Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies

• ClinicalTrials.gov Identifier: NCT03056339
• Recruitment Status: Completed
• First Posted: February 17, 2017
• Results First Posted: March 25, 2024
• Last Update Posted: March 25, 2024
• Sponsor: M.D. Anderson Cancer Center
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Tracking Information

• First Submitted Date: February 14, 2017
• First Posted Date: February 17, 2017
• Results First Submitted Date: September 22, 2023
• Results First Posted Date: March 25, 2024
• Last Update Posted Date: March 25, 2024
• Actual Study Start Date: June 21, 2017
• Actual Primary Completion Date: March 6, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2023)

Number of Events That Was Grade 3-4 Toxicities [ Time Frame: 40 days ]

Toxicity is defined as a grade 3 or 4 within 40 days of NK cell infusion.

Original Primary Outcome Measures (submitted: February 14, 2017)

• Optimal NK Cell Dose Level of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 45 days ]
  Dose-finding done using the sequentially adaptive phase I-II EffTox trade-off-based design. Toxicity is defined as a grade 3 or 4 GVHD within 45 days of NK cell infusion.
• Toxicity of Chimeric antigen receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood natural killer (CB-NK) cells in patients with relapsed/refractory CD19+ B lymphoid malignancies [ Time Frame: 2 weeks after NK cell infusion ]
  Toxicity defined ascytokine release storm (CRS) within 2 weeks of NK cell infusion requiring transfer to intensive care.
• Efficacy of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 30 days after NK cell infusion ]
  Efficacy defined as the patient being alive and in remission at day 30 post NK cell infusion.

Current Secondary Outcome Measures (submitted: March 21, 2024)

• Overall Response Rate of Participants Analyzed [ Time Frame: 30 days ]
  Participants response was defined as partial or complete response by Efftox assessment below.

  • Acute lymphoblastic leukemia: Complete response will be defined as bone marrow with < 5% blasts, the absence of circulating blasts, and no extramedullary sites of disease (as assessed by means of computed tomography or positron-emission tomography), regardless of cell-count recovery.
  • CLL: Response will be defined based on the NCI-WG/IWCLL 2008 criteria, Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia.

  Lymphomas: Response will be defined based on the Lugano criteria- Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma:
• Number of Participants Achieved an Objective Response [ Time Frame: Up to 100 days after NK cell infusion ]
  Number of participants that had Complete and Partial Response.

Original Secondary Outcome Measures (submitted: February 14, 2017)

Response of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 100 days after NK cell infusion ]

Unadjusted distributions of the time-to-event outcomes estimated using the method of Kaplan and Meier and their relationship to prognostic covariates and NK cell dose level evaluated by Bayesian piecewise exponential survival regression.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
• Official Title: Dose Escalation Study Phase I/II of Umbilical Cord Blood-Derived CAR-Engineered NK Cells in Conjunction With Lymphodepleting Chemotherapy in Patients With Relapsed/Refractory B-Lymphoid Malignancies

Brief Summary

If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

The goal of this clinical research study is to learn if giving genetically changed immune cells, called CAR-NK cells, after chemotherapy will improve the disease in stem cell transplant patients with relapsed (has returned) and/or refractory (has not responded to treatment) B-cell lymphoma or leukemia. Also, researchers want to find the highest tolerable dose of CAR-NK cells to give to patients with relapsed or refractory B-cell lymphoma or leukemia. The safety of this treatment will also be studied.

This is an investigational study. The making of and infusion of genetically changed NK cells and the drug AP1903 (if you receive it, explained below) are not FDA approved or commercially available for use in this type of disease. They are currently being used for research purposes only. The chemotherapy drugs in this study (fludarabine, cyclophosphamide, and mesna) are commercially available and FDA approved.

Up to 36 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed Description

Objectives:

Primary objective:

To determine the safety and relative efficacy of Chimeric antigen receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood natural killer (CB-NK) cells in patients with relapsed/refractory CD19+ B lymphoid malignancies.

