CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Granulocytic Sarcoma

Study Overview
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Brief Summary
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This pilot phase II trial studies how well CPI-613 (6,8-bis[benzylthio]octanoic acid), cytarabine, and mitoxantrone hydrochloride work in treating patients with acute myeloid leukemia or granulocytic sarcoma (a malignant, green-colored tumor of myeloid cells [a type of immature white blood cell]) that has returned (relapsed) or that does not respond to treatment (refractory). 6,8-bis(benzylthio)octanoic acid is thought to kill cancer cells by turning off their mitochondria. Mitochondria are used by cancer cells to produce energy and are the building blocks needed to make more cancer cells. By shutting off these mitochondria, 6,8-bis(benzylthio)octanoic acid deprives the cancer cells of energy and other supplies that they need to survive and grow in the body. Drugs used in chemotherapy, such as cytarabine and mitoxantrone hydrochloride, 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. Giving 6,8-bis(benzylthio)octanoic acid together with cytarabine and mitoxantrone hydrochloride may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the feasibility of CPI-613 when administered with high dose cytarabine, and mitoxantrone (mitoxantrone hydrochloride) in all three phases of salvage therapy (induction, consolidation and maintenance). SECONDARY OBJECTIVES: I. To observe the response rate (complete remission [CR], and CR with incomplete recovery [CRi]) of CPI-613 in combination with high dose cytarabine and mitoxantrone. II. To observe the overall survival of patients treated with CPI-613 in combination with high dose cytarabine and mitoxantrone in induction, consolidation and maintenance. III. To monitor toxicities experienced by patients treated with CPI-613 in combination with high dose cytarabine and mitoxantrone in induction, consolidation and maintenance. OUTLINE: SALVAGE INDUCTION COURSE 1: Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-5, cytarabine IV over 3 hours every 12 hours starting on day 3 for 5 doses, and mitoxantrone hydrochloride IV over 15 minutes after the first, third, and fifth doses of cytarabine. SALVAGE INDUCTION COURSE 2 (OPTIONAL, AT DISCRETION OF TREATING PHYSICIAN): Patients receive 6,8-bis(benzylthio)octanoic acid, cytarabine, and mitoxantrone hydrochloride as in course 1 or an abbreviated second course at the discretion of the treating physician. In the abbreviated course, patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-3, cytarabine IV over 3 hours every 12 hours starting on day 2 for 3 doses, and mitoxantrone hydrochloride IV over 15 minutes after the first and third cytarabine doses. SALVAGE CONSOLIDATION: Patients achieving response receive up to 2 courses of the abbreviated course of 6,8-bis(benzylthio)octanoic acid, high dose cytarabine, and mitoxantrone hydrochloride. Patients achieving response may undergo stem cell transplant at the discretion of the treating physician. Patients may proceed to maintenance after 1, 2 or no courses of consolidation at the discretion of the treating physician. MAINTENANCE THERAPY: Patients achieving response receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
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An Open Label Study to Evaluate the Feasibility of CPI-613 Given With High Dose Cytarabine and Mitoxantrone in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Conditions
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Granulocytic Sarcoma, Recurrent Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: 6,8-Bis(benzylthio)octanoic Acid
* Drug: Cytarabine
* Procedure: Hematopoietic Cell Transplantation
* Drug: Mitoxantrone Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically documented relapsed and/or refractory acute myeloid leukemia or granulocytic sarcoma Eastern Cooperative Oncology Group (ECOG) performance status of =< 3 Expected survival > 3 months Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device), and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation Fertile men must practice effective contraceptive methods during the study period, unless documentation of infertility exists Mentally competent, ability to understand and willingness to sign the informed consent form No radiotherapy, treatment with cytotoxic agents (except CPI-613), treatment with biologic agents or any anti-cancer therapy within the 2 weeks prior to treatment with CPI-613; hydroxyurea and oral tyrosine kinase inhibitors being used without grade =< 2 toxicity can be taken until day 1 of therapy; patients must have fully recovered from the acute, non-hematological, non-infectious toxicities of any prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities (returned to baseline status as noted before most recent treatment); patients with persisting, non-hematologic, non-infectious toxicities from prior treatment =< grade 2 are eligible, but must be documented as such Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 3 x upper normal limit (UNL), alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x UNL (=< 5 x upper limit of normal [ULN] if liver metastases present) Bilirubin =< 1.5 x UNL Serum creatinine =< 1.5 mg/dL or 133 umol/L International normalized ratio or INR must be < 1.5 Left ventricular ejection fraction (by transthoracic echocardiography [TTE], multigated acquisition scan [MUGA] or cardiac magnetic resonance imaging [MRI]) sufficient to safely administer mitoxantrone as determined by the treating physician Exclusion Criteria: Serious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients' risk for toxicity Patients with active central nervous system (CNS) or epidural tumor Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease) Pregnant women, or women of child-bearing potential not using reliable means of contraception Lactating females Fertile men unwilling to practice contraceptive methods during the study period Life expectancy less than 3 months Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients Unwilling or unable to follow protocol requirements Patients with large and recurrent pleural or peritoneal effusions requiring frequent drainage (e.g. weekly); patients with any amount of clinically significant pericardial effusion Active heart disease including myocardial infarction within previous 6 months, symptomatic coronary artery disease, uncontrolled arrhythmias, or symptomatic congestive heart failure Evidence of ongoing, uncontrolled infection Patients with known human immunodeficiency virus (HIV) infection Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 2 weeks prior to initiation of CPI-613 treatment (the use of Hydrea is allowed) Patients who have received immunotherapy of any type within the past 4 weeks prior to initiation of CPI-613 treatment Requirement for immediate palliative treatment of any kind including surgery Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months A history of additional risk factors for torsade de pointes (e.g., clinically significant heart failure, hypokalemia, family history of long QT syndrome)

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 (CPI-613, cytarabine, mitoxantrone hydrochloride)<br>See Detailed Description | Drug: 6,8-Bis(benzylthio)octanoic Acid<br>* Given IV<br>* Other names: CPI-613;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Procedure: Hematopoietic Cell Transplantation<br>* Undergo stem cell transplant<br>* Other names: stem cell transplantation;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of administering CPI-613 in combination with high dose cytarabine and mitoxantrone during induction, consolidation and maintenance therapies, defined as percentage of patients eligible for maintenance therapy who complete at least 3 courses |  | Up to 12 weeks of maintenance therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of toxicities experienced by the participants, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0 | The frequency of toxicities experienced by the participants will be presented by type and grade in an effort to monitor and report safety of the treatment. | Up to 3 years | 
| Overall survival | Will use Kaplan-Meier estimation to analyze overall survival. | Time from enrollment on trial to death from any cause, assessed up to 6 months after completion of therapy | 
| Response rate (CR and CRi), assessed by standard criteria for AML | Confidence intervals will be calculated around the estimates of the response rate (CR and CRi). Assuming a response rate of 0.5, with 50 participants, 95 percent confidence intervals can be created with a 0.14 margin of error (0.36, 0.64). | Up to 3 years |