Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma

NCT03549442 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: 828773
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA, with or without huCART19, in patients responding to first- or second-line therapy for high-risk multiple myeloma. The regimen evaluated in this study is based on established safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in combination with huCART19, and (4) as a single rather than split-dose infusion.

Conditions

Multiple Myeloma

Keywords

Multiple Myeloma; BCMA CART; huCART19

Outcome Measures

Primary Outcomes (1)

• Adverse event reporting

  The occurrence of adverse events that are possibly, probably or definitely related to CAR T cells.

  90 Days

Secondary Outcomes (16)

• Adverse event reporting

  15 years

• Clinical outcomes after each CAR T cell regimen

  2 years

• Duration of Response

  15 years

• Progression-free Survival (PFS)

  15 years

• Overall Survival (OS)

  15 years

Study Arms (4)

Phase A

EXPERIMENTAL

Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have relapsed/refractory myeloma after two prior regimens but who are responding to their current therapy.

Combination Product: BCMA CART + huCART19

Phase B

EXPERIMENTAL

Randomization Phase in which patients responding to first or second-line therapy will receive either CART-BCMA alone (Cohort 1) or CART-BCMA + huCART19 (Cohort 2) as split-doses after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Combination Product: CART BCMA or CART BCMA + huCART19

Phase C

EXPERIMENTAL

Single-dose infusion phase to test the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19 (Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients responding to first- or second-line therapy.

Combination Product: Single-dose infusion of CART BCMA or CART BCMA + huCART19

Phase A Expansion

EXPERIMENTAL

Once safety of CART-BCMA/huCART19 combination therapy is established in Phase A, an expansion of Phase A will occur in which the Phase A target population (patients with relapsed/refractory multiple myeloma responding to a standard salvage therapy regimen) will receive both CART-BCMA and huCART19. Enrollment into the Phase A Expansion may occur concurrently with Phase B once opened.

Combination Product: BCMA CART + huCART19

Interventions

BCMA CART + huCART19 COMBINATION_PRODUCT

The target dose for CART-BCMA and huCART19 will be 5x108 CAR-expressing cell for each product. Split dose infusions will consist of a 10% dose (of one or both products) on the first infusion day, 30% dose (of one or both products) on the second infusion day, or 60% dose (of one or both products) on the third infusion day. Infusion days may be spread over 7 calendar days due to scheduling constraints or to allow observation of suspected early cytokine release syndrome or other toxicity. Infusions will begin 3 days (+/- 1 day) after completion of lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Phase A

CART BCMA or CART BCMA + huCART19 COMBINATION_PRODUCT

The target dose for CART-BCMA and huCART19 will be 5x108 CAR-expressing cell for each product. Cohort 1 refers to the group of subjects assigned to receive CART-BCMA alone; Cohort 2 refers to the group of subjects assigned to receive CART-BCMA + huCART19. Split dose infusions will consist of a 10% dose (of one or both products) on the first infusion day, 30% dose (of one or both products) on the second infusion day, or 60% dose (of one or both products) on the third infusion day. Infusion days may be spread over 7 calendar days due to scheduling constraints or to allow observation of suspected early cytokine release syndrome or other toxicity. Infusions will begin 3 days (+/- 1 day) after completion of lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Phase B

