Phase 2 Randomized Study of Radium-224 Adsorbed in Calcium Carbonate Microparticles for Peritoneal Carcinomatosis from Colorectal Carcinoma Post-CRS and HIPEC

Trial ID: 2023-508496-37-00
Protocol: RAD-18-004
Sponsor: Oncoinvent ASA

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Diseases & Conditions

Metastases to peritoneum

Objectives

The primary objective of this study is to compare **progression-free survival (PFS)** in patients with peritoneal metastasis from colorectal carcinoma (CRC) following treatment with Radspherin® versus no treatment. This objective is clinically relevant as it evaluates the potential of Radspherin® to delay disease progression, which is crucial for improving patient outcomes in peritoneal carcinomatosis.

Secondary objectives include:

Comparing peritoneal progression-free survival (PPFS) in patients with peritoneal metastasis from CRC following Radspherin® treatment versus no treatment.
Comparing overall survival (OS) in these patients.
Assessing changes from baseline in biomarkers such as carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 125 (CA125).
Evaluating Quality of Life (QoL) in patients receiving Radspherin® versus no treatment.
Comparing the safety and tolerability of Radspherin® treatment.
Assessing rates of 30-day and 1-year post-operative complications.
Comparing the incidence of adverse events of special interest (AESIs).

These secondary objectives aim to provide a comprehensive evaluation of the therapeutic impact and safety profile of Radspherin® in this patient population.

Participants

The clinical trial involves a total of **37 participants** diagnosed with **carcinomatosis of the peritoneal cavity** secondary to colorectal carcinoma. The study population includes both male and female subjects aged 18 years and older, with no vulnerable populations selected. Participants were chosen based on their ability to provide informed consent and comply with the clinical study protocol. Key lifestyle considerations include the requirement for females of childbearing potential to use highly effective contraception methods during the treatment period and for a specified duration afterward. Similarly, non-sterile males must agree to use condoms and refrain from donating sperm during and after the treatment period. The participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate renal, hepatic, and bone marrow functions are also necessary for inclusion, ensuring participants are in a general health status that allows for safe participation in the trial. The trial aims to compare progression-free survival in patients receiving Radspherin® treatment versus no treatment.

Plans and Procedures

The clinical trial is a **Phase 2**, randomized, open-label, multicenter study designed to evaluate the efficacy and safety of an intraperitoneal **α-emitting radionuclide therapy** in patients with **peritoneal carcinomatosis** from colorectal carcinoma following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The trial aims to compare progression-free survival in patients receiving the investigational product, Radspherin, versus those receiving no treatment. The study is expected to commence recruitment in September 2024 and conclude by March 2031.

Participants will be randomly assigned to either the treatment group receiving Radspherin or the control group. The investigational product is administered as a **suspension for injection** via intraperitoneal use. The maximum treatment period is 29 days, with a daily dose not exceeding 7 MBq. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The primary endpoint is progression-free survival, assessed using CT/MRI and RECIST v1.1 criteria. Secondary endpoints include overall survival, changes in biomarkers, and patient-reported outcomes.

Participant involvement is expected to last from the date of randomization until the end of the study, with specific follow-up periods for safety assessments. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The study is conducted in accordance with ethical guidelines, and all participants must provide written informed consent prior to enrollment. Eligibility criteria include a confirmed diagnosis of colorectal carcinoma with peritoneal metastases, adequate organ function, and an ECOG performance status of 0 to 1. The trial excludes individuals who do not meet these criteria or who have unresolved adverse effects from prior treatments.

Treatment

The clinical trial involves the administration of **Radspherin**, an experimental medication formulated as a **suspension for injection**. The active substance in Radspherin is **radium-224 adsorbed in calcium carbonate microparticles**. This investigational product is designed for **intraperitoneal use**. The maximum daily dose is set at 7 MBq (megabecquerel), with a total maximum dose of 7 MBq over the treatment period. The treatment duration is limited to a maximum of 29 days. Radspherin is not a pediatric formulation and is not classified as an orphan drug. The product is developed by Oncoinvent and is identified by the sponsor product code 224Ra-CaCO3 microparticles.

In this study, Radspherin is being evaluated for its efficacy and safety in patients with peritoneal carcinomatosis from colorectal carcinoma following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The trial is a Phase 2, randomized, open-label, multicenter study. The primary objective is to compare progression-free survival in patients receiving Radspherin treatment versus those receiving no treatment. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS is defined as the time from the date of randomization until the date of first progression or death, whichever occurs first. This will be evaluated using CT/MRI imaging and according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Secondary endpoints include overall survival (OS), which is the time from randomization until death from any cause, and peritoneal progression-free survival (PPFS), defined as the time from randomization until the first progression in the peritoneum or death from any cause, assessed similarly to PFS.

