A Phase 1b Clinical Trial of CRISPR Delivered Anti-BCMA Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Multiple Myeloma

Plain English Summary

CRISPR Delivered Anti-BCMA Car-T Therapy for Relapsed or Refractory Multiple Myeloma is a Phase 1 clinical trial sponsored by Thomas Martin, MD studying Multiple Myeloma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma. This trial tests a new type of cell therapy called CRISPR-delivered CAR-T cells that are designed to target and kill multiple myeloma cells. It is for patients with multiple myeloma that has returned or not responded to at least three prior treatments. Participation involves a procedure to collect your T-cells, which are then modified in the lab and given back to you, along with chemotherapy. Alternative treatments for relapsed or refractory multiple myeloma include other types of cell therapies, chemotherapy, and targeted drugs. The trial aims to enroll 30 participants.

Official Summary

This phase Ib trial tests the safety, side effects and best dose of clustered regularly interspaced short palindromic repeats (CRISPR) delivered anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells (1XX BCMA CAR-T cells) in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Anti-BCMA CAR-T cell therapy is a type of treatment in which a person's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, such as BCMA, on the patient's cancer cells is added to the T cells in the laboratory by a tool called clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. The special receptor is called a CAR. Large numbers of the CAR-T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving chemotherapy before CAR-T cells may decrease the number of lymphocytes (a type of white blood cells) in the blood and may help the 1XX BCMA CAR-T cells fight the cancer cells. Treatment with 1XX BCMA CAR-T cells may be safe, tolerable, and/or effective in treating patients with relapsed or refractory multiple myeloma (RRMM).

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with a diagnosis of multiple myeloma that has relapsed or is refractory to treatment. Patients must have received at least three prior therapies, including specific types like proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies. You cannot have active cancer spread to the brain or spinal cord, or certain other active cancers. Good organ function (heart, kidney, liver) and bone marrow function are required. This trial is studying Multiple Myeloma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will tell us how safe this new therapy is, what the highest safe dose is, and how well it works in controlling or shrinking the multiple myeloma. The specific primary outcome measures are: Proportion of participants with treatment-emergent adverse events (Up to 12 months following CAR-T infusion); Proportion of participants who experience dose-limiting toxicity (DLT) (Dose Escalation) (Up to 30 days); Maximum Tolerated Dose (MTD) (Dose Escalation) (Up to 28 days); Best Overall Response Rate (BORR) (Dose expansion + MTD dose escalation cohort) (Up to 12 months following CAR-T infusion); Proportion of participants with of severe neurologic events (Dose Expansion) (From initiation of study treatment to 12 months following CAR-T infusion, approximately 13 months total). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial explores a novel CRISPR-enhanced CAR-T therapy, aiming to provide a more effective treatment option for patients with multiple myeloma who have exhausted standard therapies. This research targets Multiple Myeloma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma, where improved treatment options are needed.

Investor Insight

This trial targets a significant unmet need in relapsed/refractory multiple myeloma, a market with substantial patient numbers and ongoing innovation in cell therapies, suggesting potential for a valu Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of this experimental therapy, and how it compares to other available treatments. Be prepared for a process that includes cell collection, chemotherapy, and then receiving the modified cells, followed by close monitoring for side effects. You will need to use effective contraception during and for a period after treatment. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 30 participants

Interventions

• PROCEDURE: Leukapheresis — Undergo Leukapheresis
• DRUG: Cyclophosphamide — Given Intravenously (IV)
• BIOLOGICAL: Chimeric Antigen Receptor T cells (CAR-T) Targeting BCMA — Given Intravenously (IV)
• BEHAVIORAL: Quality of Life (QoL) Questionnaires — Ancillary studies
• PROCEDURE: Bone Marrow Biopsy — Undergo biopsy

Primary Outcomes

• Proportion of participants with treatment-emergent adverse events (Up to 12 months following CAR-T infusion)
• Proportion of participants who experience dose-limiting toxicity (DLT) (Dose Escalation) (Up to 30 days)
• Maximum Tolerated Dose (MTD) (Dose Escalation) (Up to 28 days)
• Best Overall Response Rate (BORR) (Dose expansion + MTD dose escalation cohort) (Up to 12 months following CAR-T infusion)
• Proportion of participants with of severe neurologic events (Dose Expansion) (From initiation of study treatment to 12 months following CAR-T infusion, approximately 13 months total)

