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Ixazomib, Mitoxantrone Hydrochloride, Etoposide, and Intermediate-Dose Cytarabine in Treating Relapsed or Refractory Acute Myeloid Leukemia

Information source: Case Comprehensive Cancer Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Intervention: ixazomib (Drug); mitoxantrone hydrochloride (Drug); etoposide (Drug); cytarabine (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Case Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Anjali Advani, Principal Investigator, Affiliation: Case Comprehensive Cancer Center

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.

Clinical Details

Official title: A Phase 1 Study of MLN9708 in Combination With MEC (Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine) for Relapsed/ Refractory Acute Myelogenous Leukemia (AML)

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

DLT assessed using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) scale version 4.03

MTD of ixazomib in combination with MEC based on the occurrence of DLT assessed using NCI CTC scale version 4.03

Recommended Phase 2 dose

Secondary outcome:

Incidence of non-DLT assessed using NCI CTC scale version 4.03

Complete response (CR) rate

Complete remission with incomplete platelet recovery (CRp) rate

Gene expression profile analysis

CD74 antigen expression expression analysis

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.

Eligibility

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

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

- 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)

- Subjects with a prior diagnosis of AML (excluding acute promyelocytic leukemia) based

on World Health Organization Classification who did not achieve complete response (CR) with their previous therapy or who have relapsed after achieving a complete response (CR) are eligible; any number of relapses will be eligible

- Patients must have > 5% blasts in the bone marrow at the time of study enrollment

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2, or 3

- Total bilirubin =< 1. 5 x the upper limit of the normal range (ULN) within 14 days of

enrollment

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN within

14 days of enrollment

- Calculated creatinine clearance >= 30 mL/min within 14 days of enrollment

- Patients with secondary AML, and patients with a prior autologous and allogeneic bone

marrow transplant are eligible

- Patients with an allogeneic transplant must meet the following conditions: the

transplant must have been performed more than 90 days before registration to this study, the patient must not have >= grade 2 acute graft versus host disease (GvHD) or either moderate or severe limited chronic GvHD, or extensive chronic GvHD of any severity; the patient must be off all immunosuppression for at least 2 weeks

- Echocardiogram or multi gated acquisition (MUGA) scan demonstrating an ejection

fraction >= 45% 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

- Known allergy to any of the study medications, their analogues, or excipients in the

various formulations of any agent

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the

oral absorption or tolerance of MLN9708 including difficulty swallowing

- Patients with prior malignancy are eligible; however, the patient must be in

remission from the prior malignancy and have completed all chemotherapy and radiotherapy at least 6 months prior to registration and all treatment-related toxicities must have resolved; patients with basal cell or squamous cell carcinoma of the skin are eligible regardless of disease status

- Patient has >= grade 2 peripheral neuropathy within 14 days of trial enrollment

- Participation in other clinical trials, including those with other investigational

agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial

- Any standard therapy for leukemia within 14 days before enrollment (except for

hydrea)

- Patients who have received prior pulmonary radiation

Locations and Contacts

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Cente, Cleveland, Ohio 44106, United States; Recruiting
Brenda Cooper, MD, Phone: 216-844-3213, Email: brenda.cooper@uhhospitals.org
Brenda Cooper, MD, Principal Investigator

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center, Cleveland, Ohio 44106-5065, United States; Recruiting
Anjali S. Advani, Phone: 216-445-9354, Email: advania@ccf.org
Anjali S. Advani, Principal Investigator

Additional Information

Starting date: October 2014
Last updated: August 18, 2015

Page last updated: August 23, 2015

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