Bortezomib, Mitoxantrone, Etoposide, and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia

Case Comprehensive Cancer Center (Case CCC)

Status and phase

Completed

Phase 1

Conditions

Adult Acute Megakaryoblastic Leukemia (M7)

Adult Erythroleukemia (M6a)

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Adult Pure Erythroid Leukemia (M6b)

Adult Acute Monoblastic Leukemia (M5a)

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Adult Acute Myelomonocytic Leukemia (M4)

Adult Acute Myeloblastic Leukemia With Maturation (M2)

Adult Acute Myeloblastic Leukemia Without Maturation (M1)

Recurrent Adult Acute Myeloid Leukemia

Adult Acute Minimally Differentiated Myeloid Leukemia (M0)

Adult Acute Monocytic Leukemia (M5b)

Adult Acute Myeloid Leukemia With Del(5q)

Treatments

Drug: mitoxantrone hydrochloride

Drug: cytarabine

Drug: bortezomib

Drug: etoposide

Other: flow cytometry

Study type

Interventional

Funder types

Other

Identifiers

NCT01127009

NCI-2010-01203 (Other Identifier)

CASE4909 (Other Identifier)

Details and patient eligibility

About

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with mitoxantrone, etoposide, and cytarabine in treating patients with relapsed or refractory acute myeloid leukemia.

Full description

PRIMARY OBJECTIVES:

I. To determine the DLT, MTD, and the recommended Phase 2 dose of bortezomib in combination with MEC in patients with relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. To describe the non-dose limiting toxicities associated with bortezomib in combination with MEC in patients with relapsed/refractory AML.

II. To describe any preliminary evidence of clinical activity of this combination (CR rate) in relapsed/refractory AML.

III. To determine the median CD74 antigen expression in patients achieving a response versus those patients not achieving a response.

OUTLINE:

This is a dose-escalation study of bortezomib.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV, etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-5 weeks.

Enrollment

3 patients

Sex

All

Ages

18 to 70 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion

Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study; female subject is not lactating
Male subject agrees to use an acceptable method for contraception for the duration of the study
Relapsed or refractory AML (excluding acute promyelocytic leukemia), based on World Health Organization Classification; all other subtypes of AML will be eligible; refractory disease will be considered failure to respond to 2 cycles of induction chemotherapy (7+3 and 5+2); any number of relapses will be eligible
No evidence of leptomeningeal disease; a lumbar puncture does not need to be performed unless there is clinical suspicion of leptomeningeal disease
Previous treatment related toxicities must have resolved to Grade 1 (excluding alopecia)
Liver enzymes (AST and ALT) can not be greater than 2.5 times the upper limits of normal (ULN), and total bilirubin =< 1.5 x ULN within 14 days of enrollment
Renal function: Serum creatinine should be =< 1.5 x ULN within 14 days of enrollment
No serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously complicate compliance with the protocol
ECOG performance status 0-3
No peripheral neuropathy >= Grade 2 within 14 days of trial enrollment
Echocardiogram or MUGAs scan demonstrating an ejection fraction >= 45%
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
No uncontrolled infections
No history of hypersensitivity to boron or mannitol
No known history of HIV or active hepatitis B or C
No major surgery within 4 weeks prior to trial enrollment

Exclusion

Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant
Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment
Female subject is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
Patient has received any standard or investigational therapy for their leukemia within 14 days before enrollment (except for hydrea)
Serious medical or psychiatric illness likely to interfere with participation in this clinical study
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
Leptomeningeal/ central nervous system involvement with AML; a lumbar puncture does not need to be performed unless there is clinical suspicion
Patients who have had prior pulmonary radiation
Prohibited Concurrent Therapy: any investigational agent other than VELCADE; G-CSF and GM-CSF are not allowed