Secondary Outcomes

• Overall Response Rate (ORR) - Long term (Up to 15 years)
• Median Duration of Response (DoR) - Beginning of response (Up to 15 years)
• Median Progression-free Survival from Study Entry (PFS-SE) (up to 15 years)
• Median DoR - First documented response (up to 15 years)
• Median Overall Survival (OS) (up to 15 years)

Full Eligibility Criteria

Inclusion Criteria:

1. Voluntarily sign informed consent form.
2. Age ≥18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. Diagnosis of multiple myeloma (per IMWG criteria) with relapsed or refractory disease and has received at least 3 prior lines of therapy including proteasome inhibitor immunomodulatory therapy, and anti-Cluster of differentiation 38 (CD38) antibody therapy.
5. Participants may have received BCMA targeted therapy and must be at least 6 months from last BCMA therapy.
6. Participants must have documented evidence of progressive disease within 12 months of the last line of therapy or be refractory/nonresponsive to their most recent line.
7. Participants must have measurable disease, defined as at least one of the criteria below:

   * Serum M-protein greater or equal to 0.5 grams per deciliter (g/dL).
   * Urine M-protein greater or equal to 200 milligrams, over a 24-hour period (mg/24 h).
   * Serum free light chain (FLC) assay: involved FLC level of ≥ 100 milligrams per liter (mg/L).
8. Adequate organ function, defined as:

   * Adequate bone marrow function for apheresis and lymphodepleting chemotherapy.
   * Hgb \>8 gm/dl (transfusions allowed).
   * Platelets \>50,000/microliter (uL) (in the absence of platelet transfusion within 7 days of apheresis, but transfusion permitted prior to lymphodepleting chemotherapy).
   * Absolute neutrophil count (ANC) \> 1000/uL in the absence of growth factor support (filgrastim within 7 days or pegfilgrastim within 14 days of apheresis, but growth factor permitted prior to lymphodepleting chemotherapy). For those patients who have evidence of duffy null, ANC \>750/uL is allowed.
   * Absolute lymphocyte count (ALC) \>300/uL.
   * Alanine aminotransferase/aspartate aminotransferase (ALT/AST) \< 3 x institutional upper limit of normal (ULN) and Total bilirubin \< 1.5 milligrams per deciliter (mg/dl) x institutional ULN, except with Gilbert's syndrome.
   * Serum creatinine clearance (CrCl) ≥ 30 milliliter per minute (mL/min) using Cockcroft-Gault formula or as measured with a 24 hour urine collection.
   * Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) \> 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) and adequate pulmonary function (measured by room air pulse oximetry ≥ 92%).
9. Women of childbearing potential must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-BCMA CAR-T cells.
10. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method for 6 months after CAR-T therapy.

Exclusion Criteria:

1. Autologous transplant within 12 weeks of planned CAR-T cell infusion.
2. Prior antitumor therapy as follows, prior to apheresis:

   * Investigational therapy within 14 days, or at least 5 half-lives.
   * Monoclonal antibody therapy within 21 days.
   * Cytotoxic therapy within 14 days.
   * Proteasome inhibitor therapy within 14 days.
   * Immunomodulatory therapy within 14 days.
   * Radiotherapy within 14 days - with the exception that if radiotherapy (XRT) covers \<5% of marrow reserve - no rest window needed.
3. Toxicity from previous anticancer therapy must resolve to baseline levels or to Grade 1 or less except for alopecia, peripheral neuropathy and baseline hematologic toxicity that otherwise meets inclusion.
4. Active CNS multiple myeloma, plasma cell leukemia, primary AL amyloidosis or POEMS syndrome.
5. Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast). Any fully treated malignancies or indolent, clinically insignificant malignancies can be discussed among the study team to determine eligibility.
6. HIV seropositivity.
7. Serologic status reflects active hepatitis B or C infection. Participants that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive participants will be excluded).
8. Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pulmonary abnormalities, or psychiatric illness/social situations that would limit compliance with study requirements.
9. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study.

   NOTE: Women of childbearing potential must have a negative serum or urine pregn

Trial Locations

• University of California, San Francisco, San Francisco, California, United States

Frequently Asked Questions

Related Conditions

• Multiple Myeloma
• Recurrent Multiple Myeloma
• Refractory Multiple Myeloma
• Plasma Cell Neoplasms
• Monoclonal Gammopathy
• Amyloidosis
• POEMS Syndrome
• Hematologic Malignancies
• Immunotherapy
• Gene Therapy

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