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

Study Overview
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Brief Summary
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This phase II trial studies how well sapanisertib works in treating patients with acute lymphoblastic leukemia that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Sapanisertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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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.

Official Title
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A Phase 2 Study of MLN0128 (TAK-228) in Relapsed and/or Refractory Acute Lymphoblastic Leukemia (ALL)

Conditions
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B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative, Recurrent Adult Acute Lymphoblastic Leukemia, Refractory Adult Acute Lymphoblastic Leukemia, T Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Sapanisertib


Participation Criteria
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Eligibility Criteria
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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

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: Treatment (sapanisertib)<br>Patients receive sapanisertib 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Sapanisertib<br>* Given PO<br>* Other names: TAK-228;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR or CRi) | Complete response rate, defined to be a complete hematologic response (CR) or complete response incomplete (CRi) noted as the objective status at any time during treatment. A CR is defined as having less than 5% blasts in a non-hypocellular marrow with a granulocyte count of 1 x109/L (or above), and a platelet count of 100 x109/L (or higher) and absence of peripheral blood blasts with complete resolution of any extra medullary disease. A patient is defined as having a CRi if they meet all CR criteria except for residual neutropenia (ANC<1 x109/L) or thrombocytopenia (platelets<100 x109/L). A CR or CRi will be considered synonymous with success. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent exact binomial confidence intervals for the true success proportion will be calculated. | 61 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response | ORR will be estimated by the total number of complete or partial responses (CR, CRi or PR), or morphologic leukemia free state [MLFS]) divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall response rate will be calculated. A CR is defined as having less than 5% blasts in a non-hypocellular marrow with a granulocyte count of 1 x109/L (or above), and a platelet count of 100 x109/L (or higher) and absence of peripheral blood blasts with complete resolution of any extra medullary disease. A patient is defined as having a CRi if they meet all CR criteria except for residual neutropenia (ANC<1 x109/L) or thrombocytopenia (platelets<100 x109/L). A Partial Response (PR) is defined as the presence of trilineage hematopoiesis in the bone marrow with recovery of ANC and platelet count to above levels, but with 5-25% bone marrow blasts and ≥50% decrease in bone marrow blast percentage from baseline. | 61 days | 
| Duration of Complete Response | The distribution of duration of complete response will be estimated using the method of Kaplan-Meier. | 0 days | 
| Frequency of Proceeding to Allogeneic Stem Cell Transplantation (SCT) After Achieving Response (Complete Hematologic Response [CR]/Complete Response Incomplete [CRi] Partial Response [PR], or Morphologic Leukemia Free State [MLFS]) to Sapanisertib | The frequency is estimated by the number of patients who proceed to allogeneic SCT after achieving response divided by the total number of evaluable patients who achieved a response. All evaluable patients who achieved a response will be used for this analysis. Exact binomial 95% confidence intervals for the true overall response rate will be calculated. | 0 days | 
| Overall Survival | The distribution of survival time will be estimated using the method of Kaplan-Meier. | 23 months | 
| Incidence of Adverse Events, Measured Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 | The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. For this endpoint, we are reporting the maximum grade adverse event per patient. | 91 days |