Secondary Objectives:

1. To assess the overall response rate (complete and partial response rates).
2. To quantify persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in the recipient.
3. To conduct comprehensive immune reconstitution studies.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• B-Lymphoid Malignancies
• Acute Lymphocytic Leukemia
• Chronic Lymphocytic Leukemia
• Non-hodgkin Lymphoma

Intervention

• Drug: Fludarabine
  30 mg/m2 by vein on Days -5 to -3.
  Other Names:

  • Fludarabine phosphate
  • Fludara
• Drug: Cyclophosphamide
  300 mg/m2 by vein on Days -5 to -3.
  Other Names:

  • Cytoxan
  • Neosar
• Drug: Mesna
  300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.
  Other Name: Mesnex
• Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells

  Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein.

  Starting dose: 10E5

  Other Name: NK cells
• Drug: AP1903
  If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they will receive AP1903 0.4 mg/kg administered as an intravenous infusion.

Study Arms

Experimental: Fludarabine + Cyclophosphamide + CAR-NK Cells

On Days -5, -4, and -3, participants receive Fludarabine and Cyclophosphamide. Participants also receive Mesna before and after the cyclophosphamide dose.

On Day 0, participants receive genetically modified NK cells as a cell infusion.

If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they receive AP1903 by vein and possibly steroids by mouth or by vein.

Interventions:

• Drug: Fludarabine
• Drug: Cyclophosphamide
• Drug: Mesna
• Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells
• Drug: AP1903

• Publications *: Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 2, 2023): 49
• Original Estimated Enrollment (submitted: February 14, 2017): 36
• Actual Study Completion Date: March 6, 2023
• Actual Primary Completion Date: March 6, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients with history of CD 19 positive B-lymphoid malignancies (ALL, CLL, NHL) who have received at least 2 lines of standard chemoimmunotherapy or targeted therapy and have persistent disease.
2. Patients with ALL, CLL, NHL with relapsed disease following standard therapy or a stem cell transplant.
3. Patients at least 3 weeks from last cytotoxic chemotherapy at the time of starting lymphodepleting chemotherapy. Patients may continue tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior to administration of lymphodepleting chemotherapy.
4. Karnofsky/Lansky Performance Scale > 70.
5. Adequate organ function: a. Renal: Creatinine clearance (as estimated by Cockcroft Gault) >/= 60 cc/min. b. Hepatic: ALT/AST </= 2.5 x ULN or </= 5 x ULN if documented liver metastases, Total bilirubin </= 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be </= 3.0 mg/dL. c. Cardiac: Cardiac ejection fraction >/= 50%, no evidence of pericardial effusion as determined by an ECHO or MUGA, and no clinically significant ECG findings. d. Pulmonary: No clinically significant pleural effusion, baseline oxygen saturation > 92% on room air.
6. Able to provide written informed consent.
7. 7-80 years of age.
8. All participants who are able to have children must practice effective birth control while on study. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor.
9. Signed consent to long-term follow-up protocol PA17-0483.

Exclusion Criteria:

1. Positive beta HCG in female of child-bearing potential defined as not postmenopausal for 24 months or no previous surgical sterilization or lactating females.
2. Known positive serology for HIV.
3. Presence of Grade 3 or greater toxicity from the previous treatment.
4. Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management. Note: Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.
5. Presence of active neurological disorder(s).
6. Concomitant use of other investigational agents.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 7 Years to 80 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03056339
• Other Study ID Numbers: 2016-0641; NCI-2018-01221 ( Registry Identifier: NCI CTRP-Clinical Trials Reporting Registry )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: M.D. Anderson Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: M.D. Anderson Cancer Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Loretta Nastoupil, MD; M.D. Anderson Cancer Center

• PRS Account: M.D. Anderson Cancer Center
• Verification Date: March 2024