Anti-CD38 A2 DAR T Cells for Multiple Myeloma

Recruiting at 2 trial locations

Overseen By Mike Royal, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sorrento Therapeutics, Inc.

Disqualifiers: Brain metastasis, Spinal cord compression, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 28

54 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop any systemic therapy for multiple myeloma at least 14 days before starting the study treatment. If you have received cellular therapy, it must be at least 8 weeks prior. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment STI-1492, Anti-CD38 A2 KOKI DAR-T cells, for multiple myeloma?

Research shows that similar CD38-targeted CAR-T cell therapies have been effective in killing multiple myeloma cells by activating the immune system to attack these cancer cells. These therapies have demonstrated the ability to reduce tumor growth in laboratory and animal studies, suggesting potential effectiveness for treating multiple myeloma. ^{1 2 3 4 5}

What safety data exists for Anti-CD38 A2 DAR T Cells in humans?

The research on CD38-targeted therapies, including CAR-T cells, shows promising anti-tumor activity with some potential safety concerns. These therapies can effectively target and kill cancer cells, but they may also affect some normal cells that express CD38, such as certain immune cells. However, strategies like using a suicide gene to control the therapy and optimizing the affinity of the CARs have been explored to minimize these effects. ^{1 3 4 5 6}

How is the treatment STI-1492 different from other treatments for multiple myeloma?

STI-1492 is a novel treatment that uses engineered T cells to specifically target and kill multiple myeloma cells by recognizing the CD38 protein on their surface, offering a unique approach compared to traditional therapies like chemotherapy or existing CD38 antibodies. ^{3 4 7 8 9}

What is the purpose of this trial?

This trial tests a new drug called STI-1492 for patients whose multiple myeloma has returned or not responded to other treatments. The drug is given through an IV, and the dose is gradually increased to find the safest and most effective amount.

Research Team

Mike Royal, MD

Principal Investigator

Sorrento Therapeutics, Inc.

Eligibility Criteria

This trial is for adults with relapsed or refractory multiple myeloma who've had previous treatments, can follow the study plan and contraception rules, have CD38 expression in their cancer cells, a life expectancy of at least 12 weeks, measurable disease levels, and good oxygen levels without assistance.

Inclusion Criteria

Your oxygen level when breathing normally is at least 92%.

My multiple myeloma has returned or didn't respond after treatment.

You are expected to live for at least 12 more weeks.

Exclusion Criteria

I have active plasma cell leukemia.

I have had cancer spread to my brain or spine.

My heart's pumping ability is below 40%.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive STI-1492 in a dose-escalation study to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)

28 days per cohort

Staggered intervals of at least 28 days between patients

Expansion Study

Participants receive STI-1492 at the determined RP2D to further assess safety and efficacy

Duration not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 54 months

Treatment Details

Interventions

• STI-1492

Trial Overview The trial tests STI-1492, an experimental therapy involving anti-CD38 T cells. It's given once through the vein to see how safe it is and what dose works best for people whose multiple myeloma has come back or didn't respond to treatment.

Participant Groups

Group I: STI-1492 Experimental Treatment 1 Intervention

Four dosing cohorts will be evaluated: Cohort 1 (1 × 10\^5 donor DAR-T cells/kg); Cohort 2 (5 × 10\^5 donor DAR-T cells/kg); Cohort 3 (1 × 10\^6 donor DAR-T cells/kg); Cohort 4 (3 × 10\^6 donor DAR-T cells/kg) where STI-1492 will be administered intravenously once.

STI-1492 is already approved in United States for the following indications:

Approved in United States as STI-1492 for:

• Relapsed or Refractory Multiple Myeloma

Who Is Running the Clinical Trial?

Sorrento Therapeutics, Inc.

Lead Sponsor

Trials

48

Recruited

2,000+

Findings from Research

The study presents a novel approach to creating CAR-NK cells that target CD38 in multiple myeloma by utilizing CD38dim NK cells, which are generated through long-term IL-2 stimulation, thus avoiding fratricide and enhancing cell viability.

The αCD38-CAR-NK cells demonstrated significant functionality against both CD38+ cell lines and primary multiple myeloma cells, indicating their potential as an effective immunotherapy for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide. Karvouni, M., Vidal-Manrique, M., Susek, KH., et al.[2023]

AMG 424, a bispecific T-cell-recruiting antibody targeting CD38 and CD3, has shown promising efficacy in killing multiple myeloma cells and inducing T-cell proliferation while minimizing excessive cytokine release, which is crucial for reducing potential side effects.

