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

• ClinicalTrials.gov Identifier: NCT02763384
• Recruitment Status: Terminated
• First Posted: May 5, 2016
• Last Update Posted: January 26, 2023
• Sponsor: Washington University School of Medicine
• Collaborators: The Leukemia and Lymphoma Society; National Institutes of Health (NIH); National Cancer Institute (NCI)
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
T-Acute Lymphoblastic Leukemia; Adult T Lymphoblastic Lymphoma	Drug: BL-8040; Drug: Nelarabine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIa Study of BL-8040 in Combination With Nelarabine for Relapsed or Refractory T-Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma
• Actual Study Start Date: December 2, 2016
• Actual Primary Completion Date: February 11, 2022
• Actual Study Completion Date: May 22, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1: BL-8040 and Nelarabine; 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; Drug: Nelarabine; Other Name: Arranon

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability of regimen as measured by frequency and grade of adverse events [ Time Frame: Up to 30 days after completion of treatment (approximately 16 weeks) ]
   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.

Secondary Outcome Measures :

1. Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by inhibition of CXCR4 signaling on lymphoblasts [ Time Frame: Completion of treatment (approximately 12 weeks) ]
   Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by inhibition of CXCR4 signaling on lymphoblasts
2. Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by mobilization of lymphoblasts into the peripheral circulation [ Time Frame: Completion of treatment (approximately 12 weeks) ]
   Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by mobilization of lymphoblasts into the peripheral circulation
3. Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by induction of apoptosis in lymphoblasts [ Time Frame: Completion of treatment (approximately 12 weeks) ]
   Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by induction of apoptosis in lymphoblasts
4. Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by alterations in lymphoblast cell cycle status [ Time Frame: Completion of treatment (approximately 12 weeks) ]
   Pharmacodynamic effects of BL-8040 on T-lymphoblasts as measured by alterations in lymphoblast cell cycle status
5. Estimate composite complete remission rate (CRc=CR+CRi) [ Time Frame: Completion of treatment (approximately 12 weeks) ]

   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

6. Estimate overall response rate (CR, CRi + PR) [ Time Frame: Completion of treatment (approximately 12 weeks) ]

   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
7. Time to response [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
   Time to response
8. Duration of response [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
   Defined as the interval from the date CR/CRi is documented to the date of recurrence.
9. Disease-free survival [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
   For patients achieving a complete remission, defined as the interval from the date of first documentation of CR/CRi to the date of recurrence or death due to any cause.
10. Event-free survival [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, or death due to any cause.
11. Overall survival [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Defined as the date of first dose of study drug to the date of death from any cause.
12. Estimate rate of patients who proceed to alloHCT after treatment [ Time Frame: Completion of treatment (approximately 12 weeks) ]
    Estimate rate of patients who proceed to alloHCT after treatment
13. Interaction of pretreatment disease and morphology on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and morphology on clinical outcome
14. Interaction of pretreatment disease and CXCR4 expression on lymphoblasts on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and CXCR4 expression on lymphoblasts on clinical outcome
15. Interaction of pretreatment disease and cytogenetics on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and cytogenetics on clinical outcome
16. Interaction of pretreatment disease and immunophenotype on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and immunophenotype on clinical outcome
17. Interaction of pretreatment disease and white blood cell count on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and white blood cell count on clinical outcome
18. Interaction of pretreatment disease and performance status on clinical outcome [ Time Frame: Up to 2 years after completion of treatment (approximately 116 weeks) ]
    Interaction of pretreatment disease and performance status on clinical outcome

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

Washington University School of Medicine

The Leukemia and Lymphoma Society

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Geoffrey L Uy, M.D.; Washington University School of Medicine

More Information

Additional Information:

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine 

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02763384
• Other Study ID Numbers: 201606146; 2P50CA171963-06 ( U.S. NIH Grant/Contract )
• First Posted: May 5, 2016
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases