A Study to Evaluate the Safety of KAND567, in Combination With Carboplatin Therapy, in Women With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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The study is a multicenter, Phase Ib/IIa, open-label, dose-escalation study to evaluate the safety and tolerability of orally administered KAND567 in combination with carboplatin therapy, and to determine the Recommended Phase II Dose (RPIID) of KAND567 in combination with carboplatin in subjects with recurrent platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. In Part 1, dose escalation will be based on the recommendation of the Safety Review Committee (SRC) after review of the emerging safety and tolerability information. Once the RPIID has been identified in Part 1, the SRC may recommend to the Sponsor to start Part 2. An expansion cohort will be enrolled in Part 2 of the study to further evaluate the RPIID (approximately 20 subjects; may range from 6 to 24 subjects, depending on Part 1). If the number of subjects with confirmed CX3CR1 expression in tumor cells is below 50%, an additional 15 subjects may be included in Part 2 of the study.

Official Title
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KANDOVA - A Two-Part Phase Ib/IIa Study to Evaluate the Safety and Tolerability of KAND567, in Combination With Carboplatin Therapy, and to Determine the Recommended Phase II Dose (RPIID) of KAND567: An Open-Label, Multicenter Dose Escalation Study With an Expansion Cohort in Women With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Conditions
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Epithelial Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Intervention / Treatment
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* Drug: KAND567
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically verified high-grade serous or high-grade endometrioid epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer Participants must have recurrent disease, defined as: 1st relapse 3 to 6 months after completion of the last dose of primary platinum containing treatment, or 2nd or 3rd relapse within 6 months after completion of the last dose of the latest platinum-containing regimen (platinum-free interval within 6 months) Participants must have had platinum-based chemotherapy in the first-line setting (primary treatment) For BRCA status, samples must be available for analysis; for HRD status, samples should be available for analysis, if possible. If not already analyzed, the subject agrees to undergo analysis of HRD and BRCA status on primary tumor tissue and/or recurrent tumor tissue ECOG performance status 0-2 Subjects must have at least 1 measurable disease according to RECIST 1.1 guidelines Able to take oral medications Adequate organ function: Absolute neutrophil count ≥ 1.5 x 10^9/L, Platelets > 100 x 10^9/L, Hemoglobin ≥ 80 g/dl, Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault formula, Total bilirubin ≤ 1.5 x ULN, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, and Serum albumin ≥ 30 g/L. Consent to biopsy taken prior to starting treatment and Week 8 (± 1 week) of treatment At least 18 years of age Life expectancy of at least 12 weeks Women of childbearing potential must use adequate birth control Willingness and ability to comply with study procedures, visit schedules, study restrictions and requirements Able to fully understand and participate in study-related procedures, including compliance and patient reported outcome Written informed consent. Subjects must give informed consent prior to any study-specific procedure Exclusion Criteria: Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers, and cancer types not mentioned in the inclusion criteria Primary platinum-refractory disease, defined as tumor progression during or within 12 weeks from end of first platinum treatment Concurrent cancer therapy Received other than platinum-containing therapy for primary disease (first-line treatment) Received non-platinum-containing chemotherapy in recurrent setting Treatment with an investigational agent concurrently, or within the past 3 months Previous malignant disease: subjects are not eligible for the study if actively being treated for invasive cancer other than ovarian cancer Immunodeficiency or organ transplant. Autoimmune or inflammatory condition that requires immunosuppressive or steroid therapy during the course of the study Live vaccines within 28 days prior to the first IMP dose Major surgery within 28 days prior to the first IMP dose, or not recovered from previous surgery to CTCAE (v5) grade 1 equivalent Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) Transient ischemic attack (TIA) or stroke, including bleeding, within the past 6 months Brain and/or liver metastases Major cardiac dysfunction defined as > NYHA II Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug Serious, uncontrolled, and active infection at enrollment, as determined by the Investigator Pregnancy or breastfeeding Persistence of clinically relevant therapy-related toxicity from previous chemotherapy (any grade 3-4 toxicity or grade ≥ 2 neuropathy) Current use of drugs sensitive to CYP3A4 inhibition which cannot be paused or switched to an alternative within the same class of medication for the period of IMP administration Continuous use of herbal preparations (e.g., St. John's wort) within 2 weeks prior to enrollment Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (e.g., compromise well-being) or that could prevent, limit, or confound the protocol-specified assessments

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose escalation to determine Recommended Phase II Dose (RPIID)<br>Part 1 of the study will include escalating doses of KAND567 administered in combination with carboplatin (according to standard of care) to approximately 10 subjects in total (may range from 6 to 24 subjects depending on DLTs). Carboplatin will be given on Day 1 of the 21-day cycle at a dose of AUC 5 according to standard of care. KAND567 will be orally administered during the first 2 weeks (Days 2 to 14) of each 21-day carboplatin cycle for up to 6 treatment cycles (or until unacceptable toxicity or disease progression). KAND567 dose escalation will apply for the first week (Days 2 to 7) of the treatment cycle. During the second week of the treatment cycle (Days 8 to 14), KAND567 will be administered at a fixed dose of 250 mg BID to all subjects. Doses of KAND567 will be escalated according to an adaptive, intra-individual dose escalation design. | Drug: KAND567<br>* KAND567 is a drug in capsule and is intended to be orally administered approximately every 12 hours (±1 hour) with an initial loading dose on Day 2 of two times the dose specified for that dose group (e.g., 2 x 250, 2 x 375, 2 x 500, or 2 x 625 mg KAND567, depending on the dose group; in Part 2, this is the RPIID), followed by a KAND567 dose (Day 2, evening dose) that corresponds to the given dose level. On Days 3 to 7, the subjects will be orally administered the specified KAND567 dose (e.g., 250, 375, 500, or 625 mg BID, depending on the dose group; in Part 2, this is the RPIID). During the second week of dosing (Days 8 to 14) in Part 1 and Part 2, the subjects will be orally administered KAND567 at a dose of 250 mg BID. One treatment cycle is defined as a 21-day period, and each subject will receive up to 6 treatment cycles (or until unacceptable toxicity or disease progression).<br>* Other names: Fractalkine;Drug: Carboplatin<br>* Carboplatin will be administered i.v. according to standard of care at a dose of AUC 5. One cycle is defined as a 21-day period with chemotherapy given on Day 1. Each subject will receive up to 6 treatment cycles (or until unacceptable toxicity or disease progression). The carboplatin dose should be calculated using the Calvert formula: Carboplatin dose (mg) = target AUC 5 × (GFR + 25). GFR should be calculated using the Cockcroft-Gault formula. The maximum carboplatin dose is based on a calculated GFR that is capped at 125 mL/min for subjects with normal renal function.<br>|
| Experimental: Part 2: Expansion cohort to evaluate RPIID<br>An expansion cohort will be enrolled in Part 2 of the study to further evaluate the RPIID (approximately 20 subjects; may range from 6 to 24 subjects, depending on Part 1). If the number of subjects with confirmed CX3CR1 expression in tumor cells is below 50%, an additional 15 subjects may be included in Part 2 of the study. Carboplatin will be given on Day 1 of the 21-day cycle at a dose of AUC 5 according to standard of care. For KAND567, the RPIID will be orally administered to the cohort during the first week of each carboplatin cycle (Days 2 to 7). During the second week of the treatment cycle (Days 8 to 14), KAND567 will be administered at 250 mg BID. Up to 6 treatment cycles will be given (or until unacceptable toxicity or disease progression). | Drug: KAND567<br>* KAND567 is a drug in capsule and is intended to be orally administered approximately every 12 hours (±1 hour) with an initial loading dose on Day 2 of two times the dose specified for that dose group (e.g., 2 x 250, 2 x 375, 2 x 500, or 2 x 625 mg KAND567, depending on the dose group; in Part 2, this is the RPIID), followed by a KAND567 dose (Day 2, evening dose) that corresponds to the given dose level. On Days 3 to 7, the subjects will be orally administered the specified KAND567 dose (e.g., 250, 375, 500, or 625 mg BID, depending on the dose group; in Part 2, this is the RPIID). During the second week of dosing (Days 8 to 14) in Part 1 and Part 2, the subjects will be orally administered KAND567 at a dose of 250 mg BID. One treatment cycle is defined as a 21-day period, and each subject will receive up to 6 treatment cycles (or until unacceptable toxicity or disease progression).