Ixazomib Citrate, Daunorubicin Hydrochloride, and Cytarabine in Treating Older Patients with Acute Myeloid Leukemia
This phase I trial studies the side effects and best dose of ixazomib citrate when given together with daunorubicin hydrochloride and cytarabine in treating older patients with acute myeloid leukemia. Ixazomib citrate blocks enzymes called proteasomes, which may help keep cancer cells from growing. Drugs used in chemotherapy, such as daunorubicin hydrochloride and cytarabine, 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 ixazomib citrate together with daunorubicin hydrochloride and cytarabine may be a better treatment for acute myeloid leukemia.
- 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care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 [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
- Male patients, even if surgically sterilized (ie, 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)
- Patients must have a diagnosis of acute myeloid leukemia (AML) according to World Health Organization (WHO) criteria; therapy-related and secondary AML (arising after a period of myelodysplastic syndrome [MDS]) allowed; prior treatment for MDS with hypomethylator-based therapy and lenalidomide allowed, but not allowed if used after the diagnosis of AML is made, since enrollment to this study is not for relapsed AML
- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2; performance status of 3 permissible if related to disease
- Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) unless related to disease or patient known to have underlying Gilbert’s disease
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
- Calculated creatinine clearance >= 30 mL/min
- Female patients who are lactating or have a positive serum pregnancy test during the screening period
- Failure to have fully recovered (ie, =< grade 1 toxicity) from the reversible effects of prior chemotherapy
- 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
- Suspected AML-related central nervous system involvement; a lumbar puncture (LP) is not required to exclude central nervous system (CNS) disease
- 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
- Ongoing or active systemic infection, known 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
- Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- Patient has >= grade 2 neuropathy, sensory, with or without pain, motor, or autonomic, on clinical examination during the screening period
- Participation in other clinical trials involving investigational agents within 21 days of the start of this trial and throughout the duration of this trial
- Prior chemotherapy treatment for AML (prior treatment with hydroxyurea and/or leukapheresis to control white blood cell count, or all-trans retinoic acid [ATRA] for suspected acute promyelocytic leukemia [APML] is acceptable); prior chemotherapy for MDS or myeloproliferative neoplasms (MPN) such as azacitidine, decitabine, and thalidomide, is permitted, but such treatments once MDS or MPN has transformed to AML is not permitted
- APL (acute promyelocytic leukemia) by WHO criteria [AML with t(15;17)]
- Cardiac ejection fraction (EF) < 40%
- Systemic treatment, during or within 48 hours of the first dose of MLN9708, 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; for this protocol prophylactic antibiotics are not recommended, at least not until 48 hours after the last dose of study drug (given on day 12), when the patient may be neutropenic.; for patients with fever and/or infections, cefepime and AmBisome are acceptable
Locations & Contacts
Contact: Philip C. Amrein
Trial Objectives and Outline
I. Maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of ixazomib citrate (MLN9708) with induction chemotherapy.
II. MTD/RP2D of MLN9708 with consolidation chemotherapy in patients who have received the MTD/RP2D of MLN9708 in induction.
I. Complete remission frequency of patients treated with MLN9708 in induction.
II. Overall and disease-free survival of patients treated with MLN9708 on this study.
I. Relationship between cluster of differentiation (CD)74 expression by flow cytometry and clinical response.
OUTLINE: This is a dose-escalation study of ixazomib citrate.
INDUCTION THERAPY: Patients receive daunorubicin hydrochloride intravenously (IV) on days 1-3, cytarabine IV continuously on days 1-7, and ixazomib citrate orally (PO) on days 2, 5, 9, and 12.
REINDUCTION THERAPY: Within 7 days of bone marrow biopsy, patients experiencing residual disease receive daunorubicin hydrochloride IV on days 1-2, cytarabine IV continuously on days 1-5, and ixazomib citrate PO on days 2, 5, 9, and 12.
CONSOLIDATION THERAPY (COURSE 1): Patients receive cytarabine IV over 3 hours on days 1-5 and ixazomib citrate PO on days 2, 5, 9, and 12.
REMISSION CONSOLIDATION THERAPY (COURSES 2-4): Patients not experiencing dose-limiting toxicity (DLT) may receive cytarabine and ixazomib citrated as in consolidation therapy course 1. Treatment repeats every 42 days for 3 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 2 months for 2 years, every 3 months 2 years, and then yearly for 6 years.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Philip C. Amrein
Secondary IDs NCI-2016-00328
Clinicaltrials.gov ID NCT02582359