Additional secondary endpoints involve changes in biomarkers such as CEA, CA19-9, and CA125, as well as changes from baseline in patient-reported outcome scores using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 quality of life forms. The incidence, relatedness, severity, and seriousness of adverse events (AEs) will be characterized using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Changes from baseline in laboratory values, vital signs, and body weight will also be monitored. The proportion of patients with documented surgical complications according to the Clavien-Dindo-Slankamenac classification during the treatment period and up to one year post-randomization will be recorded. The incidence, relatedness, severity, and seriousness of adverse events of special interest (AESIs) will also be assessed using the NCI CTCAE version 5.0.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Able and willing to provide written informed consent and to comply with the clinical study protocol (CSP).
Age ≥ 18 years.
Histologically confirmed colorectal carcinoma. In case of recurrent metastatic disease from colorectal carcinoma to the peritoneal cavity, where the clinical diagnosis seems clear, a confirmative frozen section biopsy of the peritoneal metastases (consistent with metastasis from colorectal carcinoma) during surgery is acceptable.
Peritoneal metastases eligible for cytoreductive surgery where resection to no residual tumour (CC-0) is deemed to be achievable.
AEs recovered to at least Grade 1 from the effects (excluding alopecia) of any prior medical therapy for malignancy.
Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0 to 1
Adequate renal function: Calculated creatinine clearance using the Cockcroft-Gault formula ≥ 40 ml/min or measured creatinine clearance ≥ 40 ml/min.
Adequate hepatic function: 1) Serum bilirubin < 1.5 x upper limit of normal (ULN), and 2) Aspartate transaminase and alanine transaminase ≤ 3 x ULN.
Adequate bone marrow function: 1) Absolute neutrophil count ≥ 1.0 x 10^9/l, and 2) Platelets ≥ 100 x 10^9/l, and 3) Hemoglobin ≥ 9 g/dL.
For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment.
For females of childbearing potential: agreement to use at least one of the following highly effective (failure rate < 1%) methods of contraception during the treatment period and for at least 9 months if they receive Radspherin®: 1) Total abstinence (when this is in line with the preferred and usual lifestyle of the patient), periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 2) Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before enrolment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. 3) Use of oral (oestrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Note: In addition to the use of one highly effective method of contraception as listed above, a condom is required for all male partners during the treatment period and for at least 9 months after the dose of IMP, unless vasectomised at least 6 months prior to enrolment.
For non-sterile males whose female partner is of childbearing potential: agreement to use condom during the treatment period and for at least 6 months if they received Radspherin®. The female partner should use at least one of the following highly effective (failure rate < 1%) methods of contraception during the same period: 1) Total abstinence (when this is in line with the preferred and usual lifestyle of the patient), periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. 2) Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before enrolment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. 3) Use of oral (oestrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Non-sterile males must agree to refrain from donating sperm for the entire treatment period and for up to 6 months after the dose of IMP.

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Exclusion Criteria

Presence of peritoneal metastasis originating from appendix vermiformis, other synchronous metastatic lesions, symptomatic central nervous system metastases. Suspicion of non-regional (e.g. retroperitoneal, thoracic) metastatic lymph nodes on imaging.
Rectal carcinoma previously treated with pelvic radiation.
Suspicion of peritoneal leak, shunt, or otherwise suspected atypical target compartment pharmacokinetics, based on investigator’s judgement, patient history and diagnostic images.
Pregnant or lactating (nursing) women.
Active infections requiring antibiotics and/or physician monitoring, or recurrent fever >38.0 °C associated with a clinical diagnosis of active infection.
Administration of an investigational medicinal product within 4 weeks or at least 5 times the half-life of the product, prior to enrolment.
Concurrent administration of any other cancer therapy other than the planned study treatment within 4 weeks prior to and up to 4 weeks after the surgery.
Another primary malignancy within the past 3 years (except for non-melanoma skin cancer, cutaneous melanoma stage 1, cervical cancer in situ, or in situ Stage 1 synchronous endometrial cancer).
Concurrent congestive heart failure or prior history of New York Heart Association 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 patient or interfere with the evaluation of the safety of the investigational medicinal product.
Any patient who, in the investigator’s opinion, was not able to comply with study procedures. Presence of any medical or psychological condition that would preclude participation in the study or compromise the ability of the patient to give informed consent.
Known hypersensitivity to any of the excipients in the study drug.