Radium-223 + M3814 + Avelumab for Prostate Cancer

Recruiting at 28 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

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

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the best dose of M3814 when given together with radium-223 dichloride or with radium-223 dichloride and avelumab and to see how well they work in treating patients with castrate-resistant prostate cancer that had spread to other places in the body (metastatic). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as radium-223 dichloride, may carry radiation directly to tumor cells and not harm normal cells. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to find out the better treatment between radium-223 dichloride alone, radium-223 dichloride in combination with M3814, or radium-223 dichloride in combination with both M3814 and avelumab, to lower the chance of prostate cancer growing or spreading in the bone, and if this approach is better or worse than the usual approach for advanced prostate cancer not responsive to hormonal therapy.

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.

What data supports the idea that Radium-223 + M3814 + Avelumab for Prostate Cancer is an effective treatment?

The available research shows that Radium-223, when used for prostate cancer with bone metastases, can improve overall survival and reduce pain, leading to a better quality of life compared to a placebo. It is effective in patients who have not responded to other treatments and can be used alongside other medications without reducing its effectiveness. However, there is no specific data on the combination of Radium-223 with M3814 and Avelumab, so its effectiveness as a combined treatment is not yet confirmed. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Radium-223 dichloride for prostate cancer?

Radium-223 dichloride has been shown to improve overall survival and reduce pain in men with castration-resistant prostate cancer that has spread to the bones. It also enhances quality of life compared to a placebo, and its effectiveness is not reduced when used with certain chemotherapy drugs. ^{1 2 3 4 5}

What safety data exists for the treatment of Radium-223, M3814, and Avelumab in prostate cancer?

Radium-223 dichloride (Xofigo) has been approved for treating castration-resistant prostate cancer with symptomatic bone metastases. It has shown a favorable safety profile, though it may cause hematological side effects like anemia and leukopenia. When combined with other drugs, its safety profile may change, and there is an increased risk of death and fractures when used with abiraterone and prednisone/prednisolone. More studies are needed to fully understand its safety, especially in combination therapies. Common adverse reactions include nausea, diarrhea, and peripheral edema. ^{1 6 7 8 9}

Is the combination of Radium-223, M3814, and Avelumab safe for humans?

Radium-223 dichloride, used alone, has shown a favorable safety profile with common side effects like nausea, diarrhea, and blood-related issues such as anemia (low red blood cell count). However, when combined with other drugs, its safety profile may change, and more studies are needed to fully understand the risks. ^{1 6 7 8 9}

Is the drug Radium-223 Dichloride a promising treatment for prostate cancer?

Yes, Radium-223 Dichloride is a promising treatment for prostate cancer. It has been shown to improve survival rates and enhance the quality of life for patients with advanced prostate cancer that has spread to the bones. It is approved by major health agencies like the FDA and EMA, and it is easy to use in medical settings. ^{3 4 7 9 10}

What makes the Radium-223 treatment unique for prostate cancer?

Radium-223 is unique because it is a targeted alpha therapy that specifically targets bone metastases in prostate cancer, using alpha particles to deliver high-intensity radiation directly to cancer cells in the bones, minimizing damage to surrounding healthy tissue. This approach is different from other treatments as it focuses on bone metastases and has shown to improve survival with minimal side effects. ^{3 4 7 9 10}

Research Team

Hiram Gay

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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®) 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]

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 (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 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 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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Radium-223 dichloride in patients with castration-refractory prostate cancer]. [2021]

2. England pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

Can bone scans guide therapy with radium-223 dichloride for prostate cancer bone metastases? [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

[Bone-specific therapy with radium-223 dichloride : Castration-resistant prostate cancer with symptomatic bone metastases]. [2018]

6. Switzerland 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. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

[Alpha emitter radium-223 dichloride: new therapy in castration-resistant prostate cancer with symptomatic bone metastases]. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary. [2022]

9. Canada pubmed.ncbi.nlm.nih.gov

Dosing, administration, and safety of radium-223: How I do it. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. [2022]