Single-dose infusion of CART BCMA or CART BCMA + huCART19 COMBINATION_PRODUCT

The target dose for CART-BCMA and huCART19 will be 5x108 CAR-expressing cell for each product. Cohort 1 refers to the group of subjects assigned to receive single dose infusions of CART-BCMA alone; Cohort 2 refers to the group of subjects assigned to receive single dose infusions of CART-BCMA + huCART19. Infusions will begin 3 days (+/- 1 day) after completion of lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Phase C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106 with any of the following high-risk features. Subjects in the Phase A Expansion are not required to have any high-risk features.
• Beta-2-microglobulin ≥ 5.5 mg/L and LDH greater than upper limit of normal. Note: subjects in whom LDH and/or Beta-2-microglobulin were not measured prior to initiation of systemic therapy may qualify based on measurements obtained after initiation of systemic therapy.
• High-risk FISH features: at least one of the following \[deletion 17p, t(14;16), t(14;20), t(4;14)\] in conjunction with Beta-2-microglobulin ≥ 5.5 mg/L (i.e., revised ISS stage 3). Note: subjects in whom Beta-2-microglobulin was not measured prior to initiation of systemic therapy may qualify based on measurements obtained after initiation of systemic therapy.
• Metaphase karyotype with \>3 structural abnormalities except hyperdiploidy
• Plasma cell leukemia (\>20% plasma cells in peripheral blood) at any time prior to physician-investigator confirmation of eligibility.
• Failure to achieve partial response or better (by IMWG 2016 criteria1) to initial therapy with an "imid/PI" combination (thalidomide, lenalidomide, or pomalidomide in combination with bortezomib, ixazomib, or carfilzomib).
• Early progression on first-line therapy, defined as progression (according to IMWG 2016 criteria1)
• i. Within one year of starting first-line therapy with an "imid/PI"combination ii. Within six months of completing first line therapy with an "imid/PI"combination (i.e. a patient who receives an "imid/PI" combination, transitions to observation or maintenance therapy, and progresses within six months of this transition) iii. Within one year of a high-dose melphalan and autologous stem cell transplantation (Phase A subjects only)
• Subjects must meet the following criteria with respect to prior myeloma therapy:
• a. Phase A and Phase A expansion:
• a. Subjects must meet the following criteria with respect to prior multiple myeloma therapy: i. have disease that has relapsed after or has been refractory to at least two regimens, including a proteasome inhibitor and thalidomide analog (thalidomide, lenalidomide, pomalidomide), OR ii. have disease that has relapsed after or has been refractory to one prior regimen if their prior/current therapy collectively has included all of the following: an "imid/PI" combination, pomalidomide, lenalidomide, daratumumab, and carfilzomib.
• Note: Refractoriness is defined as disease progression on-therapy or within 60 days of stopping therapy.
• b. Subjects must have achieved at least a minimal response (as defined by IMWG 2016 criteria1) to their current regimen.
• c. Subjects must not have received prior treatment with anti-BCMA cellular therapy. Subjects may have received treatment with other BCMA-directed agents (e.g., anti-BCMA antibody-drug conjugates or bispecific antibodies).
• b. Phases B and C:

You may not qualify if:

• Pregnant or lactating women
• RETIRED WITH PROTOCOL V6
• Active hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection.
• Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.
• NYHA Class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (\>30 seconds) ventricular tachyarrhythmias.
• Have active auto-immune disease, including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy.
• Have prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease, parenchymal masses) with myeloma. Screening for this (e.g. with lumbar puncture) is not required unless suspicious symptoms or radiographic findings are present. Subjects with calvarial disease that extends intracranially and involves the dura will be excluded, even if CSF is negative for myeloma.

Sponsors & Collaborators

• University of Pennsylvania: lead
• Novartis: collaborator

Study Sites (1)

Univ. of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (1)

• Zhang Z, Markmann C, Yu M, Agarwal D, Rostami S, Wang W, Liu C, Zhao H, Ochoa T, Parvathaneni K, Xu X, Li E, Gonzalez V, Khadka R, Hoffmann J, Knox JJ, Scholler J, Marcellus B, Allman D, Fraietta JA, Samelson-Jones B, Milone MC, Monos D, Garfall AL, Naji A, Bhoj VG. Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies. Cell Rep Med. 2023 Dec 19;4(12):101336. doi: 10.1016/j.xcrm.2023.101336.

  PMID: 38118406 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Alfred Garfall, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Three separate phases. Phases A and C are non-randomized, Phase B is randomized

Study Record Dates

• First Submitted: April 27, 2018
• First Posted: June 8, 2018
• Study Start: May 9, 2018
• Primary Completion (Estimated): March 1, 2036
• Study Completion (Estimated): March 1, 2036
• Last Updated: June 26, 2025

Record last verified: 2025-06

Locations

US (1)