| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. | |
| E.1.1.1 | Medical condition in easily understood language | | Recurrent ovarian cancer. | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10033128 | | E.1.2 | Term | Ovarian cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | Part 1 (Phase Ib): Evaluate the safety and tolerability of KAND567, in combination with carboplatin therapy and to determine the Recommended Phase II Dose (RPIID) of KAND567 in combination with carboplatin therapy in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. 1
Part 2 (Phase IIa): Evaluate safety and tolerability of KAND567 in combination with carboplatin therapy at the RPIID of KAND567 in recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.1
1Defined as 1st relapse between 3 to 6 months after end of primary platinum-containing treatment; or 2nd or 3rd relapse within 6 months after last platinum-containing treatment.
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| E.2.2 | Secondary objectives of the trial | Secondary objectives:
Evaluate Overall Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Gynecologic Cancer Intergroup (GCIG) definitions.
•Assess signs of anti-tumor activity of KAND567 in combination with carboplatin therapy.
•Determine the plasma exposure of KAND567.
• Assess effect on pain symptoms of KAND567 in combination with carboplatin therapy.
Exploratory objectives:
•Assess tumor and immune activity of KAND567 in combination with carboplatin therapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 or non-measurable disease according to RECIST 1.1 guidelines. Non-measurable disease must be evaluable using GCIG CA 125 criteria (CA 125 ≥ 2 x upper limit of normal [ULN]). If the subject has only 1 measurable lesion, 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.
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.
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| E.4 | Principal exclusion criteria | 1.Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers, and cancer types not mentioned in the inclusion criteria.
2.Primary platinum-refractory disease, defined as tumor progression during or within 12 weeks from end of first platinum treatment.
3.Concurrent cancer therapy. (including anti-hormonal therapy for breast cancer unless it is omitted at the latest at study enrollment).
4.Received other than platinum-containing therapy for primary disease (first-line treatment).
5.Received non-platinum-containing chemotherapy line (e.g. weekly paclitaxel) in treatment of recurrent ovarian cancer. Maintenance with bevacizumab and/or PARP-inhibitor is allowed.
6.Treatment with an investigational agent concurrently, or where the last dose was administered within 5 elimination half-lives or where pharmacological activity may still be present as assessed by the Investigator.
7.Previous malignant disease: subjects are not eligible for the study if actively being treated for invasive cancer other than ovarian cancer. Subjects with previous malignant disease other than ovarian cancer who are relapse-free and treatment-free for more than three years may enter this study (exception: anti-hormonal therapy, which must be omitted at the latest at study enrollment). Subjects with previous history of in situ carcinoma, stage 1A cervical cancer or non-invasive basal cell and squamous cell skin carcinoma can enter this trial.
8.Immunodeficiency or organ transplant. Autoimmune or inflammatory condition that requires immunosuppressive or steroid therapy during the course of the study. Subjects using immunosuppressive medications within 14 days prior to the first IMP dose, except for topical medications (intranasal, inhaled, local injection, systemic [prednisolone equivalent 10 mg/day or less]) or as needed for hypersensitivity reactions such as CT scan premedication.
9.Live vaccines within 28 days prior to the first IMP dose.
10.Major surgery within 28 days prior to the first IMP dose, or not recovered from previous surgery to CTCAE (v5) grade 1 equivalent.
11.Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
12.Transient ischemic attack (TIA) or stroke, including bleeding, within the past 6 months.
13.Brain metastases.
14.Major cardiac dysfunction defined as > NYHA II.
15.Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug.
16.Serious, uncontrolled, and active infection at enrollment, as determined by the Investigator.
17.Pregnancy or breastfeeding.
18.Persistence of clinically relevant therapy-related toxicity from
previous chemotherapy (≥ CTCAE grade 3, except for liver and
gastrointestinal ≥ CTCAE grade 2).
19.Need for concomitant use of drugs that are:
-moderate or strong inhibitors of CYP3A4 that may increase
concentrations of KAND567. Treatment with such drugs should have been stopped at least five half-lives before initiation of KAND567 therapy. A list is provided in Appendix 3.
-Inducers of CYP3A4 that may decrease concentrations of KAND567. Treatment with such drugs should have been stopped at least five halflives before initiation of KAND567 therapy. A list is provided in Appendix 3.
-highly dependent on CYP2B6, CYP2C8 or CYP3A4 for their metabolism where KAND567 may increase their concentrations. Treatment with suchdrugs should have been stopped at least five half-lives before initiation of KAND567 therapy. A list is provided in Appendix 3
20.Continuous use of herbal preparations (e.g., St. John’s wort) within 2 weeks prior to enrollment.
21.Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
22.Known or suspected hypersensitivity to any of the IMPs.
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| E.5 End points |
| E.5.1 | Primary end point(s) | •Occurrence of adverse events (AEs), serious adverse events (SAEs), and dose limiting toxicities (DLTs).
•The safety endpoint parameters are frequency and severity of AEs, vital signs, electrocardiography (ECG), and the results of laboratory safety tests and urinalysis.
•RPIID of KAND567 in combination with carboplatin therapy will be determined based on safety and tolerability (Part 1/Phase Ib only).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | •ORR (overall response rate) at Weeks 12 and 18, according to RECIST 1.1 and GCIG criteria based on CA125 response, i.e., best overall response in subjects with measurable disease, or without measurable disease, evaluable by CA 125.
•Progression-free survival (PFS) at Weeks 12 and 18.
•Overall survival (OS) at end of study.
•Disease control rate (DCR) (Complete response [CR] + Partial response [PR] + Stable disease [SD]) at Weeks 12 and 18.
•Duration of response according to RECIST 1.1 and GCIG definitions (time from documentation of tumor response to disease progression).
•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).
•Change in pain score, as measured by the Numeric Rating Scale (NRS) from baseline (Week 1) to Weeks 4, 7, 10, 13, 16 and 20.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point | Weeks 12 and 18, End of study.
NRS-score from baseline (Week 1) to Weeks 4, 7, 10, 13, 16 and 20.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
