment. Treatment cycles are administered every 3 weeks for the chemotherapy arm and daily for INCB123667, with safety assessments (vitals, ECG, laboratory tests) at each cycle and tumor imaging performed approximately every 8 weeks to evaluate the primary endpoints of progression‑free survival and overall survival. Follow‑up visits continue until disease progression, unacceptable toxicity, withdrawal of consent, death, or completion of the protocol‑defined follow‑up period, after which an end‑of‑study visit captures final assessments, including health‑related quality‑of‑life questionnaires. Participants are therefore involved for the duration of treatment plus a post‑treatment follow‑up period, typically ranging from 12 to 24 months, with early termination criteria encompassing disease progression, treatment‑related adverse events requiring discontinuation, or significant protocol deviations.
Treatment
The investigational agents consist of two oral tablets, each containing 100 mg of the active substance INCB123667 (also identified as incb123667) or the chemically described 8‑ethoxy‑N‑((3R,4S)‑3‑methyl‑1‑(methylsulfonyl)piperidin‑4‑yl)‑7‑(1H‑pyrazol‑4‑yl)‑[1,2,4]triazolo[1,5‑a]pyridin‑2‑amine. Both are supplied in tablet form and are administered via the oral route at a dose of 100 mg per tablet according to the study dosing schedule.
Comparator treatments are selected by the investigator from the following chemotherapy options: paclitaxel administered by intravenous infusion at 80 mg/m²; topotecan hydrochloride given intravenously at 4 mg/m²; gemcitabine hydrochloride administered intravenously at 1000 mg/m²; and Caelyx pegylated liposomal doxorubicin hydrochloride provided as an intravenous solution for infusion at 40 mg/m². Each comparator agent is delivered according to standard oncology infusion protocols.
All study medications are given in accordance with the dosing regimen specified in the protocol. Oral investigational tablets are taken under direct observation when possible, and compliance is assessed through pill counts and documented administration records. Intravenous chemotherapy administrations are recorded in the treatment log, and infusion-related parameters are monitored to ensure adherence to dosing guidelines.
Efficacy
Efficacy will be evaluated using time‑to‑event and response endpoints. The primary endpoints are progression‑free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS), both defined from the date of randomization to the earliest occurrence of disease progression or death, respectively. Disease progression and response are determined according to RECIST v1.1 criteria.
Key secondary efficacy assessments include objective response rate (CR or PR) and duration of response (DOR) evaluated by BICR, as well as investigator‑assessed PFS, objective response, and DOR, each defined similarly to the primary endpoints. Health‑related quality of life is measured through changes from baseline in the EORTC QLQ‑C30, EORTC QLQ‑OV28, and EQ‑5D‑5L questionnaires.
Central radiologic review and investigator assessments will be performed at predetermined imaging timepoints according to the protocol schedule. Response evaluations and progression determinations will be recorded in the case report forms and analyzed using appropriate survival analysis methods, with Kaplan‑Meier estimates and hazard ratios for comparative efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ability to comprehend and willingness to sign a written ICF for the study.
- Female participants aged 18 years or older at the time of signing the ICF (in France, participants should be aged 18 to 99 years, inclusive, at the time of signing the ICF).
- Willingness and ability to conform to and comply with all Protocol requirements, including all scheduled visits and Protocol procedures.
- Histological diagnosis of 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 platinum-containing regimen, had a response (CR or PR) or had non-measurable disease at the start of platinum-based therapy, and then progressed between > 3 months 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 provide archival tumor tissue or, if not available or inadequate, undergo a fresh pretreatment biopsy. Note: An archival FFPE tumor tissue block or slides collected within 5 years prior to signing the prescreening ICF is acceptable
- Tumor FRα expression level must be known (see also Section 8.5.3 in the Protocol).
- Received at least 1 and no more than 4 prior lines of systemic therapy following the initial diagnosis, after which single-agent chemotherapy is considered an appropriate next therapeutic option. Points to consider when determining the number of therapies received: • Neoadjuvant systemic therapy followed by postoperative adjuvant therapy will be considered as 1 line of therapy. • Maintenance therapy (eg, bevacizumab or PARP inhibitors) will not be considered as a separate line of therapy. • Hormonal therapy will not be considered as a separate line of therapy. • Therapy changes due to toxicity in the absence of disease progression will not be considered as a separate line of therapy.
- Should have received prior treatment with bevacizumab unless there was a contraindication for its use.
- Should have received prior treatment with mirvetuximab soravtansine if the tumor is positive for FRα, unless there is an exception for its use on medical grounds. Medical exceptions include: active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring (eg, uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision).
- Have had documented disease progression during or after their last line of anticancer therapy prior to study entry.
- Measurable disease per RECIST v1.1 on CT or MRI. Note the following: • Lesions situated in a previously irradiated field are considered measurable if progression has subsequently been demonstrated. • Tumor lesions that have been biopsied should not be selected as target lesions unless post-biopsy imaging confirms that it still qualifies as a RECIST-defined measurable lesion.
- Ability to take medication orally.
- ECOG performance status of 0 or 1 (see Table 23 in the Protocol).
- 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 INCB123667, paclitaxel, gemcitabine, or topotecan, and 240 days after the last dose of PLD 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 treatment. Permitted methods in preventing pregnancy (see Appendix A in the Protocol) 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 in the Protocol are eligible.
