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

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ClinicalTrials.gov Identifier: NCT03549442
Recruitment Status : Recruiting
First Posted : June 8, 2018
Last Update Posted : June 20, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Combination Product: BCMA CART + huCART19 Combination Product: CART BCMA or CART BCMA + huCART19 Combination Product: Single-dose infusion of CART BCMA or CART BCMA + huCART19 Phase 1

Detailed Description:

Phase A: 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. - Phase B: 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-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. Phase C: 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Three separate phases. Phases A and C are non-randomized, Phase B is randomized
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Phase 1 Study of CART-BCMA With or Without huCART19 as Consolidation of Standard First or Second-Line Therapy for High-Risk Multiple Myeloma
Actual Study Start Date : May 9, 2018
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Phase A
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
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.

Experimental: Phase B
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
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.

Experimental: Phase C
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
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.




Primary Outcome Measures :
  1. Adverse event reporting [ Time Frame: 90 Days ]
    The number of participants with adverse events that are possibly, probably or definitely related to CAR T cells.


Secondary Outcome Measures :
  1. Clinical outcomes after each CAR T cell regimen [ Time Frame: 2 years ]
    Attainment of PET-negative response (absence of detectable FDG-avid disease by PET/CT).

  2. CART cell disposition [ Time Frame: 2 years ]
    Evaluate CAR T cell disposition using quantitative molecular methods

  3. Evaluate effects of huCART19 on correlative parameters of CART BCMA resistance and clonogenic multiple myeloma cells, such as the following: [ Time Frame: 2 years ]

    Persistence of clonal BCMAdim/neg or CD19+ plasma cells as measured by flow cytometry and immunohistochemistry

    1. Depletion of multiple myeloma clonogenicity as measured using in vitro colony formation assays on bone marrow samples
    2. Induction of anti-Sox2 and other anti-myeloma immune responses
    3. Depletion of clonal CD19+ B cells

  4. Composition of investigative products [ Time Frame: 2 years ]
    Evaluate cellular composition of apheresis product and CARTBCMA/ huCART19 cells.

  5. Maintenance therapy effects on persistence [ Time Frame: 28 days post infusion - 2 years ]
    Evaluate effects of post-infusion maintenance therapy on CAR T cell persistence using quantitative molecular methods.

  6. Maintenance therapy effects on adverse events [ Time Frame: 28 days post infusion - 2 years ]
    Evaluate effects of post-infusion maintenance therapy on CAR T cell adverse events.

  7. Immune cell phenotyping [ Time Frame: 2 years ]
    Characterize the cellular phenotype of multiple myeloma cells that persist after CAR T cell treatment using qualitative molecular methods.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must have a diagnosis of multiple myeloma according to IMWG 2014 criteria106 with any of the following high-risk features:

    1. 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.
    2. High-risk FISH features: 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.
    3. Metaphase karyotype with >3 structural abnormalities except hyperdiploidy
    4. Plasma cell leukemia (>20% plasma cells in peripheral blood) at any time prior to enrollment
    5. 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) 2. Subjects must meet the following criteria with respect to prior myeloma therapy:

    a. Phase A:

    a. Subjects must 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). 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.

    b. Phases B and C:

    1. Subjects must be in their first line of multiple myeloma therapy, with the following exception: subjects who have advanced to second-line therapy due to disease progression during first-line therapy are eligible if such progression occurred within six months of beginning first-line therapy. Lines of therapy are defined by IMWG 2016 criteria1.
    2. Subjects must not have received cytotoxic chemotherapy (e.g., doxorubicin, cyclophosphamide, etoposide, cisplatin) with the following exceptions:

    i. Low-dose weekly cyclophosphamide (≤500 mg/m2/week) ii. Continuous infusion cyclophosphamide, if limited to a single cycle. c. Subjects must not have undergone autologous or allogeneic stem cell transplantation. d. Subjects must have initiated systemic therapy for multiple myeloma ≤1 year prior to enrollment.

    e. Subjects must have received at least 3 complete cycles of their current regimen and have achieved at least a minimal response (as defined by IMWG 2016 criteria1) to the most recent line of therapy.

    3. Subjects must not have achieved a complete or stringent complete response according to IMWG 2016 criteria1 at time of enrollment unless clonal plasma cells are detectable in bone marrow by flow cytometry. (I.e., subjects in complete or stringent complete response are eligible if minimal residual disease can be documented by bone marrow flow cytometry). 4. Subjects must have signed written, informed consent. 5. Subjects must be ≥ 18 years of age. 6. Subjects must have adequate vital organ function:

    1. Serum creatinine ≤ 2.5 or creatinine clearance ≥30 ml/min (measured or estimated according to CKD-EPI) and not dialysis-dependent.
    2. Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if bone marrow plasma cells are ≥50% of cellularity).
    3. SGOT ≤ 3x the upper limit of normal and total bilirubin ≤ 2.0 mg/dl (except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome).
    4. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been performed within 8 weeks of enrollment.

      7. Toxicities from prior/ongoing therapies, with the exception of peripheral neuropathy attributable to multiple myeloma therapy, must have recovered to grade ≤ 2 according to the CTCAE 4.03 5.0 criteria or to the subject's prior baseline.

      8. Subjects must have an ECOG performance status of 0-2. 9. Subjects must be willing to forego first-line ASCT. 10. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.

      Exclusion Criteria:

      1. Pregnant or lactating women
      2. Inadequate venous access for or contraindications to leukapheresis.
      3. Active hepatitis B, hepatitis C, or HIV infection, or other active, uncontrolled infection.
      4. Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.
      5. NYHA Class III or IV heart failure (see Appendix 2), unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (>30 seconds) ventricular tachyarrhythmias.
      6. 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 investigator) autoimmune disease requiring prolonged immunosuppressive therapy.
      7. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03549442


Contacts
Contact: Emerging Medicine 855-216-0098 PennCancerTrials@emergingmed.com

Locations
United States, Pennsylvania
Univ. of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Alfred Garfall, MD         
Sponsors and Collaborators
University of Pennsylvania
Novartis
Investigators
Principal Investigator: Alfred Garfall, MD University of Pennsylvania

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03549442     History of Changes
Other Study ID Numbers: 828773
First Posted: June 8, 2018    Key Record Dates
Last Update Posted: June 20, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Pennsylvania:
Multiple Myeloma
BCMA CART
huCART19

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites