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

• Sponsor: Precision BioSciences, Inc.
• Information provided by (Responsible Party): Precision BioSciences, Inc.

Study Description

Brief Summary:

This is a multicenter, nonrandomized, open-label, parallel assignment, single-dose, 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 a single intravenous (IV) infusion of PBCAR0191. 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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Intervention Model: Single Group Assignment
• 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: July 2020
• Estimated Study Completion Date: June 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: PBCAR0191-01; 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, and a classic "3+3" dose escalation will be applied.; Other Name: Allogeneic Anti-CD19 CAR T cells; Drug: Fludarabine; Fludarabine is used for lymphodepletion.; Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.

Outcome Measures

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. Area Under the Curve [AUC] [ Time Frame: Up to 1 year ]
   To evaluate Area Under the Curve [AUC] of PBCAR0191 in patients tested.

Eligibility Criteria

• 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

Contacts

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

Locations

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, Massachusetts

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Clinical Trials 877-338-7425

United States, Texas

MD Anderson; Not yet recruiting

Houston, Texas, United States, 77030

Contact: Clinical Research 855-761-8004

Sponsors and Collaborators

Precision BioSciences, Inc.

Investigators

• Study Chair: Chris Heery, MD; Precision BioSciences, Inc.

More Information

• Responsible Party: Precision BioSciences, Inc.
• ClinicalTrials.gov Identifier: NCT03666000 History of Changes
• Other Study ID Numbers: PBCAR0191-01
• First Posted: September 11, 2018
• Last Update Posted: July 23, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Burkitt Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Lymphoma, B-Cell; 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