Clinical Trials /

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

NCT04171843

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: PBCAR269A-01
  • NCT ID: NCT04171843

Conditions

  • Relapsed/Refractory Multiple Myeloma

Interventions

DrugSynonymsArms
FludarabinePBCAR269A at Dose Level 1
CyclophosphamidePBCAR269A at Dose Level 1

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
PBCAR269A at Dose Level 1ExperimentalThe starting dose of PBCAR269A will be 6 x 10^5 CAR T cells/kg body weight.
  • Fludarabine
  • Cyclophosphamide
PBCAR269A at Dose Level 2Experimental2 × 10^6 CAR T cells/kg body weight.
  • Fludarabine
  • Cyclophosphamide
PBCAR269A at Dose Level 3Experimental6 × 10^6 CAR T cells/kg body weight.
  • Fludarabine
  • Cyclophosphamide

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of PBCAR269A
Time Frame:Day 1 - Day 28
Safety Issue:
Description: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

Measure:Number of Participants with Dose Limiting Toxicity(ies)
Time Frame:1 year
Safety Issue:
Description:To assess adverse events as dose limiting toxicities as defined by the protocol and CTCAE v5.0.
Measure:Objective Response Rate of Patients
Time Frame:1 year
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Precision BioSciences, Inc.

Last Updated

April 20, 2020