Summary

This phase I/II trial studies the side effects and best dose of OBI-3424 and how well it works in treating patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as OBI-3424, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. OBI-3424 may reduce the amount of leukemia in the body.

Objectives

PRIMARY OBJECTIVES:
I. To assess the safety of AKR1C3-activated prodrug OBI-3424 (OBI-3424) and to determine the maximum tolerated dose (MTD) of OBI-3424 in this regimen for patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL). (Phase I)
II. To assess the response rate (complete remission [CR] or CR with incomplete count recovery [CRi]) of patients treated with OBI-3424 at the MTD determined in the Phase I portion of the trial in this patient population. (Phase II)

SECONDARY OBJECTIVES:
I. To estimate the frequency and severity of toxicities of OBI-3424 in this patient population.
II. To estimate event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS) in this patient population.

TRANSLATIONAL MEDICINE OBJECTIVES:
I. To estimate minimal/measurable residual disease (MRD) negativity (among patients who achieve CR or CRi).
II. To assess AKR1C3 expression levels in this patient population.
III.To evaluate associations between AKR1C3 expression and response to OBI-3423, achievement of MRD-negative remission, and relapse from remission.
IV. To bank specimens for future research.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive AKR1C3-activated prodrug OBI-3424 intravenously (IV) over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients who have not achieved a partial remission (PR) by the 4th cycle of treatment are removed from the study (unless clinically benefiting in the opinion of the treating investigator). Patients undergo blood sample collection during screening and cerebrospinal fluid (CSF) sample collection every 4-6 weeks throughout the study. Patients also undergo bone marrow aspirate or core biopsy during screening, after two cycles of treatment and before each treatment cycle until CR/CRi and at time of disease relapse. Patients may undergo computed tomography (CT) during screening and follow up.

After completion of study treatment, patients are followed up every month for 1 year, every 2 months for 1 year, every 3 months for 1 year, and then every 6 months for up to 5 years from registration.

Eligibility

1. Patients must have a diagnosis of relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) based on World Health Organization (WHO) classification. Patients with relapsed/refractory T-cell lymphoblastic lymphoma are eligible if lymphoblasts are >= 5% in the bone marrow or in the peripheral blood
2. Patients must have evidence of acute leukemia in their peripheral blood or bone marrow. Patients must have >= 5% lymphoblasts in the peripheral blood or bone marrow within 14 days prior to registration. Patients with only extramedullary disease are not eligible
3. Patients must be refractory to or have relapsed following a standard induction therapy * A chemotherapy induction regimen is defined as any program of treatment that includes: ** Vincristine and corticosteroids plus at least one more chemotherapy agent ** Cytarabine and anthracycline, or ** High dose cytarabine (defined as at least 1 gr/m^2 per individual dose unless adjustments were required for renal/liver function)
4. Patients must have no evidence of central nervous system disease within 28 days prior to registration based on cerebrospinal fluid (CSF) studies. Patients with clinical signs or symptoms consistent with central nervous system (CNS) involvement must have a lumbar puncture which is negative for CNS involvement; the lumbar puncture must be completed within 28 days prior to registration. Note that the patients may receive intrathecal chemotherapy with the initial lumbar puncture. The Steinherz/blyer Algorithm will be used to interpret CNS involvement in the presence of circulating blasts in the peripheral blood
5. Prior nelarabine therapy is not required. In addition, patients who receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy
6. Patients must not have had chemotherapy or investigational agents within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea. For participants who have received radiation therapy, at least 7 days must have elapsed from the end of radiation prior to registration and participants must not currently be experiencing toxicities from radiation therapy
7. Patients must not have undergone allogeneic hematopoietic transplant within 90 days prior to registration
8. Patients must have no evidence of >= grade 2 acute graft versus host disease (GVHD) or moderate or severe limited chronic GVHD and must have no history of extensive GVHD of any severity within 90 days prior to registration. Patients posttransplant must be off calcineurin inhibitors for at least 21 days to be eligible. Extensive GVHD is defined as 1) generalized skin involvement or 2) localized skin involvement and/or hepatic dysfunction plus liver histology or cirrhosis or involvement of eye or minor salivary organ or oral mucosa or any other target organ
9. Patients must be >= 18 years of age
10. Patients must have a Zubrod performance status of 0-3
11. Patients must not have systemic fungal, bacterial, viral or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) within 14 days prior to registration
12. Patients must have creatinine clearance > 30 mL/min within 14 days prior to registration according to the Cockcroft Gault equation
13. Patients must have direct bilirubin =< 1.5 x institutional upper limit of normal (ULN) within 14 days prior to registration
14. Patients must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x institutional upper limit of normal (ULN) or =< 5.0 x ULN (if thought to be related to leukemic involvement) within 14 days prior to registration
15. Prothrombin time (PT)/partial thromboplastin time (PTT)/ (or activated [a] PTT) fibrinogen (as clinically indicated) (within 14 days prior to registration to obtain baseline measurements)
16. From comprehensive metabolic panel: sodium, potassium, chloride, carbon dioxide (CO2), and blood urea nitrogen (BUN) (within 14 days prior to registration to obtain baseline measurements)
17. Patients with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test within 6 months prior to registration. (HIV viral load testing is required only for patients with known HIV infection). Patients must not be receiving antiviral therapies that are known strong inhibitors or inducers of CYP3A4
18. Patients with evidence of chronic hepatitis B virus (HBV) infection may be eligible provided that they have an undetectable HBV viral load within 28 days prior to registration. Patients may be currently receiving HBV treatment. (HBV viral load testing is required only for patients with known HBV infection). Patients must not be receiving antiviral therapies that are known strong inhibitors or inducers of CYP3A4
19. Patients with known history of hepatitis C virus (HCV) infection may be eligible provided that they have an undetectable HCV viral load within in 28 days prior to registration. Patients may be currently receiving treatment. (HCV viral load testing is required only for patients with known HCV infection). Patients must not be receiving antiviral therapies that are known strong inhibitors or inducers of CYP3A4
20. Patients must not have a known history of prolonged QT interval by Fridericia (QTcF) (interval > 450 msec for males; > 470 msec for females)
21. Patients must not be pregnant or nursing due to the teratogenic potential of the drug used on this study. Females of reproductive potential must have a negative serum pregnancy test within 14 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method during and up to 6 months after treatment. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
22. Patients must not have other active malignancies for which they have received treatments within 6 months prior to registration excluding localized malignancies that do not require systemic treatment
23. Patients must agree to have bone marrow and blood specimens submitted for MRD testing
24. Patients must be offered the opportunity to participate in specimen banking. With patient consent, residuals from specimens submitted will be retained and banked for future research
25. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. For participants with impaired decision making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
26. As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
27. This trial will use a slot reservation system to enroll the Phase I portion of the study. Patients planning to enroll at this phase of the study must first have a slot reserved in advance of the registration. All site staff will use OPEN to create a slot reservation