Exclusion Criteria
- Have endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of these histologies, or low-grade/borderline ovarian cancer.
- 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 still requires active management.. 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. Known endoscopically-determined active gastroduodenal ulcer(s). g. Gastrointestinal bleeding (e.g. hematemesis, hematochezia, and melena) within 3 months before the first dose of study treatment.
- For participants assigned to receive paclitaxel only: unresolved > Grade 1 neuropathy.
- History of thromboembolism while on optimal anticoagulation therapy.
- History of thromboembolism and having been on therapeutic anticoagulation for less than 2 weeks before the first dose of study treatment.
- 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 treatment, with the exception of ≤ Grade 2 alopecia and skin hypo-/hyperpigmentation.
- 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 treatment.
- Any major surgery within 28 days before the first dose of study treatment.
- Any radiation therapy within 14 days before the first dose of study treatment. Note: Radiation-related toxicities must have improved to ≤ Grade 1.
- Current treatment with another investigational medication or having been treated with an investigational medication other than the study treatment within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
- Have primary platinum-refractory disease, defined as progression on or within 3 months after the last dose of first-line platinum-containing therapy.
- Current use of prohibited medication as described in Section 6.6.3 in the Protocol.
- For participants assigned to receive INCB123667 only: current treatment with any strong CYP3A4/CYP3A5 inhibitor or inducer (Appendix G in the Protocol) or having been treated with a strong tYP3A4/CYP3A5 inhibitor or inducer within 5 half-lives or 28 days (whichever is shorter) before the first dose of INCB123667.
- 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. Additionally, these participants are also excluded if they: • have not been on anti-HBV treatment (per local practice) for a minimum of 14 days before the first dose of study treatment, and • are not willing to continue on anti-HBV treatment during the study.
- 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 and any of the following: • CD4+ T-cell count < 350 cells/µL, • Detectable HIV RNA, or • On an ART regimen containing drugs that are strong CYP3A4/CYP3A5 inhibitors or inducers. Note: Switching to an alternative ART regimen with drugs that are weak or moderate CYP3A4/CYP3A5 inhibitors or inducers is allowed but must be taken for at least 28 days before the first dose of study treatment.
- Any other infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 1 week before the first dose of study treatment.
- For participants assigned to receive PLD only: previous clinical diagnosis of noninfectious ILD, including noninfectious pneumonitis.
- Known hypersensitivity or severe reaction to any component of study drug(s)/treatment or formulation components.
- 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 INCB123667, paclitaxel, gemcitabine or topotecan, and 240 days after the last dose of PLD. For Japan, women who are breastfeeding and wish to enroll must discontinue breastfeeding at least 90 days before receiving study treatment. They must also refrain from breastfeeding during the course of study and for 90 days after the last dose of study treatment.
- 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.
- Clinically significant or uncontrolled cardiac disease within 6 months before the first dose of study treatment, 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 treatment are allowed.
- The following participants are excluded in France: 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, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code.
- History or presence of an ECG abnormality that, in the investigator's opinion, is clinically meaningful. Participants with screening QTcF interval > 470 milliseconds are excluded; in the event that a single QTcF interval measurement is > 470 milliseconds, the participant may enroll if the average QTcF interval length for the 3 ECGs is < 470 milliseconds.
- For participants assigned to receive PLD only: LVEF below the institutional limit of normal as measured in accordance with local practice guidelines.
- Known active CNS metastases and/or carcinomatous meningitis. Note: Participants with previously treated and clinically stable brain or CNS metastases (without evidence of progression by imaging for at least 4 weeks before the first dose of study treatment and any neurologic symptoms have returned to baseline), who have no evidence of new or enlarging brain metastasis or CNS edema, and who have not required steroids for at least 7 days before the first dose of study treatment are eligible.
- Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 3 years before the first dose of study treatment. Exceptions include: cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, 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.
- Participants with laboratory values at screening defined in Table 7 in the Protocol.
- Significant concurrent, uncontrolled medical condition.
- For participants assigned to receive PLD only: known hypersensitivity to peanuts or soya.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 20 Feb 2026 | 23 |
 France | Not Yet Recruiting | 20 Feb 2026 | 90 |
 Germany | Not Yet Recruiting | 20 Feb 2026 | 23 |
 Ireland | Not Yet Recruiting | 20 Feb 2026 | 22 |
 Italy | Not Yet Recruiting | 20 Feb 2026 | 85 |
 The Netherlands | Recruiting | 20 Feb 2026 | — |
 Poland | Not Yet Recruiting | 20 Feb 2026 | 20 |
 Spain | Not Yet Recruiting | 20 Feb 2026 | 22 |
| Netherlands | — | — | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 40.00 | 24 | PRD9163065 |
PACLITAXEL | Comparator | — | INTRAVENOUS INFUSION | 80.00 | 24 | SUB09583MIG |
GEMCITABINE HYDROCHLORIDE | Comparator | — | INTRAVENOUS | 1000.00 | 24 | SUB02324MIG |
TOPOTECAN HYDROCHLORIDE | Comparator | — | INTRAVENOUS | 4.00 | 24 | SUB04921MIG |