Associate professor, consultant, PhD
Trine Lembrecht Jørgensen
Odense University Hospital, dep. of oncology
| Projekt styring | ||
| Projekt status | Open | |
| Data indsamlingsdatoer | ||
| Start | 27.11.2023 | |
| Slut | 31.12.2024 | |
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
Short summary
This is a phase Ib/IIa study including patients with platinum resistant epithelial ovarian cancer (OC). Patients will be treated with carboplatin and the study drug, KAND567, a fractalkine receptor antagonist. KAND567 has been shown in vitro to restore platinum sensitivity in OC cells. In the phase Ib study, primary objective is to evaluate safety and tolerability and to identify the recommended phase II dose. In phase 2a we will evaluate safety and tolerability and effect.
Rationale
The study objective is to evaluate the safety and tolerability of KAND567, in combination with carboplatin, and to determine the Recommended Phase II Dose (RPIID) of KAND567 in combination with carboplatin, for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (Part 1; Phase Ib). In Part 2 of the study (Phase IIa), anti-tumor activity and safety of KAND567, in combination with carboplatin, will be evaluated in the study population. KAND567 is currently developed to target hyperinflammation cardiovascular conditions with an inflammatory component. KAND567 has undergone clinical studies in healthy volunteers (FiH dose titration), for treatment of hyperinflammation in COVID-19 patients (moderate to severe), and in patients with acute myocardial infarctions. KAND567 has been well-tolerated without treatment-related serious adverse events (SAEs) or clinically significant deviations in vital signs, electrocardiography (ECG) measurements, or laboratory parameters in healthy young and elderly female and male subjects following oral single ascending doses up to 2500 mg and following 7 days of oral dosing up to 500 mg BID. The maximum tolerated dose (MTD) was deemed to have been exceeded at 800 mg BID when 4 of 6 subjects developed moderate to severe gastrointestinal AEs and clinically significant increases in AST/ALT after 4 to 6 days of dosing (one subject also had modest increase in alkaline phosphatase [ALP]). These were fully reversible after cessation of dosing. Additional analysis of the liver findings could not explain the increase in AST/ALT by effects on bile transporters, mitochondrial dysfunction, oxidative stress, or hepatocyte apoptosis/necrosis. The observed changes in bilirubin (less than 2 x ULN) are judged to be related to the inhibition of bilirubin transporter and not hepatoxicity [27]. No elevation was observed regarding inflammatory cytokines and myeloperoxidase (MPO) in plasma. Additionally, no other significant renal AEs were identified in COVID-19 patients, in comparison with the frequency of the placebo group (see [27] for further details). Chemotherapeutics, such as platinum drugs, are used to treat numerous cancers by exerting antiproliferative actions such as introducing DNA crosslinks. Unfortunately, their therapeutic potential is limited due to adverse side effects and acquired resistance, the latter often associated with enhanced DNA repair capacity. KAND567 has the potential to restore platinum sensitivity to patients with high-grade serous endometrioid ovarian cancer and thereby decrease morbidity, increase quality of life, and prolong survival. Supportive preclinical data have been obtained in cell studies and in vivo in zebrafish and murine models supporting a proposed causality between CX3CR1 antagonism by KAND567, inhibition of the FA DNA repair pathway and depletion of tumor-promoting cells of the TME, as well as cancer cell apoptosis and reduction of ovarian cancer growth. Kancera AB now aims to test KAND567 in cancer patients. Ovarian cancer is an insidious disease that threatens both the survival and quality of life of thousands of women globally. Platinum-based chemotherapy (usually in combination with surgery) is the mainstay first-line drug treatment for ovarian cancer tumours. Despite therapeutic advances in recent years, the unfortunate truth is that ovarian cancer often remains an incurable disease for which survival rates have only modestly improved. There is an urgent unmet need to develop new treatment strategies, such as restoring platinum sensitivity, for patients with recurrent ovarian cancer.
Description of the cohort
For inclusion in the study, subjects must fulfill the following criteria: 1. Histologically verified high-grade serous or high-grade endometrioid epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer. 2. 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) *Prior treatment with PARPi is allowed. In bevacizumab-naive patients, bevacizumab can be included as part of treatment after tumor progression on study drugs according to local clinical practice. 3. Participants must have had platinum-based chemotherapy in the first-line setting (primary treatment). 4. 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. 5. ECOG performance status 0-2. 6. Subjects must have at least 1 measurable disease according to RECIST 1.1 guidelines. This should not be the same lesion used for biopsy, nor should it be in a previously irradiated area. 7. Able to take oral medications. 8. Adequate organ function • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L • Platelets > 100 x 109/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. • Serum albumin ≥ 30 g/L 9. Consent to biopsy taken prior to starting treatment and Week 8 (± 1 week) of treatment. DocuSign Envelope ID: A3E139C0-BA60-436F-B03B-6D597D71D6CD Clinical Study Protocol (CSP): KAN0007 Sponsor: Kancera AB CSP Version Date: 06 July 2023 Investigational Product: KAND567 CSP Version: 3.0 Final EudraCT No.: 2022-002792-11 CONFIDENTIAL 59(100) 10. At least 18 years of age. 11. Life expectancy of at least 12 weeks. 12. Women of childbearing potential must use adequate birth control for the study duration and 6 months afterwards. She must use contraceptive methods with a failure rate of < 1% to prevent pregnancy* and drug exposure of a partner. Male partners must refrain from donating sperm from their partner's first IMP dose until 6 months after their partner's last IMP dose. * Combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD) or intrauterine hormone-releasing system (IUS); bilateral tubal occlusion, vasectomy, and sexual abstinence. 13. Willingness and ability to comply with study procedures, visit schedules, study restrictions and requirements. 14. Able to fully understand and participate in study-related procedures, including compliance and patient reported outcome (PRO). 15. Written informed consent. Subjects must give informed consent prior to any study-specific procedure.
Data and biological material
Blood samples and urinanalysis wil be drawn regularly during the 18 weeks of therapy. harmacokinetics will also be analyzed. Biopsies and ascites will be collected if possible baseline and at 2nd cycle. Data on toxicity and pain score will be collected at each cycle