Study of Radspherin® in Recurrent Ovarian Cancer Subjects With Peritoneal Carcinomatosis

Study Overview
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Brief Summary
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RAD-18-001 is a First-In-Man, Dose Escalation study conducted at 2 sites. The dose escalation will be performed based on a 3 + 3 design. Increasing dose levels starting at 1 MBq will be followed by 2, 4 and 7 MBq. If the highest dose level of 7 MBq is reached without Dose Limiting Toxicicities (which will stop the dose escalation), this will be the recommended dose for further exploration. Each subject will be followed until disease progression (in the abdominal cavity), or for 24 months after the administration of Radspherin® (whichever comes first). In the expansion cohort the subject will receive the recommended dose. The expansion cohort will be conducted at 4 sites. Each subject will be followed until disease progression (in the abdominal cavity), or for 24 months after the administration of Radspherin® (whichever comes first).

Detailed Description
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The maximum number of subjects enrolled in this study is 49. The following number of subjects will be recruited in the different cohorts: Dose escalation cohorts: 3 - 24 Subjects Expansion cohort: Up to 25 Subjects

Official Title
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A Phase 1 Study to Evaluate the Dose, Safety and Tolerability of an Intraperitoneal α-emitting Radionuclide Therapy (Radspherin®) in Patients With Platinum Sensitive Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Carcinoma With Peritoneal Carcinomatosis Following CRS

Conditions
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Peritoneal Carcinomatosis, Ovarian Cancer

Intervention / Treatment
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* Drug: Radspherin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent and to comply with the clinical study protocol Age ≥ 18 years Histologically confirmed epithelial ovarian, fallopian tube and primary peritoneal carcinoma Platinum sensitive recurrences of ovarian carcinoma who are eligible for debulking surgery to R0. AEs recovered to at least grade 1 from the effects (excluding alopecia) of any prior medical therapy for malignancy at time of first administration of Radspherin® ECOG Performance Status Score of 0 - 1 Adequate renal function Creatinine ≤ 1.8 mg/dl (159 μmol/l) and calculated creatinine clearance using the Cockcroft-Gault formula ≥ 45 ml/min, or measured creatinine clearance ≥ 45 ml/min Adequate hepatic function Serum bilirubin <1.5 x upper limit of normal (ULN) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/l Platelets ≥ 100 x 10^9/l Haemoglobin ≥ 9 g/dL Adequate coagulation tests: INR ≤ 1.5 x ULN For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment For females of childbearing potential who have a male partner: agreement to use two adequate methods of contraception (e.g. barrier, intrauterine device, hormonal implants, combined oral contraceptives or vasectomized partner), during the treatment period and for at least 3 months after the last dose of IMP. Exclusion Criteria: Neuroendocrine tumors, or non-epithelial ovarian cancers (e.g. germ cell tumors, Sex-cord tumors) Tumors of borderline malignancy Other synchronous visceral metastatic lesions, symptomatic CNS metastases. Metastatic lymph nodes are acceptable, except thoracic lymph nodes. Pregnant or lactating (nursing) women Active infections requiring antibiotics, and/or physician monitoring or recurrent fever >38.0 ⁰C associated with a clinical diagnosis of active infection Active liver disease with positive serology for active hepatitis B, hepatitis C or known HIV Administration of an investigational medicinal product within 28 days, or at least 5 times the half-life, prior to enrolment Concurrent administration of any cancer therapy other than planned study treatment within 4 weeks prior to, and up to 4 weeks after the last study treatment Another primary malignancy within the past 3 years (except for non-melanoma skin cancer, cervical cancer in situ or in situ stage 1 synchronous endometrial cancer) Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease Any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise the safety of the subjects or interfere with the evaluation of the safety of the IMP In the Investigator's opinion not able to comply with study procedures. Any medical or psychological condition that would preclude participation in the study or compromise the ability to give informed consent Treatment with bevacizumab (Avastin®) within 5 weeks prior to CRS Known hypersensitivity to any of the excipients in the study drug Persons who have been placed in an institution under an official or judicial order Persons who are dependent on the sponsor financially must be excluded from participation Persons with active SARS-CoV-2 infection must be excluded from participation

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: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: 3+3 dose escalation study followed by an expansion cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radspherin<br> | Drug: Radspherin<br>* Radspherin® suspension consists of bio-degradable calcium carbonate micro particles with the α-emitting radionuclide 224Ra in suspension. 224Ra has a physical half-life of 3.6 days. The Sponsor will provide Radspherin® in single dose glass vial and the dose for each subject will be prepared at the site.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Dose Limiting Toxicities as assessed by CTCAE v5.0. | To investigate safety and toxicity of Radspherin® | 24 months | 
| Maximum Tolerated Dose (MTD) | To determine the MTD of Radspherin®, among the four suggested doses 1, 2, 4 and 7 MBq, as a single intraperitoneal (IP) injection and two repeated IP injections following cytoreductive surgery (CRS) | 21 days |