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A Dose-escalation Study to Evaluate the Safety and Clinical Activity of PBCAR269A in Study Participants With Relapsed/Refractory Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04171843
Recruitment Status : Recruiting
First Posted : November 21, 2019
Last Update Posted : July 30, 2020
Sponsor:
Information provided by (Responsible Party):
Precision BioSciences, Inc.

Brief Summary:
This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR269A in adults with r/r MM.

Condition or disease Intervention/treatment Phase
Relapsed/Refractory Multiple Myeloma Genetic: PBCAR269A Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

Detailed Description:
This is a multicenter, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR269A in adults with r/r MM. Before initiating the study treatment PBCAR269A, all study participants will be administered lymphodepletion chemotherapy. The initial lymphodepletion chemotherapy regimen will be composed of fludarabine and cyclophosphamide during the Screening Period. On Day 0 of the Treatment Period, study participants will receive a single intravenous (IV) infusion of PBCAR269A. All subjects are monitored during the treatment period through Day 28. All subjects who receive a dose of PBCAR269A will be followed in a separate long-term follow-up (LTFU) study for 15 years after exiting this study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: In Phase I, 3 escalating dose groups will be enrolled and treated sequentially, with the possibility of a single de-escalation. Within each dose group, at least 3 and at most 6 study participants will be treated with a single dose of PBCAR269A using a standard 3 + 3 design. The starting dose of PBCAR269A will be 6 x 105 CAR T cells/kg body weight. Subsequent dose groups will be treated with escalating doses to a maximum dose of 6 x 106 CAR T cells/kg. In the absence of DLTs, the dose will be increased using a fixed-dose scheme.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a, Open-label, Dose-escalation, Dose-expansion Study to Evaluate the Safety and Clinical Activity of PBCAR269A in Study Participants With Relapsed/Refractory Multiple Myeloma
Actual Study Start Date : April 30, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: PBCAR269A at Dose Level 1
The starting dose of PBCAR269A will be 6 x 10^5 CAR T cells/kg body weight.
Genetic: PBCAR269A
Allogeneic anti-BCMA CAR T-cell

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.

Experimental: PBCAR269A at Dose Level 2
2 × 10^6 CAR T cells/kg body weight.
Genetic: PBCAR269A
Allogeneic anti-BCMA CAR T-cell

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.

Experimental: PBCAR269A at Dose Level 3
6 × 10^6 CAR T cells/kg body weight.
Genetic: PBCAR269A
Allogeneic anti-BCMA CAR T-cell

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of PBCAR269A [ Time Frame: Day 1 - Day 28 ]
    To determine the maximum tolerated dose (MTD), which is defined as the dose level at which fewer than 33% of patients experience a dose limiting toxicity (DLT) using a 3+3 strategy.


Secondary Outcome Measures :
  1. Number of Participants with Dose Limiting Toxicity(ies) [ Time Frame: 1 year ]
    To assess adverse events as dose limiting toxicities as defined by the protocol and CTCAE v5.0.

  2. Objective Response Rate of Patients [ Time Frame: 1 year ]

    To assess ORR to treatment with PBCAR269A through Day 360 will be noted using the IMWG response criteria.

    The ORR is defined as the proportion of study participants meeting the definition of response within the study population to the response evaluable population. ORR will be summarized by number and percentage of study participants meeting the definition of ORR along with the corresponding exact 95% CIs. DoR, defined as the duration (days) from initial response to disease relapse, progression, or death will be descriptively analyzed using Kaplan-Meier methods. The number of study participants achieving DoR at 3, 6, 9, and 12 months will also be calculated. Exploratory efficacy analyses include changes from Baseline in CBC counts, CAR T cells, cytokines, and CRP levels.




Information from the National Library of Medicine

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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:

  1. Diagnosis of MM with relapsed and/or refractory disease according to the IMWG criteria.
  2. Measurable disease at Screening including at least 1 of the criteria below. Note: Study participants with immunoglobulin (Ig) A myeloma in whom serum protein electrophoresis is deemed unreliable due to comigration of normal serum proteins with the paraprotein in the beta region may be considered eligible provided total serum IgA level is >400 mg/dL.

    1. Serum myeloma (M)-protein ≥0.5 g/dL or, urine M-protein >200 mg/24 hour.
    2. Serum free light chain >10mg/dL with abnormal kappa:lambda ratio.
    3. Imaging consistent plasmacytoma and the presence of any clonal plasma cells in peripheral blood or bone marrow.
  3. Study participants must be refractory to 2 prior MM treatment regimens including an immunomodulatory imide drug and a protease inhibitor prior to entering the study. Study participants must have recovered or stabilized to Grade ≤2 from any AEs experienced during prior treatment with the exception of neuropathy. Prior therapy requirements are as follows:

    1. Undergone ≥1 complete cycle of treatment for each regimen, unless progressive disease was the best response to the regimen.
    2. Must have received an immunomodulatory agent, a proteasome inhibitor, and an anti- CD38 antibody.
    3. Study participants who are not candidates for ≥1 of the above treatments may still be considered eligible.
  4. Has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
  5. Has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function defined as:

    1. Estimated glomerular filtration rate >60 mL/min/1.73 m2. A 24-hour urine collection for creatinine clearance may be used at the investigator's discretion.
    2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both

      ≤3 times of upper limit of normal, unless there is suspected disease in the liver, in which case, no limit is set provided serum bilirubin is within eligibility criterion.

