CD4-directed CAR T-cell therapy for T-cell leukemia and lymphoma

A Phase I, Multicenter Study of CD4- Directed Chimeric Antigen Receptor Engineered T-cells (CD4CAR) in Patients With Relapsed or Refractory CD4+ Hematological Malignancies

This study is testing a new type of CAR T-cell therapy to see if it can help people with hard-to-treat T-cell leukemia and lymphoma feel better.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 12 Years and up
• Sex: All
• Sponsor: Indiana University (Academic / other)
• Drugs / interventions: chemotherapy, Prednisone, chimeric antigen receptor
• Locations: 6 sites (Miami, Florida and 5 other locations)
• Trial ID: NCT03829540 on ClinicalTrials.gov

What this trial studies

This Phase I clinical trial evaluates the safety and feasibility of CD4-directed chimeric antigen receptor (CAR) engineered T-cells in patients with relapsed or refractory T-cell leukemia and lymphoma. The study follows a dose-escalation protocol and aims to recruit 20 subjects across multiple centers, including Stony Brook and Indiana University. Participants will undergo leukapheresis to obtain peripheral blood mononuclear cells, which will be engineered to create CD4CAR T-cells. Following conditioning chemotherapy, eligible patients will receive the CD4CAR T-cells to assess treatment response.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 12 and older with relapsed or refractory CD4+ T-cell hematologic malignancies.

Not a fit: Patients with non-CD4+ hematologic malignancies or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a novel treatment option for patients with aggressive CD4+ T-cell malignancies.

How similar studies have performed: While CAR T-cell therapies have shown success in other hematologic malignancies, this specific approach targeting CD4+ T-cells is novel and has not been extensively tested.

Eligibility criteria

Inclusion Criteria

In order to be eligible to participate in this study, an individual will be enrolled if they meet the following criteria:

1. Patients must voluntarily sign and date informed consent forms that state his or her willingness to comply with all study procedures and availability for the duration of the study.
2. Age 12 years old or older
3. Subjects with any documented CD4+ T cell hematologic malignancies. Male and female subjects with CD4+ T-cell hematologic malignancies with either relapsed or refractory disease (including those patients who have undergone a prior transplant (if allogeneic, subjects are eligible if there are no remaining donor cells) and patients with an inadequate response after 4-6 cycles of standard chemotherapy) are eligible. Response criteria for each disease subset will be evaluated based on Standard of Care Guidelines.
4. Creatinine clearance of \> 60 ml/min (or otherwise non clinically-significant, per study investigator)
5. ALT/AST \< 3 x ULN
6. Bilirubin \< 2 x ULN
7. No supplemental oxygen at rest Note: Pulmonary Function Test (PFT) only required per treating physician discretion
8. Adequate cardiac function with EF of ≥50%
9. Adequate venous access for apheresis and no other contraindications for leukapheresis

Exclusion Criteria

1. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential (see definition below) must have a negative serum or urine pregnancy test prior to initiation of conditioning chemotherapy, per research sites' clinical policy.
2. Uncontrolled active infection necessitating systemic therapy.
3. Active hepatitis B or hepatitis C infection. Active hepatitis C is defined as the hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower detection limit.

   Note the following subjects will be eligible:
   * Subjects with a history of hepatitis B but have received antiviral therapy and have nondetectable viral DNA for 6 months prior to enrollment are eligible
   * Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine with no signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible
   * Subjects who had hepatitis C but have received antiviral therapy and show no detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible
   * If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
4. Concurrent use of systemic glucocorticoids in greater than replacement doses (unless as a part of a standard of care salvage therapy or conditioning protocol), or steroid dependency defined in rheumatological and pulmonary diseases as uninterrupted corticosteroid intake for more than a year at a dosage of 0.3 mg/kg/day or greater, and where the underlying disease worsens on temporary stoppage of steroid therapy, with symptoms of steroids withdrawal (eg, lethargy, headache, weakness, pseudorheumatism, emotional disturbances, etc) precipitated by the temporary stoppage.

