Radium-223 + M3814 + Avelumab for Prostate Cancer

Recruiting at 34 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiandrogen therapy, Bone health agents

Must not be taking: CYP3A4/5 inhibitors, CYP2C19 inducers

Disqualifiers: Autoimmune conditions, Recent chemotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to identify the best combination of treatments for castrate-resistant prostate cancer that has spread to other parts of the body. It tests radium-223 dichloride (a radioactive drug) alone, with M3814 (also known as Peposertib, an experimental treatment), or with both M3814 and avelumab (an immunotherapy drug) to determine which option most effectively slows cancer growth or spread in the bones. The trial seeks individuals with prostate cancer that progresses despite hormonal therapy and have two or more bone metastases. Participants should not have active autoimmune conditions or be on medications that interact with the trial drugs. As a Phase 1, Phase 2 trial, it focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications for this trial?

The trial protocol does not specify all medications that need to be stopped, but you must discontinue medications that are strong inhibitors or inducers of CYP3A4/5 or CYP2C19. Strong inhibitors must be stopped at least 1 week before the first M3814 dose, and strong inducers must be stopped at least 3 weeks before. Drugs mainly metabolized by CYP3A with a narrow therapeutic index must be stopped at least 1 day before. Radium-223 dichloride should not be given with abiraterone plus prednisone/prednisolone. Consult with the study doctor about other medications.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect liver enzymes (CYP3A4/5 or CYP2C19) before starting the study. Strong inhibitors must be stopped at least 1 week prior, and strong inducers at least 3 weeks prior to the first dose. You should discuss with the study doctor to see if your current medications are affected.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of radium-223, M3814 (peposertib), and avelumab is generally well-tolerated. Earlier studies found that these treatments did not cause serious side effects for most patients. Radium-223, a radioactive drug, targets cancer cells specifically, usually sparing healthy cells. M3814 blocks certain enzymes necessary for cancer growth and proved safe in early human testing. Avelumab, an immunotherapy, aids the immune system in attacking cancer cells and has been used safely in various cancer treatments.

Overall, testing of this combination in people found it manageable, with few severe side effects reported. However, like any medical treatment, some risks may still exist. Discuss these with a healthcare provider before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a fresh approach to tackling prostate cancer. Unlike traditional treatments such as hormone therapy or chemotherapy, this study combines radium-223 dichloride with the DNA repair inhibitor peposertib and the immune checkpoint inhibitor avelumab. Radium-223 targets bone metastases by emitting radiation, which could be particularly effective for cancer that has spread to the bones. Peposertib enhances the effect by interfering with the cancer cells' ability to repair their DNA. Avelumab further boosts the body's immune response to target and destroy cancer cells. This multi-pronged approach aims to deliver a more comprehensive attack on prostate cancer, potentially improving outcomes for patients.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that radium-223 dichloride can extend the lives of patients with advanced prostate cancer by targeting bone cancer. In this trial, participants in Arm A will receive radium-223 dichloride alone. Arm B will test the combination of radium-223 dichloride with M3814, which might inhibit enzymes that promote cancer growth, potentially preventing tumor enlargement. Arm C will evaluate the combination of radium-223 dichloride, M3814, and avelumab. Early studies suggest that using these three treatments together shows promise. Avelumab may help the immune system fight cancer and prevent its spread. Overall, these treatments aim to reduce the risk of prostate cancer growing or spreading in the bones. ^{1 3 6 7 8}

Who Is on the Research Team?

Hiram Gay

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for men aged 18+ with advanced prostate cancer that's spread and doesn't respond to hormonal therapy. They must have a life expectancy of at least 6 months, be on or willing to continue antiandrogen therapy, and have certain blood levels within specific ranges. HIV-positive patients can join if they're on effective treatment with an undetectable viral load.

Inclusion Criteria

Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

Patients must be able to swallow orally administered medication

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]) with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria

Patients who are receiving any other investigational agents

Patients who have had previous hemibody external radiation

Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive radium-223 dichloride, with or without M3814 and avelumab, for up to 6 cycles

24 weeks

6 cycles, each 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• M3814
• Radium-223 Dichloride

Trial Overview The study tests different combinations of treatments: radium-223 alone, radium-223 with M3814 (a cell growth blocker), or all three including avelumab (an immunotherapy). It aims to find the best dose and combination for treating metastatic castrate-resistant prostate cancer by comparing these approaches.

How Is the Trial Designed?

Group I: Arm C (radium-223 dichloride, nedisertib, avelumab) Experimental Treatment 8 Interventions

Patients receive radium-223 dichloride IV as in Arm A and peposertib PO QD or BID as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 15 of cycles 2-6. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Group II: Arm A (radium-223 dichloride) Active Control 6 Interventions

Patients receive radium-223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Group III: Arm B (radium-223 dichloride, nedisertib) Active Control 7 Interventions

Patients receive radium-223 dichloride as in Arm A and peposertib PO or BID on days 3-26. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Radium-223 Dichloride is already approved in United States, European Union for the following indications:

Approved in United States as Xofigo for:

• Castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease

Approved in European Union as Xofigo for:

• Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Radium-223 dichloride (Ra-223) is an effective treatment for patients with castration-resistant prostate cancer and symptomatic bone metastases, showing a 30% reduction in the risk of death compared to placebo.

