Clinical Trials /

Dose-escalation Study of Safety of PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL

NCT03666000

Description:

This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR0191 in adults with r/r B ALL (Cohort A) and in adults with r/r B-cell NHL (Cohort N).

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Grade 3b Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Primary Mediastinal B-Cell Lymphoma
  • Richter Syndrome
  • Small Lymphocytic Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose-escalation Study of Safety of PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL
  • Official Title: Phase 1/2a, Open-label, Dose-escalation/Expansion, Parallel Assignment Study to Evaluate Safety and Clinical Activity of PBCAR0191 in Subjects With Relapsed/Refractory (r/r) Non-Hodgkin Lymphoma and r/r B-cell Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: PBCAR0191-01
  • NCT ID: NCT03666000

Conditions

  • Non-Hodgkin Lymphoma
  • B-cell Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
FludarabineDose Level 1
CyclophosphamideDose Level 1

Purpose

This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, dose-escalation, and dose-expansion study to evaluate the safety and clinical activity of PBCAR0191 in adults with r/r B ALL (Cohort A) and in adults with r/r B-cell NHL (Cohort N).

Detailed Description

      This is a multicenter, nonrandomized, open-label, parallel assignment, dose-escalation, and
      dose-expansion study to evaluate the safety and tolerability, find an appropriate dose to
      optimize safety and efficacy, and evaluate clinical activity of PBCAR0191 in subjects with
      relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin
      lymphoma (NHL). Before initiating PBCAR0191, subjects will be administered lymphodepletion
      chemotherapy composed of fludarabine and cyclophosphamide. At Day 0 of the Treatment Period,
      subjects will receive an intravenous (IV) infusion of PBCAR0191. Subjects who receive a split
      dose will also receive an IV infusion of PBCAR0191 on Day 10 and/or Day 14. Subjects may be
      considered for retreatment. All subjects are monitored during the treatment period through
      Day 28. All subjects who receive a dose of PBCAR0191 will be followed in a separate long-term
      follow-up (LTFU) study for 15 years after exiting this study.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1ExperimentalPBCAR0191, 3 x 10^5 CAR T cells per kg body weight. In this study, PBCAR0191, allogeneic anti-CD19 CAR T Cells, is used to treat patients with relapsed or refractory (r/r) Non-Hodgkin Lymphoma and r/r B-cell Acute Lymphoblastic Leukemia. Route of Administration: Intravenous infusion. Lymphodepletion Conditioning: Lymphodepletion will be conducted several days prior to PBCAR0191 infusion. A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.
  • Fludarabine
  • Cyclophosphamide
Dose Level 2ExperimentalPBCAR0191, 1 x 10^6 CAR T cells per kg body weight.
  • Fludarabine
  • Cyclophosphamide
Dose Level 3aExperimentalPBCAR0191, 3 x 10^6 CAR T cells per kg body weight.
  • Fludarabine
  • Cyclophosphamide
Dose Level 3bExperimentalPBCAR0191, 3 x 10^6 CAR T cells per kg body weight as 3 administrations of 1 x 10^6 CAR T cells per kg body weight administered after a single lymphodepletion.
  • Fludarabine
  • Cyclophosphamide
Dose Level 4ExperimentalPBCAR0191, 6 x 10^6 CAR T cells per kg body weight as 2 administrations of 3 x 10^6 CAR T cells per kg body weight administered after a single lymphodepletion.
  • Fludarabine
  • Cyclophosphamide
Dose Level 5ExperimentalPBCAR0191, 9 x 10^6 CAR T cells per kg body weight as 3 administrations of 3 x 10^6 CAR T cells per kg body weight administered after a single lymphodepletion.
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

        Key Inclusion Criteria*

        Criteria for B-ALL:

          -  Relapsed or refractory CD19+ B-cell acute lymphoblastic leukemia (B-ALL).

          -  Philadelphia chromosome positive (Ph+) disease can be eligible if they are intolerant
             to tyrosine kinase inhibitor (TKI) therapy or if they have relapsed/refractory
             disease.