   Subjects who receive daily corticosteroids in replacement doses can be included in the study. The replacement doses are defined as following:
   1. Hydrocortisone 25mg/day or less
   2. Prednisone 10mg/day or less
   3. Dexamethasone 4mg or less Note: Recent or current use of inhaled glucocorticoids is not exclusionary, as this route pertains extremely minimal systemic penetration.
5. Any uncontrolled active medical disorder that would preclude participation as outlined in the opinion of the treating investigator and/or study chair
6. HIV infection.
7. Subjects declining to consent for treatment
8. Subjects who have received or will receive live vaccines within 30 days before the first experimental cell treatment. Inactivated seasonal flu vaccination is allowed.
9. Subjects with active autoimmune diseases who need systematic treatments (such as disease modifying agents, corticosteroids and immunosuppressive drugs) in the last 2 years. Note: Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement therapy (up to10 mg of oral daily prednisone or equivalent in hydrocortisone and dexamethasone) to treat adrenal dysfunction or pituitary dysfunction) is not considered as systematic therapy. Subjects who need inhalation corticosteroid therapy can be included in this trial. Subjects with vitiligo or in long-term remission of pediatric asthma or allergic diseases can be included in this trial.
10. Subjects with a history of mental disorders or drug abuse that may influence treatment compliance.
11. Active malignancy not related to a T-cell malignancy that has required therapy in the last 3 years or is not in complete remission. Exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy. Other similar malignant conditions may be discussed with and permitted by the Principal Investigator.
12. Treatment with any investigational cell/gene therapy within the past 6 months
13. Treatment with any investigational anticancer agent within 14 days of study entry or 5 half-lives (whichever is shorter)

Eligibility for Conditioning Chemotherapy

1. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values.
2. Review of co-morbidities to confirm no major changes in health status (examples of major changes include heart attack, stroke, and any major trauma).
3. Planned infusion dose was successfully manufactured and met release criteria.
4. Negative pregnancy testing (if applicable).

Eligibility for CD4CAR infusion:

Inclusion

1. Afebrile and not receiving antipyretics, and no evidence of active infection.
2. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values. The following test does not need repeated: EF if obtained within 6 weeks of initial assessment.
3. If previous history of corticosteroid chemotherapy, subject must be off all but adrenal replacement doses 3 days before the CD4CAR infusion.

Exclusion

Note: A subject may still receive the CD4CAR infusion up to 10 days post conditioning chemotherapy as long as they do not meet any of the following at time of infusion:

1. Requirement for supplemental oxygen to keep saturation greater than 95% or presence of radiographic abnormalities on a clinically indicated chest x-ray that are progressive.
2. New cardiac arrhythmia not controlled with medical management.
3. Hypotension requiring pressor support.
4. Positive blood cultures for bacteria, fungus, or virus within 48-hours of T cell infusion.

Contraception and Reproductive Potential Guidelines Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure \[hysterectomy or bilateral oophorectomy\]) must have a negative serum or urine pregnancy test prior to conditioning chemotherapy.

Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception from time of consent through at least 90 days after CD4CAR infusion.

Acceptable birth control includes a combination of two of the following methods:

* Condoms (male or female) with or without a spermicidal agent.
* Diaphragm or cervical cap with spermicide
* Intrauterine device (IUD)
* Hormonal-based contraception Subjects who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception. Acceptable documentation of sterilization, azoospermia, and menopause is specified next:

Written or oral documentation communicated by clinician or clinician's staff of one of the following:

* Physician report/letter
* Operative report or other source documentation in the subject record (a laboratory report of azoospermia is required to document successful vasectomy)
* Discharge summary
* Laboratory report of azoospermia
* Follicle stimulating hormone measurement elevated into the menopausal range

Where this trial is running

Miami, Florida and 5 other locations

• University of Miami Sylvester Comprehensive Cancer Center — Miami, Florida, United States (Recruiting)
• Indiana University Melvin and Bren Simon Comprehensive Cancer Center — Indianapolis, Indiana, United States (Recruiting)
• Riley Hospital for Children — Indianapolis, Indiana, United States (Recruiting)
• Albert Einstein Health Network — New York, New York, United States (Recruiting)
• Stony Brook Cancer Center — Stony Brook, New York, United States (Active_not_recruiting)
• The University of Texas MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Huda Salman, MD — Indiana University
• Study coordinator: Cristina Roach, RN

Conditions T-cell Lymphoma; T-cell Leukemia; CD4; T-cell; lymphoma; leukemia; chimeric antigen; CAR-T