Phase I/II Study of CAR.70- Engineered IL15-transduced Cord Blood-derived NK Cells in Conjunction With Lymphodepleting Chemotherapy for the Management of Relapse/Refractory Hematological Malignances

The goal of this clinical research study is to learn about the safety of giving immune cells called natural killer (NK) cells with chemotherapy to patients with leukemia, lymphoma, or multiple myeloma.

Immune system cells (such as NK cells) are made by the body to attack foreign or cancerous cells. Researchers think that NK cells you receive from a donor may react against cancer cells in your body, which may help to control the disease.

Study Overview

• Status: Recruiting
• Conditions: B-Cell Lymphoma; Myelodysplastic Syndromes (MDS); Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine phosphate; Drug: CAR.70/IL15-transduced CB-NK cells

Detailed Description

Primary Objective:

To determine the safety, efficacy and optimal cell dose of CAR.70/IL15-transduced CB-NK cells in patients with relapsed/refractory hematological malignances. The efficacy and optimal dose will be identified for individual diseases.

Secondary Objectives:

• To quantify persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in the recipient.
• To conduct comprehensive immune reconstitution studies.

• Study Type: Interventional
• Enrollment (Estimated): 94
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: David Marin; Phone Number: (713) 792-4179; Email: dmarin@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: David Marin, MD; Phone Number: 713-792-4179; Email: dmarin@mdanderson.org
      • Principal Investigator: David Marin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Patients with hematological malignances with an expression of CD70 in the pre-enrollment tumor sample ≥ 10% measured by immunohistochemistry or flow cytometry.
• Patients must meet diseases specific eligibility criteria (see below)
• 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 three days prior to administration of lymphodepleting chemotherapy.
• Localized radiotherapy to one or more disease sites are allowed prior the infusion provided that there are additional disease sites that are not irradiated
• Karnofsky Performance Scale > 50%.

• Adequate organ function:

  1. Renal: Serum creatinine </= 1.5 mg/dL and estimated Glomerular Filtration Rate (eGFR using the CKI-EPI equation) >/= 30 ml/min/1.73 m2.
  2. 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. No history of liver cirrhosis. No ascites.
  3. Cardiac: Cardiac ejection fraction >/= 50%, no clinically significant pericardial effusion as determined by an ECHO or MUGA, and no uncontrolled arrhythmias or symptomatic cardiac disease.
  4. Pulmonary: No clinically significant, , pleural effusion (per PI discretion), baseline oxygen saturation > 92% on room air and adequate pulmonary function with FEV1, FVC and DLCO (corrected for Hgb) >50%.
• Able to provide written informed consent.
• 18-75 years of age.
• Weight ≥40 kg
• All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of study therapy. 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.
• Signed consent to long-term follow-up protocol PA17-0483.

Exclusion criteria:

• Positive beta HCG in female of child-bearing potential defined as not postmenopausal for 24 months or no previous surgical sterilization or lactating females.
• Presence of clinically significant Grade 3 or greater toxicity from the previous treatment, as determined by PI.
• Presence of uncontrolled fungal, bacterial, viral, or other infection not responding to appropriate therapy.
• HIV with detectable viral load
• Presence of active neurological disorder(s).
• Active autoimmune disease within 12 months of enrollment
• Amyloidosis or POEMS syndrome
• Active cerebral or meningeal involvement by the malignancy
• Active (defined as requiring therapy) acute or chronic GVHD
• Any other malignancy known to be active, except for treated cervical intra-epithelial neoplasia and non-melanoma skin cancer.
• Presence of any other serious medical condition that may endanger the patient at investigator discretion.
• Major surgery <4 weeks prior to first dose of the preparatory chemotherapy
• Allogeneic SCT or DLI <12 weeks prior to first dose of preparatory chemotherapy
• Concomitant use of other investigational agents.
• Concomitant use of other anti-cancer agents.
• Patients receiving systemic steroid therapy at time of enrollment (physiological substitutive doses are allowed), or have received antithymocyte globulin or lymphocyte immune globulin within 14 days of enrollment or alemtuzumab within 28 days of enrollment.
• Patients receiving immunosuppressive therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyclophosphamide; Cyclophosphamide is dosed per adjusted body weight for patients weighing > 20% above their ideal body weight using the calculation.	Drug: Cyclophosphamide; Given by IV; Other Names: Cytoxan®; Neosar®; Drug: Fludarabine phosphate; Given by IV; Other Names: Fludara®; Fludarabine
Experimental: CAR.70/IL15-transduced CB-NK cells; Patients will receive a single flat dose of CAR-NK.	Drug: CAR.70/IL15-transduced CB-NK cells; Given by IV
Experimental: Fludarabine phosphate; Fludarabine is dosed using actual body weight.	Drug: Cyclophosphamide; Given by IV; Other Names: Cytoxan®; Neosar®; Drug: Fludarabine phosphate; Given by IV; Other Names: Fludara®; Fludarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE Version 5.0.	CTCAE Version 5.0 - General grading: Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required beyond prophylaxis. Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment. Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line treatment. Grade 4: Life Threatening: discomfort that represents immediate risk of death	through study completion, an average of 1 year
Number of Participants with Complete or Partial Response		Up to 30 days after the last treatment
Number of Participants who are Alive and in Remission	Number of Participants who are Alive and in Remission after 6 months.	Up to 180 days

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: David Marin, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: October 13, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 25, 2021

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia; Leukemia, Myeloid; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: 2021-0386; NCI-2021-12093 (Other Identifier: NCI-CTRP Clinical Trials Reporting)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No