    3. Total bilirubin <2.0 mg/dL, except in study participants with Gilbert's syndrome.
    4. Platelet count >50,000/μL (platelet transfusions acceptable); neutrophils >750/μL.
    5. Left ventricular ejection fraction (LVEF) >45% as assessed by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan performed within 1 month before starting lymphodepleting chemotherapy. ECHO results performed within 6 months before Screening and at least 28 days after the last cancer treatment may be acceptable if the study participant has not received any treatment with cardiotoxicity risks.
    6. No clinically significant evidence of pericardial effusion or pleural effusion based on investigator's opinion.
    7. Baseline oxygen saturation >92% on room air.
    8. Pulmonary function tests including forced expiratory volume at 1 sec, forced vital capacity, total lung capacity, diffusion capacity of lung for carbon monoxide ≥50% of predicted values. Study participant characteristics
  6. All study participants must be willing to practice birth control and refrain from donating sperm or oocytes from the time of enrollment in this study through 3 months after receiving the study treatment.
  7. Women of childbearing potential (WOCBP) must test negative for pregnancy at Screening because of the potentially harmful effects of the preparative chemotherapy to the fetus. WOCBP are defined as any women who are not postmenopausal or who have not had a hysterectomy. Postmenopausal is defined as women over the age of 55 who have not had a menstrual period for ≥1 year.
  8. Capable of giving signed informed consent.

Exclusion Criteria:

  1. Study participant has clinically significant organ involvement by amyloid protein.
  2. Study participant has plasma cell leukemia, Waldenstrom's macroglobulinemia, or POEMS syndrome.
  3. History of class III or IV congestive heart failure or severe non-ischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months of starting study treatment.
  4. History or presence of clinically relevant central nervous system (CNS) pathology.
  5. Active uncontrolled fungal, bacterial, viral, protozoal, or other infection.
  6. Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease).
  7. History of human immunodeficiency virus (HIV) infection.
  8. Active hepatitis B or hepatitis C confirmed by polymerase chain reaction (PCR). Study participant positive for inactive hepatitis B will be allowed to enroll if on prophylactic treatment.
  9. History of hypertension crisis or hypertensive encephalopathy within 3 months prior to Screening.
  10. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  11. Abnormal findings during the Screening Period or any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the study participant's safety.
  12. History of genetic syndrome such as Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome.
  13. Study participants with active hemolytic anemia.
  14. Study participant has received autologous stem cell transplant within 12 weeks of Screening or an allogeneic stem cell transplant within 6 months of starting study treatment. Study participants who have received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of GvHD.
  15. Study participants with second malignancies in addition to MM if the second malignancy has required treatment within the last 3 years or is not in complete remission, with the exception of non-metastatic basal cell or squamous cell skin carcinoma.
  16. Study participant has received systemic biologic agent within 28 days. Participation in non-interventional registries or epidemiological studies is not excluded.
  17. Study participant has received live vaccine within 4 weeks before Screening. Non-live virus vaccines are not excluded.
  18. Before initiation of lymphodepletion, study participants must have recovered or stabilized to Grade ≤2 from any AEs experienced during prior treatment with the exception of neuropathy.
  19. Radiotherapy within 4 weeks before Screening should be discussed with the monitor.
  20. Presence of pleural/peritoneal/pericardial catheter.
  21. Current use of any anticoagulant or antiplatelet therapy.

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): NCT04171843


Contacts
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Contact: Clinical Precision BioSciences, Inc. 919-314-5512 clinical@precisionbiosciences.com

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Maung Myo Htut, MD         
Principal Investigator: Maung Myo Htut, MD         
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94115
Principal Investigator: Nina Shah, MD         
United States, Massachusetts
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: Omar Nadeem, MD         
United States, New York
Columbia University Irving Medical Center Recruiting
New York, New York, United States, 10032
Principal Investigator: Ran Reshef, MD         
United States, Texas
MD Anderson Not yet recruiting
Houston, Texas, United States, 77030
Principal Investigator: Krina Patel, MD         
Sponsors and Collaborators
Precision BioSciences, Inc.
Investigators
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Study Chair: Chris R Heery, MD Precision BioSciences, Inc.
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Responsible Party: Precision BioSciences, Inc.
ClinicalTrials.gov Identifier: NCT04171843    
Other Study ID Numbers: PBCAR269A-01
First Posted: November 21, 2019    Key Record Dates
Last Update Posted: July 30, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists