A Phase 1 Study of MLN9708 in Combination With MEC (Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine) for Relapsed/ Refractory Acute Myelogenous Leukemia (AML)
Overview
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 30
- Locations
- 2
- Primary Endpoint
- MTD of ixazomib in combination with MEC based on the occurrence of DLT assessed using NCI CTC scale version 4.03
Overview
Brief Summary
This phase I trial studies the side effects and best dose of ixazomib when given in combination with mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine in treating patients with acute myeloid leukemia that is unresponsive to initial induction chemotherapy or recurs following an initial complete remission. Acute myeloid leukemia is a cancer of the bone marrow cells; bone marrow is where blood cells are normally made. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine are standard treatment for relapsed or refractory acute myeloid leukemia. Giving ixazomib with mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine may improve the effectiveness of the chemotherapy.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose of MLN9708 (ixazomib) in combination with mitoxantrone hydrochloride, etoposide, intermediate-dose cytarabine (MEC) in patients with relapsed/ refractory acute myeloid leukemia (AML).
SECONDARY OBJECTIVES:
I. To describe the non-dose limiting toxicities associated with MLN9708 in combination with MEC in patients with relapsed/ refractory AML.
II. To describe any preliminary evidence of clinical activity of this combination (compete response [CR] rate) in relapsed/ refractory AML.
III. To determine the median cluster of differentiation (CD)74 antigen expression in patients achieving a response versus those patients not achieving a response.
IV. To determine if gene expression profile pre- and post-treatment correlates with response to therapy.
OUTLINE: This is a dose-escalation study of ixazomib.
Patients receive ixazomib orally (PO) on days 1, 4, 8, and 11, mitoxantrone hydrochloride intravenously (IV), etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6.
After completion of study treatment, patients are followed up for 4-5 weeks.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
- •Female patients who:
- •Are postmenopausal for at least 1 year before the screening visit, OR
- •Are surgically sterile, OR
- •If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- •Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)
- •Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
- •Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Exclusion Criteria
- •Female patients who are lactating or have a positive serum pregnancy test during the screening period
- •Failure to have fully recovered (i.e., ≤ grade 1 toxicity) from the reversible effects of prior chemotherapy, excluding alopecia
- •Major surgery within 14 days before enrollment
- •Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708
- •Central nervous system involvement; a lumbar puncture does not need to be performed unless there is clinical suspicion of leptomeningeal disease
- •Uncontrolled infections
- •Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
- •Systemic treatment, within 3 days before the first dose of MLN9708, with strong inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
- •Ongoing or active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
Arms & Interventions
Treatment (ixazomib, MEC)
Patients receive ixazomib PO on days 1, 4, 8, and 11; they receive mitoxantrone hydrochloride IV, etoposide IV over 1 hour; the receive intermediate-dose cytarabine IV over 6 hours on days 1-6.
Intervention: ixazomib (Drug)
Treatment (ixazomib, MEC)
Patients receive ixazomib PO on days 1, 4, 8, and 11; they receive mitoxantrone hydrochloride IV, etoposide IV over 1 hour; the receive intermediate-dose cytarabine IV over 6 hours on days 1-6.
Intervention: mitoxantrone hydrochloride (Drug)
Treatment (ixazomib, MEC)
Patients receive ixazomib PO on days 1, 4, 8, and 11; they receive mitoxantrone hydrochloride IV, etoposide IV over 1 hour; the receive intermediate-dose cytarabine IV over 6 hours on days 1-6.
Intervention: etoposide (Drug)
Treatment (ixazomib, MEC)
Patients receive ixazomib PO on days 1, 4, 8, and 11; they receive mitoxantrone hydrochloride IV, etoposide IV over 1 hour; the receive intermediate-dose cytarabine IV over 6 hours on days 1-6.
Intervention: cytarabine (Drug)
Outcomes
Primary Outcomes
MTD of ixazomib in combination with MEC based on the occurrence of DLT assessed using NCI CTC scale version 4.03
Time Frame: Up to 5 weeks
Recommended Phase 2 dose
Time Frame: Up to 5 weeks
DLT assessed using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) scale version 4.03
Time Frame: Up to 5 weeks
Secondary Outcomes
- Gene expression profile analysis(Up to 5 weeks)
- Incidence of non-DLT assessed using NCI CTC scale version 4.03(Up to 5 weeks)
- Complete response (CR) rate(Up to 5 weeks)
- Complete remission with incomplete platelet recovery (CRp) rate(Up to 5 weeks)
- CD74 antigen expression expression analysis(Up to 5 weeks)