Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Primary Purpose
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia in Remission
Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
clofarabine
melphalan
allogeneic hematopoietic stem cell transplantation
tacrolimus
sirolimus
Pharmacological Study
Sponsored by
About this trial
This is an interventional treatment trial for Adult Acute Lymphoblastic Leukemia in Remission
Eligibility Criteria
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
Sites / Locations
- City of Hope Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (clofarabine, melphalan, transplant)
Arm 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.
Outcomes
Primary Outcome Measures
Progression-free Survival at 2 Years
Progression-free survival (PFS) is defined as time from start of protocol treatment to disease relapse/progression, death or last contact, whichever occurs first. Progression-free survival was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.
Secondary Outcome Measures
Overall Survival at 2 Years
Overall survival (OS) is defined as time from start of protocol treatment to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.
Full Information
NCT ID
NCT01885689
First Posted
June 21, 2013
Last Updated
March 31, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01885689
Brief Title
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Official Title
Phase II Study of Clofarabine and High-Dose Melphalan Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation for Myelodysplasia or Acute Leukemia in Remission
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 10, 2014 (Actual)
Primary Completion Date
December 27, 2019 (Actual)
Study Completion Date
December 30, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia in Remission, Myelodysplastic Syndrome, Secondary Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Therapy-Related Myelodysplastic Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
72 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (clofarabine, melphalan, transplant)
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
clofarabine
Other Intervention Name(s)
CAFdA, Clofarex, Clolar
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
melphalan
Other Intervention Name(s)
Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic hematopoietic stem cell transplant
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
Given IV or PO
Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
AY 22989, Rapamune, rapamycin, SLM
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Progression-free Survival at 2 Years
Description
Progression-free survival (PFS) is defined as time from start of protocol treatment to disease relapse/progression, death or last contact, whichever occurs first. Progression-free survival was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.
Time Frame
From start of protocol treatment to death due to any cause, disease relapse/progression, or last follow-up, whichever comes first, assessed up to 2 years.
Secondary Outcome Measure Information:
Title
Overall Survival at 2 Years
Description
Overall survival (OS) is defined as time from start of protocol treatment to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula.
Time Frame
From start of protocol treatment to death due to any cause, or last follow-up, whichever comes first, assessed up to 2 years.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Monzr Al Malki
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
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