Ra-223 is considered to have low toxicity, making it a safe option for patients, and it has been approved by both the FDA and EMA for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Alpha emitter radium-223 dichloride: new therapy in castration-resistant prostate cancer with symptomatic bone metastases]. Heinzer, H., König, F., Klutmann, S.[2021]

Radium-223 dichloride is a unique radiopharmaceutical that uses alpha-emission to effectively treat metastatic castrate resistant prostate cancer (mCRPC) with minimal side effects, particularly low myelosuppression.

Following the successful ALSYMPCA trial, radium-223 was FDA approved in 2013 for patients with mCRPC and symptomatic bone metastases, highlighting its efficacy in prolonging survival in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosing, administration, and safety of radium-223: How I do it. Dan, TD., Doyle, L., Raval, AJ., et al.[2018]

Radium Ra 223 dichloride (Ra-223) significantly improves overall survival in patients with castration-resistant prostate cancer and symptomatic bone metastases, with a median survival of 14.0 months compared to 11.2 months for placebo.

Ra-223 is associated with common side effects such as nausea and diarrhea, and it is the first radiopharmaceutical to show a survival advantage in this type of cancer, marking a significant advancement in treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary. Kluetz, PG., Pierce, W., Maher, VE., et al.[2022]

Radium-223 is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases, offering a new treatment option that requires careful management.

Expert recommendations from 11 nuclear medicine centres across six countries emphasize the importance of structured coordination and communication to optimize radium-223 treatment delivery and enhance patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. Du, Y., Carrio, I., De Vincentis, G., et al.[2023]

Radium-223 dichloride (Xofigo®) significantly improves overall survival and reduces the time to the first symptomatic skeletal event in men with castration-resistant prostate cancer and symptomatic bone metastases, as shown in the ASYMPCA clinical trial.

The treatment is safe, with no adverse events reported for a second cycle, and it can be used alongside chemotherapy without losing efficacy, although further validation is needed for its combination with other treatments like abiraterone or enzalutamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radium-223 dichloride in patients with castration-refractory prostate cancer]. Winter, BM., von Rundstedt, FC., Grimm, MO.[2021]

Radium-223 dichloride (Xofigo®) has shown significant survival benefits for prostate cancer patients with bone metastases and a generally favorable safety profile, but its combination with abiraterone and prednisone may increase risks of death and fractures.

A retrospective analysis of approximately 1500 prostate cancer patients revealed that radium-223 can lead to hematological-related side effects, and its safety profile may vary when used with other treatments, highlighting the need for further studies to clarify its toxicological effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data. Soldatos, TG., Iakovou, I., Sachpekidis, C.[2020]

Radium-223 dichloride is a first-in-class radiopharmaceutical that significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases, based on findings from the Phase III ALSYMPCA trial.

The treatment has a favorable safety profile, with low rates of hematologic adverse events, making it a valuable option for both pre- and post-docetaxel settings in CRPC management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radium-223 dichloride for the treatment of bone metastatic castration-resistant prostate cancer: an evaluation of its safety. Nilsson, S.[2018]

In a study involving 921 patients with castration-resistant prostate cancer and symptomatic bone metastases, radium-223 significantly improved health-related quality of life (QOL) compared to placebo, with 29.2% of patients experiencing meaningful improvement in QOL scores versus 18.5% in the placebo group.

Radium-223 not only enhanced survival rates but also resulted in a slower decline in QOL over time, indicating that it provides both therapeutic and quality of life benefits for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Nilsson, S., Cislo, P., Sartor, O., et al.[2022]

Radium-223 dichloride (Xofigo®) is effective for treating metastatic castration-resistant prostate cancer with bone metastases, showing significant improvements in overall survival and quality of life compared to placebo in the ALSYMPCA trial.

As a calcium mimetic, Radium-223 targets bone lesions and emits high-energy alpha particles that destroy tumor cells, and recent studies indicate it may work even better when combined with newer hormonal treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bone-specific therapy with radium-223 dichloride : Castration-resistant prostate cancer with symptomatic bone metastases]. Tauber, R., Gschwend, J., Scheidhauer, K., et al.[2018]

In a study of 20 patients with metastatic castrate-resistant prostate cancer (mCRPC) treated with Ra-223 dichloride, those with lower baseline PSA levels and fewer bone lesions had a higher likelihood of a favorable response to therapy, indicating better treatment outcomes.

The study found that 8 out of 20 patients showed improvement in pain and functional status after treatment, while 10 patients did not respond favorably, highlighting the importance of patient selection for optimizing Ra-223 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can bone scans guide therapy with radium-223 dichloride for prostate cancer bone metastases? Gayed, I., Salama, V., Dawood, L., et al.[2023]

Citations

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Radiation Medication (Radium-223 Dichloride) Versus ... To determine the safety of radium-223 dichloride, M3814, and avelumab combination treatment. III. To observe and record anti-tumor activity. IV. To evaluate ...

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Phase I study of peposertib and avelumab with or without ... Peposertib (M3814) is a potent and selective DNA-PK inhibitor that had a well-tolerated safety profile in a first-in-human study. In preclinical ...

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A Phase I and Randomized Phase II Trial of Radium-223 ... A trial assessing radium-223, peposertib, and avelumab in advanced metastatic castrate-resistant prostate cancer (mCRPC).