Sapanisertib in Treating Patients With Relapsed and/or Refractory Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To determine the complete hematologic response (CR)/complete response incomplete (CRi) rate when sapanisertib (MLN0128 [TAK-228]) is administered to adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (CR, CRi/partial response (PR)/morphologic leukemia free state [MLFS]).

II. To determine the CR/CRi duration when MLN0128 (TAK-228) is administered to adult patients with relapsed/refractory ALL.

III. To determine the frequency of proceeding to allogeneic stem cell transplantation (SCT) for patients with relapsed/refractory ALL who achieve a response on MLN0128 (TAK-228).

IV. To determine the overall survival for relapsed/refractory ALL patients on MLN0128 (TAK-228).

TERTIARY OBJECTIVES:

I. To examine the pharmacokinetics of MLN0128 (TAK-228) in ALL patients. II. To assess whether phosphorylation of the mTOR substrate 4EBP1 decreases in leukemic blasts harvested from the bone marrow on day 8 compared to baseline.

III. To assess in an exploratory fashion whether MLN0128 (TAK-228) enhances expression of the pro-apoptotic proteins Bim and Puma in marrow ALL cells.

IV. To assess in an exploratory fashion whether Mcl-1 levels decrease in blast cells during MLN0128 (TAK-228) treatment.

V. To assess in an exploratory fashion whether a) the phospho-protein pattern at baseline or b) MLN0128 (TAK-228)-associated changes in the phospho-protein pattern differs between ALL samples that respond to therapy and those that do not.

OUTLINE:

Patients receive sapanisertib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who are non-responders and in PR at the end of course 4 may receive sapanisertib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion criteria

• World Health Organization (WHO)-defined acute lymphoblastic leukemia and either:

• Relapsed after achieving remission
• Refractory to therapy
• Newly diagnosed and ineligible for intensive chemotherapy induction Note: patients with T lineage and B lineage ALL are eligible for this trial; likewise, patients with Philadelphia chromosome positive (Ph+) (as long as they are not candidate for other therapies for Ph+) and Ph- ALL are eligible
• Bone marrow blasts of at least 10%
• At least 4 weeks away from any previous antineoplastic or investigational agent; patients may receive hydroxyurea or glucocorticoids for suppression of leukocytosis, but these must be stopped at least 24 hours (h) prior to initiation of therapy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Life expectancy of > 2 months
• Total bilirubin =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine =< 1.5 x institutional upper limit of normal
• Fasting blood glucose (FBG) < 130 mg/dL
• Hemoglobin A1C (HbA1C) < 7.0%
• Relapse after SCT is allowed but no active graft-versus-host disease (GVHD) as per treating physician; also must not exceed the number of prior induction regimens listed above; SCT does not count as line of therapy
• Negative serum pregnancy test result; Note: women of child-bearing potential and men must agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [e.g. United States product insert (USPI), Summary of Product Characteristics (SmPC), etc]) after the last does of study drug; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use highly effective barrier contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN0128 (TAK-228) administration
• Ability to understand and the willingness to sign a written informed consent document
• No prior therapy with mTOR inhibitors except for rapalog treatment as part of graft-versus-host (GVH) prophylaxis or treatment
• Human immunodeficiency virus (HIV) infected patients (if HIV positive)

• HIV infected individuals are eligible provided they meet all the protocol eligibility criteria in addition to the following:

• No history of acquired immune deficiency syndrome (AIDS) defining illness other than a historic CD4+ T-cell nadir < 200/mm^3
• Prior to leukemia diagnosis, the HIV disease was uncomplicated as evidenced by:

• The CD4+ T-cell counts were generally in excess of 300/mm^3
• The HIV viral loads were less than 200 copies/ml if on anti-HIV therapy
• If the HIV is newly diagnosed or there is no history of using anti-HIV therapy, there are no AIDS defining conditions or other HIV-related symptoms
• Zidovudine is not allowed as part of the anti-HIV therapy
• Patients with diabetes controlled by diet or medication are allowed on trial; controlled diabetes is defined as FBG < 130 mg/kL in the context of this study

Exclusion criteria

• Patients who have had chemotherapy or radiotherapy =< 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; treatment with glucocorticoids, hydroxyurea, and tyrosine kinase inhibitors is allowed up to 24 hour prior to initiation of therapy
• Patients with white blood cell (WBC) > 30,000 are not eligible to start therapy; however, it is permissible to use glucocorticoids and/or hydroxyurea to diminish peripheral WBC to less than 30,000 provided these agents are stopped at least 24 hours prior to the first dose of MLN0128 (TAK-228)
• Patients who are receiving any other investigational agents
• Patients with known other active cancers; skin cancers (basal or squamous) are exempted
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228)
• There are no prohibitions of specific medications on the basis of anticipated drug-drug interactions
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; no ischemic myocardial or cerebrovascular event, placement of pacemaker, or pulmonary embolism within six months of receiving first dose of MLN0128 (TAK-228)
• Any patient receiving chronic corticosteroid administration prior to study enrollment is ineligible
• Baseline prolongation of the rate-corrected QT interval (QTc) > 480 milliseconds or history of congenital long QT syndrome or Torsades de pointes
• Concomitant administration of any proton pump inhibitor (PPI) is not permitted during the study; patients receiving PPI therapy before enrollment must stop using the PPI for 7 days before their first dose of study drugs