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

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ClinicalTrials.gov Identifier: NCT03666000
Recruitment Status : Recruiting
First Posted : September 11, 2018
Last Update Posted : January 20, 2021
Sponsor:
Information provided by (Responsible Party):
Precision BioSciences, Inc.

Study Description
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Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma B-cell Acute Lymphoblastic Leukemia Genetic: PBCAR0191 Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: In each cohort (NHL and B-ALL), up to 6 dose levels will be enrolled and treated sequentially. Within each dose level, up to 6 subjects will be treated with PBCAR0191 using a standard 3 + 3 design. The starting dose of PBCAR0191 will be 3 × 10^5 CAR T cells/kg body weight. Subsequent dose groups will be treated with escalating doses to a maximum dose of 9 × 10^6 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: 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
Actual Study Start Date : March 11, 2019
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose Level 1

PBCAR0191, 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.

 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 2
PBCAR0191, 1 x 10^6 CAR T cells per kg body weight.
 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 3a
PBCAR0191, 3 x 10^6 CAR T cells per kg body weight.
 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 3b
PBCAR0191, 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.
 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 4
PBCAR0191, 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.
 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.
Experimental: Dose Level 5
PBCAR0191, 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.
 Genetic: PBCAR0191
Single dose of Allogeneic Anti-CD19 CAR T cells will be infused
Other Name: Allogeneic Anti-CD19 CAR T cells

Drug: Fludarabine
Fludarabine is used for lymphodepletion.

Drug: Cyclophosphamide
Cyclophosphamide is used for lymphodepletion.


Outcome Measures
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Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ 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.

  2. 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.


Secondary Outcome Measures :
  1. Objective Response Rate of Patients [ Time Frame: 1 year ]
    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.

  2. Duration of Response [ Time Frame: 1 year ]
    To assess the duration (days) of response from initial response until disease relapse or progression

  3. Progression-free Survival [ Time Frame: 1 year ]
    To assess the duration (days) of response from Day 0 to disease progression or death

  4. Overall Survival [ Time Frame: 1 year ]
    To assess the duration (days) of response from Day 0 to death

  5. Time to next treatment [ Time Frame: 1 year ]
    To assess the duration (days) of response from Day 0 to institution of next therapy


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

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
Contacts and Locations
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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): NCT03666000


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: Clinical Research    626-218-1133      
United States, Florida
H. Lee Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Clinical Research    888-663-3488      
United States, Georgia
Northside Hospital Cancer Institute Recruiting
Atlanta, Georgia, United States, 30342
Contact: Scott Solomon, MD    404-255-1930    ssolomon@bmtga.com   
Principal Investigator: Scott Solomon, MD         
United States, Indiana
Indiana Blood and Marrow Recruiting
Indianapolis, Indiana, United States, 46237
Contact: Luke P Akard, MD       lakard@ibmtindy.com   
Principal Investigator: Luke P Akard, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Clinical Trials    877-338-7425      
United States, Michigan
Barbara Ann Karmanos Cancer Institute (Wayne State University) Recruiting
Detroit, Michigan, United States, 48201
Contact: Abhinav Deol, MD    313-576-8093    deola@karmanos.org   
Principal Investigator: Abhinav Deol, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Fiona He, MD       fionahe@umn.edu   
Principal Investigator: Fiona He, MD         
United States, New York
Weill Cornell Medical College - NY Presbyterian Hospital Recruiting
New York, New York, United States, 10021
Contact: Koen Van Besien, MD    646-962-7950    kov9001@med.cornell.edu   
Principal Investigator: Koen Van Besien, MD         
Columbia University Irving Medical Center/New York Presbyterian Hospital Recruiting
New York, New York, United States, 10032
Contact: Ran Reshef, MD       rr3036@cumc.columbia.edu   
Principal Investigator: Ran Reshef, MD         
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Craig Sauter, MD         
United States, Rhode Island
Lifespan Cancer Institute at Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Adam Olszewski, MD       adam_olszewski@brown.edu   
Principal Investigator: Adam Olszewski, MD         
United States, Texas
MD Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research    855-761-8004      
Sponsors and Collaborators
Precision BioSciences, Inc.
Investigators
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Study Chair: Chris Heery, MD Precision BioSciences, Inc.
More Information
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Responsible Party: Precision BioSciences, Inc.
ClinicalTrials.gov Identifier: NCT03666000    
Other Study ID Numbers: PBCAR0191-01
First Posted: September 11, 2018    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
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