        Criteria for NHL:

          -  r/r CD19+ B-cell NHL that is histologically confirmed by archived tumor biopsy tissue
             from last relapse and corresponding pathology report. The following types of lymphoma
             are included:

               -  Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation

               -  Primary mediastinal B-cell lymphoma (PMBL)

               -  FL including Grade 3B or transformed FL

               -  High-grade B-cell lymphoma

               -  Small lymphocytic lymphoma (SLL)

               -  Mantle cell lymphoma (MCL)

          -  Received at least 2 prior chemotherapy-containing regimens. Subjects with SLL must
             have previously failed at least 2 lines of chemotherapy/immunotherapy that included
             ibrutinib and idelalisib plus rituximab.

          -  Measurable or detectable disease according to the Lugano Classification.

          -  Criteria for both B-ALL and NHL:

          -  Eastern Cooperative Oncology Group performance status score of 0 or 1.

          -  An estimated life expectancy of at least 12 weeks according to the investigator's
             judgment.

          -  Seronegative for human immunodeficiency virus antibody (i.e., intact immune function).

          -  Subject has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function
             defined as:

               1. Estimated glomerular filtration rate (eGFR) >50 mL/min/1.73 m2.

               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.

               3. Total bilirubin <2.0 mg/dL, except in subjects with Gilbert's syndrome.

               4. Platelet count ≥30,000/µL (platelet transfusions acceptable).

               5. Left ventricular ejection fraction >45% as assessed by echocardiogram (ECHO) or
                  multiple gated acquisition 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 subject has not received any treatment with cardiotoxicity risks.

               6. No clinically significant evidence of pericardial effusion or pleural effusion.

               7. Baseline oxygen saturation >92% on room air.

        Key Exclusion Criteria*

        Criteria for B-ALL:

          -  Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.

          -  Active CNS leukemia.

        Criteria for NHL:

          -  Active hemolytic anemia.

          -  Active CNS lymphoma.

          -  Criteria for B-ALL and NHL:

          -  Previous malignancy, besides the malignancies of inclusion (B-ALL or NHL), that has a
             high risk of relapse in the next 2 years.

          -  Uncontrolled and serious fungal, bacterial, viral, protozoal, or other infection.

          -  Any form of primary immunodeficiency.

          -  Active hepatitis B or C.

          -  Uncontrolled cardiovascular disease.

          -  Hypertension crisis or hypertensive encephalopathy within 3 months.

          -  Concomitant genetic syndrome or any other known bone marrow failure syndrome.

          -  Active uncontrolled autoimmune disease requiring active immunosuppression (excluding
             subjects needing steroids for physiologic replacement).

          -  Received stem cell transplant within 90 days.

          -  Active GvHD symptoms.

          -  Received systemic biologic agent within 30 days or 5 half-lives.

          -  Received systemic immunostimulatory agent within 30 days or 5 half-lives.

          -  Radiotherapy within 4 weeks determined on a case-by-case basis.

          -  Presence of pleural/peritoneal/pericardial catheter.

          -  Received live vaccine within 4 weeks before Screening.

          -  Current use of any anticoagulant or antiplatelet therapy.

               -  Additional criteria apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
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:Objective Response Rate of Patients
Time Frame:1 year
Safety Issue:
Description:To assess clinical activity as response in B-ALL by the NCCN Guidelines on ALL (NCCN, 2017) and in NHL by the revised Lugano Classification (Cheson et al, 2016), both reported as objective response rate.
Measure:Duration of Response
Time Frame:1 year
Safety Issue:
Description:To assess the duration (days) of response from initial response until disease relapse or progression
Measure:Progression-free Survival
Time Frame:1 year
Safety Issue:
Description:To assess the duration (days) of response from Day 0 to disease progression or death
Measure:Overall Survival
Time Frame:1 year
Safety Issue:
Description:To assess the duration (days) of response from Day 0 to death
Measure:Time to next treatment
Time Frame:1 year
Safety Issue:
Description:To assess the duration (days) of response from Day 0 to institution of next therapy

Details

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

Last Updated

March 10, 2020