In preclinical models, AMG 424 effectively inhibited tumor growth in mouse models of multiple myeloma and demonstrated B-cell depletion in cynomolgus monkeys, supporting its potential as a new therapeutic option for patients with this cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release. Zuch de Zafra, CL., Fajardo, F., Zhong, W., et al.[2020]

Researchers developed two new second-generation CAR-T cells that specifically target CD38, a protein commonly found on multiple myeloma cells, showing promising results in laboratory tests.

These CD38 CAR-T cells demonstrated effective activation and tumor-killing abilities, significantly outperforming untransduced T cells, and showed potential for rapid tumor elimination in live models, suggesting they could be a new treatment option for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma. Li, X., Feng, Y., Shang, F., et al.[2021]

The newly developed CD38-CAR-T cells, utilizing a nanobody targeting CD38, effectively proliferated and produced inflammatory cytokines, demonstrating strong potential for treating multiple myeloma by lysing CD38+ cancer cells.

In vivo studies showed that these CD38-CAR-T cells inhibited tumor growth in mice, indicating their efficacy as a promising therapeutic strategy for multiple myeloma with minimal off-target effects on healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Multiple Myeloma Activity of Nanobody-Based Anti-CD38 Chimeric Antigen Receptor T Cells. An, N., Hou, YN., Zhang, QX., et al.[2019]

CD38-chimeric antigen receptor-transduced T cells showed strong anti-tumor effects against multiple myeloma and acute myeloid leukemia, effectively killing cancer cells in a dose-dependent manner, indicating their potential as a targeted cancer therapy.

While these engineered T cells can also attack some healthy CD38-positive cells, they do not prevent the growth of hematopoietic progenitor cells, and their activity can be controlled using a suicide gene, suggesting a safety mechanism for managing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Drent, E., Groen, RW., Noort, WA., et al.[2018]

Affinity-optimized CD38CAR NK cells effectively target and eliminate multiple myeloma (MM) cells while sparing nonmalignant cells, demonstrating a strong safety profile.

These engineered NK cells showed significant anti-MM effects in preclinical models, including in patients who were resistant to existing therapies like daratumumab, highlighting their potential as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38-specific Chimeric Antigen Receptor Expressing Natural Killer KHYG-1 Cells: A Proof of Concept for an "Off the Shelf" Therapy for Multiple Myeloma. Stikvoort, A., van der Schans, J., Sarkar, S., et al.[2021]

CD38 is a promising target for immunotherapy in Multiple Myeloma (MM) due to its high and uniform expression on myeloma cells, leading to the development of therapies like monoclonal antibodies (daratumumab and isatuximab).

Recent studies in pre-clinical models and clinical trials show that CD38-targeted immunotherapies, including radioimmunotherapy and CAR T-cell therapy, have potential efficacy in treating MM, although there are still limitations to consider.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Morandi, F., Horenstein, AL., Costa, F., et al.[2020]

This study found that myeloma plasma cells, specifically CD38(bright,++) and CD38(dim,+) cells from eight multiple myeloma patients, can function as antigen-presenting cells, stimulating T-cell responses.

The plasma cells expressed various surface markers and could present antigens, leading to T-cell proliferation and IFN-gamma secretion, indicating a potential role in immune responses despite their cancerous nature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. Yi, Q., Dabadghao, S., Osterborg, A., et al.[2021]

CD38 antibodies, like daratumumab and isatuximab, are effective in treating multiple myeloma by inducing cell death through immunomodulation and enhancing T-cell activity, particularly in patients who respond well to treatment.

Resistance to CD38-targeting therapies can arise from tumor-specific factors, such as reduced CD38 expression, and changes in the immune environment, but strategies exist to overcome these challenges by targeting other pathways involved in immune activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. Bisht, K., Fukao, T., Chiron, M., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide. [2023]

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

Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma. [2021]

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

Anti-Multiple Myeloma Activity of Nanobody-Based Anti-CD38 Chimeric Antigen Receptor T Cells. [2019]

5. Italy pubmed.ncbi.nlm.nih.gov

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. [2018]

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

CD38-specific Chimeric Antigen Receptor Expressing Natural Killer KHYG-1 Cells: A Proof of Concept for an "Off the Shelf" Therapy for Multiple Myeloma. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. [2020]

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

Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. [2021]

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

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. [2023]