Radioimmunotherapy for Multiple Myeloma

Recruiting in Palo Alto (17 mi)

Overseen by Scott R Goldsmith

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: City of Hope Medical Center

Must be taking: Anti-CD38 antibodies

Must not be taking: Chemotherapy, Radiation, Biologics

Disqualifiers: Asthma, COPD, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for patients with difficult-to-treat or returning multiple myeloma. The treatment aims to target and kill cancer cells more effectively by delivering radiation directly to them.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you cannot receive concurrent chemotherapy, radiation, or biologic treatments for cancer. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Actinium Ac 225-DOTA-Daratumumab for multiple myeloma?

Research shows that Actinium Ac 225-DOTA-Daratumumab, a combination of a radioactive substance and the drug daratumumab, significantly increased its ability to kill cancer cells in multiple myeloma compared to using daratumumab alone. This combination was effective in targeting and destroying cancer cells in laboratory and animal studies without significant side effects. ^{1 2 3 4 5}

Is radioimmunotherapy with daratumumab safe for humans?

Daratumumab, used in various forms including radioimmunotherapy, has been generally well tolerated in clinical trials for multiple myeloma, with common side effects being mild to moderate infusion-related reactions. More serious side effects like low blood cell counts and infections have been observed, but the radioimmunotherapy version with Actinium-225 showed no significant side effects in animal studies, suggesting it may be safe for humans. ^{1 3 4 6 7}

What makes the drug Actinium Ac 225-DOTA-Daratumumab unique for treating multiple myeloma?

This drug is unique because it combines the anti-CD38 antibody daratumumab with a radioactive element, Actinium-225, to enhance its ability to kill cancer cells. This approach, known as radioimmunotherapy, uses radiation to target and destroy multiple myeloma cells more effectively than traditional treatments. ^{1 2 3 4 8}

Research Team

Scott R Goldsmith

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults over 18 with multiple myeloma that's resistant to treatment or has returned. They must have tried at least two prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and anti-CD38 monoclonal antibody. Participants need good organ function and performance status, not be pregnant or breastfeeding, use effective birth control if applicable, and can't have other active cancers or severe lung/heart conditions.

Inclusion Criteria

Your absolute neutrophil count is at least 1,000 per cubic millimeter.

I am a man and will use protection if I have sex with a woman who can have children.

My multiple myeloma cells show CD38 expression.

Exclusion Criteria

Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study

I have not had a heart attack in the last 12 months.

You have a serious abnormality in your heart's electrical activity as shown by an ECG test.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daratumumab IV over 45 minutes, followed by 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Weekly for 8 weeks, every 2 weeks for 4 weeks, every 4 weeks for 16 weeks, then periodically up to 12 months

Treatment Details

Interventions

• Actinium Ac 225-DOTA-Daratumumab (Radioimmunotherapy)
• Daratumumab (Monoclonal Antibodies)
• Indium In 111-DOTA-Daratumumab (Radioimmunotherapy)

Trial Overview The trial tests the safety and optimal dose of a new therapy combining three agents: Actinium Ac 225-DOTA-daratumumab (radioimmunotherapy), Daratumumab (monoclonal antibody), and Indium In 111-DOTA-daratumumab (another radioimmunotherapy). This combination aims to target cancer cells more effectively in those with refractory or recurrent multiple myeloma.

Participant Groups

Group I: Treatment (daratumumab, 225Ac/111In-DOTA-daratumumab) Experimental Treatment 3 Interventions

Patients receive daratumumab IV over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Robert Stone

City of Hope Medical Center

Chief Executive Officer since 2014

Juris Doctorate from the University of Chicago, Bachelor's degree in Political Science from the University of Redlands

Sumanta (Monty) Pal

City of Hope Medical Center

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Daratumumab, when radiolabeled with the alpha-emitter 225Ac, effectively kills CD38-positive tumor cells in vitro while maintaining its original immune functions, suggesting enhanced therapeutic potential for multiple myeloma.

In mouse models, 225Ac-daratumumab showed significantly increased antitumor effects compared to the non-radiolabeled version, with prolonged tumor retention and no significant side effects observed over a 50-day treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors. Dawicki, W., Allen, KJH., Jiao, R., et al.[2021]

Daratumumab is a monoclonal antibody that effectively targets CD38 on multiple myeloma cells, leading to cell death through various mechanisms such as complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

It has shown a favorable safety profile and significant clinical activity as both a standalone treatment and in combination with lenalidomide for patients with relapsed multiple myeloma who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: monoclonal antibody therapy to treat multiple myeloma. Xia, C., Ribeiro, M., Scott, S., et al.[2018]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

Daratumumab, a monoclonal antibody targeting CD38, has shown significant efficacy as a monotherapy in relapsed/refractory multiple myeloma, achieving an overall response in about one-third of patients, with rapid and durable effects.

In combination with other treatments like bortezomib or lenalidomide, daratumumab significantly prolonged progression-free survival, although the overall survival benefit is still being evaluated, and it was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Blair, HA.[2018]

The study successfully developed 89Zr-DFO-daratumumab, a radiolabeled monoclonal antibody that targets CD38 on multiple myeloma cells, showing high radiochemical purity and specificity in preclinical models.

In a phase I trial with 10 patients, 89Zr-DFO-daratumumab was found to be safe and effective for immunologic PET imaging, allowing visualization of myeloma sites in the bone, which could improve disease burden assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging. Ulaner, GA., Sobol, NB., O'Donoghue, JA., et al.[2021]

Daratumumab administered subcutaneously (SC) significantly reduces the time healthcare providers spend on drug preparation and administration compared to intravenous (IV) administration, with a 63.8% reduction in active HCP time for first treatments.

The SC formulation also drastically decreases patient chair time by 97%, making the treatment process more efficient and potentially increasing patient access to care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma. Slavcev, M., Spinelli, A., Absalon, E., et al.[2022]

In a preclinical study of multiple myeloma, the α-emitter 225Ac-DOTA-daratumumab showed superior efficacy compared to the β-emitter 177Lu-DOTA-daratumumab, significantly extending survival and delaying tumor growth at lower doses.

While both therapies had potential for toxicity at higher doses, 225Ac-DOTA-daratumumab achieved better outcomes with less whole-body toxicity, indicating it may be a more effective targeted therapy for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model. Minnix, M., Adhikarla, V., Caserta, E., et al.[2022]

References

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

Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors. [2021]

2. Spain pubmed.ncbi.nlm.nih.gov

Daratumumab: monoclonal antibody therapy to treat multiple myeloma. [2018]

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

Daratumumab: First Global Approval. [2018]

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

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. [2018]

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

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging. [2021]

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

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

EMA Review of Daratumumab for the Treatment of Adult Patients with Multiple Myeloma. [2020]

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

Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model. [2022]