Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia

City of Hope

Status and phase

Active, not recruiting

Phase 2

Conditions

Secondary Myelodysplastic Syndrome

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome

Therapy-Related Myelodysplastic Syndrome

Adult Acute Myeloid Leukemia in Remission

Adult Acute Lymphoblastic Leukemia in Remission

Myelodysplastic Syndrome

Chronic Myelomonocytic Leukemia

Treatments

Drug: melphalan

Other: Pharmacological Study

Drug: sirolimus

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: clofarabine

Drug: tacrolimus

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01885689

NCI-2013-01193 (Registry Identifier)

13130

Details and patient eligibility

About

This phase II trial studies how well clofarabine and melphalan before a donor stem cell transplant works in treating patients with a decrease in or disappearance of signs and symptoms of myelodysplasia or acute leukemia (disease is in remission), or chronic myelomonocytic leukemia. Giving chemotherapy, such as clofarabine and melphalan, before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into a patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving clofarabine and melphalan before transplant may help prevent the cancer from coming back after transplant, and they may cause fewer side effects than standard treatment.

Full description

PRIMARY OBJECTIVES:

I. Following a patient safety lead-in, determine the anti-tumor activity of clofarabine given in combination with high-dose melphalan as assessed by 2-year progression-free survival (PFS).

II. Estimate overall survival (OS), cumulative incidence (CI) of relapse/progression and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

III. Summarize toxicities/complications by organ and severity, including acute and chronic graft-vs-host disease (GVHD), and infection.

OUTLINE:

CONDITIONING REGIMEN: Patients receive clofarabine intravenously (IV) over 2 hours on days -9 to -5 and melphalan IV over 30 minutes on day -4.

TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

GVHD PROPHYLAXIS: Beginning on day -3, patients receive tacrolimus IV or orally (PO) and sirolimus PO once daily with taper per City of Hope standard operating procedure.

After completion of study treatment, patients are followed up once weekly for 60 days, at 100, and 180 days, at one year, and then yearly for up to 5 years.

Enrollment

72 patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients in 1st or 2nd remission with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), who are eligible for stem cell transplant. Remission defined as no circulating blasts, < 5% blasts in the bone marrow, normalization of previously detected cytogenetic abnormalities, no extramedullary disease
High risk myelodysplastic syndrome (MDS)
- Intermediate II and high risk by International Prognostic Scoring System (IPSS)
- Intermediate, high, or very high by World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS)
- Transfusion dependent
- Therapy-related MDS or MDS evolved from previous hematological disorder (excepting myelofibrosis)
Patients with chronic myelomonocytic leukemia (CMML) are allowed to be enrolled
Patients with MDS that has evolved to AML must be in remission
Patients must not be eligible for full ablative regimens by the attending physician
Patients with AML or MDS arising from myeloproliferative neoplasm can be enrolled after principal investigator (PI) approval on case to case basis, depends on the spleen size and degree of bone marrow fibrosis
Performance status of >= 70% on the Karnofsky scale
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect she is pregnant while participating on the trial, she should inform her treating physician immediately
Bone marrow and peripheral blood studies must be available for confirmation of diagnosis; cytogenetics, flow cytometry, and molecular studies (such as Flt-3 status) will be obtained as per standard practice
Bone marrow aspirates/biopsies should be performed within 28 (+ 4 day window) days from registration to confirm disease remission status
A pretreatment measured creatinine clearance (absolute value) of >= 60 mL/minute
Patients must have a serum bilirubin =< 2.0 mg/dl
Patients must have serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2.5 times the institutional upper limit of normal
Ejection fraction measured by echocardiogram or multi gated acquisition scan (MUGA) > 50%
Diffusing capacity of the lung for carbon monoxide (DLCO) or forced expiratory volume in 1 second (FEV1) > 45% predicted
Availability of a human leukocyte antigen (HLA) matched (6/6) sibling donor or 8/8 matched unrelated donor; Donors with mismatch at HLA-A, HLA-B, HLA-C, and HLA-DR will be reviewed by matched unrelated donor (MUD) committee and allowed if their mismatch with the recipient does not require additional GVHD prophylaxis (other than tacrolimus and sirolimus), donors with mismatch at HLA-DQ or HLA-DPB are eligible; donor evaluation according to City of Hope (COH) standard operating procedure (SOP)
Donor stem cell source can be either peripheral blood or bone marrow
All patients must have a psychosocial evaluation prior to transplant as per COH SOP
All subjects must have the ability to understand and the willingness to sign a written informed consent
ALL or AML patients who received chemotherapy (induction or consolidation) can proceed to transplant once bone marrow cellularity is > 10 % with no evidence of leukemia

Exclusion criteria

Patients who have received a prior autologous or allogeneic transplant are excluded
Patients with significant hepatic dysfunction (not meeting liver function tests [LFT] eligibility criteria)
Patients with MDS evolved into AML that is not in remission
Patients with acute promyelocytic leukemia
Patients with myeloproliferative neoplasms
Patients with suspected or proven central nervous system (CNS) leukemia; (diagnostic lumbar puncture not required before enrollment)
Uncontrolled intercurrent illness including, but not limited to ongoing or active or poorly controlled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant and lactating women are excluded from this study
Patients who do not agree to practice effective forms of contraception
Human immunodeficiency virus (HIV)-positive patients are excluded from this study
Patients are excluded if they are hepatitis B surface antigen (sAg), hepatitis B (Hep B) core antibody (cAb), or hepatitis C (Hep C) positive. Patients with Hepatitis B cAB positive and Hepatitis B PCR negative are eligible if they started prophylactic treatment prior to registration to trial
Patients who have received radiation therapy as part of their leukemia treatment may be ineligible and individual cases must be presented to the study principal investigator (PI) for determination of eligibility
Any psychiatric, social or compliance issues that, in the treating physician's opinion, will interfere with completion of the transplant treatment and follow up
Medical or psychiatric reasons which make the donor unlikely to tolerate or cooperate with filgrastim (G-CSF) therapy or leukapheresis or bone marrow harvest
Known allergies to clofarabine, melphalan, sirolimus or tacrolimus
Patients with other active malignancies (besides AML, ALL, MDS) requiring treatment or where there is concern of progression are ineligible for this study; however, patients with previously treated skin cancer, early stage cervical or prostate cancer may be eligible if there is no evidence of residual disease
Cord blood as a donor source is not acceptable
Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

72 participants in 1 patient group

Treatment (clofarabine, melphalan, transplant)

Experimental group

Description:

CONDITIONING REGIMEN: Patients receive clofarabine IV over 2 hours on days -9 to -5 and melphalan IV over 30 minutes on day -4. TRANSPLANT: Patients undergo allogeneic hematopoietic stem cell transplant on day 0. GVHD PROPHYLAXIS: Beginning on day -3, patients receive tacrolimus IV or PO and sirolimus PO once daily with taper per City of Hope standard operating procedure.