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

NCT02070458 | Completed Phase 1 DMC FDA Drug

• 4 other identifiers: CASE7913NCI-2014-00371X16014_MLN9708P30CA043703
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

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.

Conditions

Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

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

  Up to 5 weeks

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

  Up to 5 weeks

• Recommended Phase 2 dose

  Up to 5 weeks

Secondary Outcomes (5)

• 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

• Gene expression profile analysis

  Up to 5 weeks

• CD74 antigen expression expression analysis

  Up to 5 weeks

Study Arms (1)

Treatment (ixazomib, MEC)

EXPERIMENTAL

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.

Drug: ixazomib; Drug: mitoxantrone hydrochloride; Drug: etoposide; Drug: cytarabine

Interventions

ixazomib DRUG

Given PO

Also known as: MLN9708, proteasome inhibitor MLN9708

Treatment (ixazomib, MEC)

mitoxantrone hydrochloride DRUG

Given IV

Also known as: CL 232315, DHAD, DHAQ, Novantrone

Treatment (ixazomib, MEC)

etoposide DRUG

Given IV

Also known as: EPEG, VP-16, VP-16-213

Treatment (ixazomib, MEC)

cytarabine DRUG

Given IV

Also known as: ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Treatment (ixazomib, MEC)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106-5065, United States

Location

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

ixazomib; Mitoxantrone; Etoposide; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Anjali Advani

  Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2014
• First Posted: February 25, 2014
• Study Start: October 8, 2014
• Primary Completion: March 17, 2017
• Study Completion: August 15, 2017
• Last Updated: December 13, 2018

Record last verified: 2018-12

Locations

US (2)