BL-8040 and Nelarabine for Relapsed or Refractory T-Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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The outcome of patients with relapsed or refractory adult T-acute lymphoblastic leukemia (T-ALL) and the related disease T-lymphoblastic lymphoma (T-LBL) is extremely poor with 30% of the patients responding to first salvage therapy and long-term survival of only 10%. Therefore, novel therapies for patients with relapsed/refractory T-ALL/LBL represent an unmet clinical need. Recent data provide strong evidence that CXCR4 signaling plays a major role in T-cell leukemia cell maintenance and leukemia initiating activity, and targeting CXCR4 signaling in T-ALL cells reduces tumor growth in an animal model. In this study, the investigators propose that the addition of BL-8040 to nelarabine as a salvage therapy for patients with relapsed/refractory T-ALL/LBL will result in a higher complete remission (CR) rate than nelarabine alone without an increase in toxicity and will allow patients to proceed to a potentially curative allogeneic hematopoietic cell transplant.

Official Title
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A Phase IIa Study of BL-8040 in Combination With Nelarabine for Relapsed or Refractory T-Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma

Conditions
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T-Acute Lymphoblastic Leukemia, Adult T Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: BL-8040
* Drug: Nelarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of T-acute lymphoblastic leukemia/ lymphoblastic lymphoma according to WHO criteria which has relapsed or is refractory to chemotherapy. Peripheral blood lymphoblasts ≤ 50,000 mcL. Hydroxyurea and/or leukapheresis is permitted to reduce the peripheral blast count prior to enrollment and treatment. Age ≥ 18 years ECOG performance status ≤ 2. Adequate organ function defined as: Calculated creatinine clearance ≥ 50 ml/min using the Cockroft-Gault formula AST, ALT, total bilirubin ≤ 2 x institutional ULN except for Gilbert's disease or when in the opinion of treating physician elevated levels are due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia), in which case ALT and AST may be elevated up to ≤ 5 x IULN. Women of childbearing potential and men must agree to use adequate contraception with a highly effective method (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Abstinence is acceptable if this is the established and preferred contraception for the subject. Female subjects must have a negative urine or serum pregnancy test within 72 hours prior to start of study treatment if of childbearing potential or be of non-childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as: *≥ 45 years of age and has not had menses for > 2 years Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a FSH value in the postmenopausal range upon pretrial (screening) evaluation Post-hysterectomy, oophorectomy, or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. Able to understand and willing to sign an IRB-approved written informed consent document. Exclusion Criteria: Previous treatment with nelarabine for relapsed or refractory disease. Pregnant or nursing. Received any other investigational agent or systemic cytotoxic chemotherapy within the preceding 2 weeks. Active CNS involvement with leukemia Active HIV or hepatitis B or C infection. Any medical condition which, in the opinion of the clinical investigator, would interfere with the evaluation of the patient. Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, laboratory tests, and according to the investigator's judgment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: BL-8040 and Nelarabine<br>Cycle 1: BL-8040 subcutaneous daily from Day 1 to Day 6 and nelarabine intravenously over 2 hours on Days 2, 4, and 6 Cycles 2-4: BL-8040 subcutaneous daily from Day 1 to Day 5 and nelarabine intravenously over 2 hours on Days 1, 3, and 5 Treatment may be repeated every 21 days for up to 4 cycles | Drug: BL-8040<br> <br> Drug: Nelarabine<br> <br> * Other names: Arranon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Regimen as Measured by Number of Participants With Adverse Events | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all adverse event reporting. | Up to 30 days after completion of treatment (median follow-up of 51.5 days, full range 24-120 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Complete Remission Rate (CRc=CR+CRi) | Complete remission (CR) = an absolute neutrophil count (segs and bands) > 1,000/mcL, no circulating lymphoblasts, platelets ≥ 100,000/mcL; and < 5% marrow leukemia blast cells with complete disappearance of all measurable disease as confirmed by physical examination, CT scan and/or FDG-PET (Deauville criteria score of 1, 2, or 3) -Morphologic complete remission with incomplete blood count recovery (CRi)=Defined as CR with the exception of neutropenia < 1,000/mcL or thrombocytopenia <100,000/mcL | Completion of treatment (approximately 12 weeks) | 
| Overall Response Rate (CR, CRi + PR) | Complete remission (CR) = an absolute neutrophil count (segs and bands) > 1,000/mcL, no circulating lymphoblasts, platelets ≥ 100,000/mcL; and < 5% marrow leukemia blast cells with complete disappearance of all measurable disease as confirmed by physical examination, CT scan and/or FDG-PET (Deauville criteria score of 1, 2, or 3) Morphologic complete remission with incomplete blood count recovery (CRi)=Defined as CR with the exception of neutropenia < 1,000/mcL or thrombocytopenia <100,000/mcL Partial remission (PR)=A PR requires all of the CR criteria except that marrow may still contain 5-25% leukemia blast cells. An absolute neutrophil count (segs and bands) ≥ 1000/mcL, no circulating blasts, and platelets > 100,000/mcL are requires as for a CR. For patients with measurable disease, a reduction of 50% or more in the sum of the products of the perpendicular diameters of all measurable lesions compared with pretreatment measurements and with no new or enlarging lesions | Through completion of treatment (median treatment length of 37.5 days, full range of 13-90 days) | 
| Time to Response | Response is CR or CRi Complete remission (CR) = an absolute neutrophil count (segs and bands) > 1,000/mcL, no circulating lymphoblasts, platelets ≥ 100,000/mcL; and < 5% marrow leukemia blast cells with complete disappearance of all measurable disease as confirmed by physical examination, CT scan and/or FDG-PET (Deauville criteria score of 1, 2, or 3) Morphologic complete remission with incomplete blood count recovery (CRi)=Defined as CR with the exception of neutropenia < 1,000/mcL or thrombocytopenia <100,000/mcL | Through completion of treatment (median treatment length of 37.5 days, full range of 13-90 days) | 
| Duration of Response | Defined as the interval from the date CR/CRi is documented to the date of recurrence or completion of follow-up if recurrence has not occurred. | Through date of recurrence or completion of follow-up (maximum of 2 years after completion of treatment) | 
| Event-free Survival (EFS) | EFS is defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, of death due to any cause. | Through completion of follow-up (maximum of 2 years after completion of treatment) | 
| Overall Survival | Defined as the date of first dose of study drug to the date of death from any cause. | Through completion of follow-up (maximum of 2 years after completion of treatment) | 
| Rate of Patients Who Proceed to alloHCT After Treatment | Estimate rate of patients who proceed to alloHCT after treatment | Through completion of treatment (median treatment length of 37.5 days, full range of 13-90 days) |