Anti-CD7 CAR-T Cells in Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia or Lymphoma

This will be a Phase 1, open-label study to evaluate the safety and efficacy of BEAM-201 in patients with R/R T-ALL or T-LLy. BEAM-201 is an allogeneic anti-CD7 CART therapy.

Despite favorable outcomes in newly diagnosed patients, approximately 20% of pediatric and young adult T-ALL patients and 40% of adult patients will have refractory disease or will relapse within 2 years of their initial diagnosis. Survival rates of patients with relapsed disease remain below 35%. For recurrent disease, allogeneic hematopoietic stem cell transplant (HSCT) is the only known potentially curative treatment. However, a prerequisite to HSCT is obtaining a complete remission, which remains a significant challenge as only 40 to 50% of patients achieve a second remission with current reinduction regimens with salvage rates even lower for patients with disease that is refractory to first-line chemotherapy.

BEAM-201 is an allogeneic anti-CD7 CAR T cell product that has shown promising early evidence of efficacy, with 3 out of 4 adult T-ALL patients infused had a CRi/CR ≥28 days after infusion. Safety of BEAM-201 has been favorable and consistent with known adverse events associated with other CAR T cell therapies.

Given the current treatment landscape of T-ALL/T-LLy, promising clinical experience with BEAM-201, and that \>98% of T-ALL cases highly and homogenously express CD7 protein on the surfaces of their lymphoblasts, the investigators think there is compelling rationale in further investigating the safety and efficacy of BEAM-201 in pediatric patients.

Eligibility Criteria:
Inclusion Criteria:

1. Ages 0 to 29 years.
2. T-ALL/T-LLy in second or greater relapse, first relapse post-transplant, or chemotherapy-refractory disease. Specifically:

   * Second or greater relapse or post-transplant relapse, defined as:

     * BM with ≥ 5% lymphoblasts by morphologic assessment or evidence of extramedullary disease after second documented CR; OR
     * Flow cytometric confirmation of relapsed T-ALL of at least 0.1% after second CR documented to have been MRD negative \< 0.1%; OR
     * Any detectable relapsed disease post-allogeneic HSCT with flow cytometric confirmation of T-ALL of at least 0.1%; OR
     * Biopsy confirmed evidence of relapsed T-LLy after second CR; OR
     * Any detectable disease post-allogeneic transplant with biopsy confirmed evidence of T-LLy
   * Refractory disease, defined as:

     * Primary refractory T-ALL or T-LLy, defined as failure to achieve CR after induction chemotherapy, per investigator assessment and based on biopsy- or MRD-confirmed evidence of residual T-ALL or T-LLy; OR
     * Relapsed, refractory disease, defined as \> 0.1 % MRD or morphologic evidence of disease or evidence of residual T-LLy after 1 course of re-induction chemotherapy for patients who have relapsed after previously achieving a CR

   NOTE: Patients with mixed phenotype acute leukemia with T cell dominant phenotype may be enrolled if the aforementioned criteria are met.
3. Documentation of CD7 expression on leukemic blasts (defined as at least 20% of blasts positive for CD7 by flow cytometry or immunohistochemistry).
4. Patients with prior or current history of CNS3 disease will be eligible if CNS disease is responsive to therapy
5. Eligible for myeloablative conditioning for and allogeneic HSCT based on the investigator's assessment with an available donor identified by a FACT accredited transplant center.
6. Lansky Performance Status (ages \< 16 years at time of consent) or Karnofsky Performance Status (KPS) (ages ≥ 16 years at time of consent) score of ≥ 50.
7. Patients of childbearing potential must have a negative urine or serum pregnancy test at screening.
8. Patients who are sexually active and of reproductive potential must agree to use an acceptable form of highly effective contraception from consent to 12 months after BEAM 201 infusion.
9. Patients (ages ≥ 18 years) or parent/legal guardians (for patients ages \< 18 years) must provide signed, written informed consent according to local IRB and institutional requirements.

Exclusion Criteria:

1. CNS disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
2. Clinically active CNS dysfunction or known history of irreversible central neurological toxicity related to prior antileukemic therapy.
3. Receipt of prior CD7 targeted therapy.
4. Systemic antileukemic therapy intended to induce remission within 14 days prior to completion of screening.
5. Radiation therapy within 2 weeks prior to completion of screening, other than prophylaxis for CNS disease.
6. Acute GVHD that is grade ≥ 2 and requiring systemic immunosuppression (corticosteroids), or chronic GVHD that is mild, moderate, or severe and requiring systemic immunosuppression (corticosteroids). Grade 1 acute GVHD not requiring immunosuppression is allowable.
7. Undergone HSCT within 90 days prior to completion of screening (or donor leukocyte infusion, if received within 30 days prior to completion of screening).
8. Evidence of organ dysfunction including:

   * Serum ALT ≥ 5 × ULN for age
   * Total bilirubin ≥ 3 × ULN for age
   * Serum creatinine that exceeds the maximum values listed in the protocol.
   * Any of the following cardiac criteria:

     i. Atrial fibrillation/flutter (not including isolated episodes that responded to medical management) ii. Myocardial infarction within the last 12 months iii. QT interval corrected for heart rate using Fridericia's method (QTcF) \> 480 msec iv. Cardiac echocardiography (ECHO) with left ventricular shortening fraction (LVSF) \< 30% or left ventricular ejection fraction (LVEF) \< 50% or clinically significant pericardial effusion v. Cardiac dysfunction NYHA (New York Heart Association) III or IV
   * A minimum level of pulmonary reserve defined as \>Grade 1 dyspnea and \>Grade 3 hypoxia; DLCO 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the investigator
9. Positive serology for:

   * Human immunodeficiency virus (HIV) (HIV-1 or HIV2)
   * Human T-cell lymphotropic virus (HTLV) (HTLV-1 or HTLV-2)
   * Hepatitis B (positive surface Ag or positive core Ab unless Hep B DNA negative by polymerase chain reaction \[PCR\])
   * Hepatitis C (if hepatitis C virus \[HCV\] antibody positive) must be HCV RNA PCR negative. Patients with sustained viral response \> 12 weeks following antiviral therapy are eligible as long as no history of hepatic cirrhosis is present.
10. Uncontrolled, active bacterial, viral, or fungal infection.
11. Any other condition that would make the patient ineligible for HSCT as determined by the investigator.
12. Patients with an autoimmune disorder requiring systemic immunosuppressive therapy that cannot be safely withheld for 3 months.
13. Concurrent use of systemic corticosteroids for diagnoses unrelated to T-ALL/T-LLy is prohibited, with exception of physiologic corticosteroid replacement therapy treatment for adrenal insufficiency.
14. Known primary immunodeficiency or BM failure syndrome.
15. Pregnant or breastfeeding.