<br>* Other names: Fractalkine;Drug: Carboplatin<br>* Carboplatin will be administered i.v. according to standard of care at a dose of AUC 5. One cycle is defined as a 21-day period with chemotherapy given on Day 1. Each subject will receive up to 6 treatment cycles (or until unacceptable toxicity or disease progression). The carboplatin dose should be calculated using the Calvert formula: Carboplatin dose (mg) = target AUC 5 × (GFR + 25). GFR should be calculated using the Cockcroft-Gault formula. The maximum carboplatin dose is based on a calculated GFR that is capped at 125 mL/min for subjects with normal renal function.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, as measured by the occurence of adverse events (AEs) | Measured by occurence of AEs and serious adverse events (SAEs) | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Evaluate the safety and tolerability of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, as measured by the occurrence of dose limiting toxicities (DLTs) | Measured by the occurrence of DLTs | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Evaluate the safety and tolerability of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, as measured by vital signs | Measured by the occurrence of clinically abnormal vital signs | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Evaluate the safety and tolerability of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, as measured by ECG | Measured by the occurrence of clinically abnormal electrocardiography (ECG) | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Evaluate the safety and tolerability of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, as measured by lab safety tests | Measured by the occurrence of clinically abnormal lab test results (routine clinical chemistry, haematology, and urinalysis) | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Recommended Phase II Dose (RPIID) of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer | In Part 1/Phase Ib, RPIID of KAND567 in combination with carboplatin therapy will be determined based on safety and tolerability (DLTs). | From the first KAND567 IMP administration to the subject (Day 2) until the end of study visit (Week 20). | 
| Overall Response Rate (ORR) | Evaluate ORR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions, i.e., best overall response in subjects with measurable disease who are evaluable by CA 125. | Week 12 and 18 | 
| Progression-Free Survival (PFS) | Evaluate PFS according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions, i.e., the time from start of treatment to disease progression or death. | From the first IMP administration to the subject (Day 1) to Week 12 and 18 | 
| Overall survival (OS) | Evaluate OS according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions, i.e., the time from the start of treatment to death due to any cause. | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Disease control rate (DCR) | Evaluate DCR, i.e., Complete response (CR) + Partial response (PR) + Stable disease (SD), according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions, where: CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameter; and SD= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. | Week 12 and 18 | 
| Duration of response | Evaluate duration of response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions, i.e., time from documentation of tumor response to disease progression. | From the first IMP administration to the subject (Day 1) until the end of study visit (Week 20) | 
| Change in pain score | Change in pain score (patient reported outcome), as measured by the Numeric Rating Scale (NRS). The NRS is a scale rating pain from no pain to worst pain possible from 0 to 10, where a higher value indicates greater pain intensity. | From baseline (Week 1) to Weeks 4, 7, 10, 13, 16 and 20. | 
| Determine the plasma exposure of KAND567 | Blood samples will be collected for the determination of concentrations of KAND567 in plasma. The determination of the total concentration of KAND567 in plasma will be carried out using Liquid Chromatography - Tandem Mass Spectrometry (LC-MS/MS). KAND567 PK drug concentration data will be graphically visualized together with normalized PK drug concentration data from the previous KAN0001 study (i.e., no formal PK analysis will be performed). | For each 21-day treatment cycle, on Day 7 (0, 1, 2, and 4 hours after KAND567 morning dose) and Day 14 (0, 2 and 4 hours after KAND567 morning dose). Each subject receives up to 6 treatment cycles (or until unacceptable toxicity or disease progression) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fractalkine, Ovarian cancer