Clinical trial NCT01768897: CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: An Open Label, Dose-Escalation Study to Evaluate Safety, Tolerability, Maximum Tolerated Dose (MTD), Efficacy, and Pharmacokinetics (PKs) of CPI-613 Given With High Dose Cytarabine and Mitoxantrone in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Recurrent Adult Acute Myeloid Leukemia
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2013-01-16
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial studies the side effects and best dose of CPI-613 when given together with cytarabine and mitoxantrone hydrochloride in treating patients with relapsed or refractory acute myeloid leukemia. Drugs used in chemotherapy, such as CPI-613, cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. CPI-613 may help cytarabine and mitoxantrone hydrochloride work better by making cancer cells more sensitive to the drugs

Detailed description: PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerated dose (MTD) of CPI-613 when administered with high dose cytarabine, and mitoxantrone (mitoxantrone hydrochloride).

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics (PKs) of CPI-613 following intravenous (IV) administration in combination with high dose cytarabine and mitoxantrone.

II. To observe the response rate (complete response \[CR\], complete response with incomplete platelet recovery \[CRi\] and partial response \[PR\]) of CPI-613 in combination with high dose cytarabine and mitoxantrone.

III. To observe the overall survival of patients treated with CPI-613 in combination with high dose cytarabine and mitoxantrone.

OUTLINE: This is a dose-escalation study of CPI-613.

Patients receive CPI-613 intravenously (IV) over 2 hours on days 1-5, cytarabine IV over 3 hours every 12 hours for 5 doses beginning on day 3, and mitoxantrone hydrochloride IV over 15 minutes after the 1st, 3rd, and 5th doses of cytarabine. . Treatment repeats every 14 days for up to 2 courses\* in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients undergoing a second course of therapy receive CPI-613 IV over 2 hours on days 1-3, cytarabine IV over 3 hours every 12 hours for 5 doses beginning on day 2, and mitoxantrone hydrochloride IV over 15 minutes after the 1st and 3rd doses of cytarabine.

After completion of study treatment, patients are followed up for 6 months.

Eligibility criteria: Inclusion Criteria:

* Patients must have histologically or cytologically documented relapsed and/or refractory acute myeloid leukemia
* 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; (Note: Pregnant patients are excluded because the effects of CPI-613 on a fetus are unknown)
* 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; 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 μmol/L
* International Normalized Ratio or INR must be \< 1.5

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 (because the teratogenic potential of CPI-613 is unknown)
* Lactating females because the potential of excretion of CPI-613 into breast milk (Note: Lactating females are excluded because the effects of CPI-613 on a nursing child are unknown)
* 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
* Albumin \< 2.0 g/dL or \< 20 g/L
* Evidence of ongoing, uncontrolled infection
* Patients with known human immunodeficiency virus (HIV) infection; (Note: Patients with known HIV infection are excluded because patients with an immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, and because there may be unknown or dangerous drug interactions between CPI-613 and anti-retroviral agents used to treat HIV infections)
* 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)

Primary outcomes:
measure: MTD of CPI-613 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE 3.0)
timeFrame: 14 days
Secondary outcomes:
measure: Response rate (CR, CRi, and PR)
timeFrame: Day 14 of course 1
measure: Overall survival
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center of Wake Forest University
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Timothy Pardee
role: PRINCIPAL_INVESTIGATOR
References: