High Dose Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil in Preventing Graft Versus Host Disease in Patients With Hematological Malignancies Undergoing Myeloablative or Reduced Intensity Donor Stem Cell Transplant
Study Details
Study Description
Brief Summary
This pilot phase II trial studies how well high dose cyclophosphamide, tacrolimus, and mycophenolate mofetil work in preventing graft versus host disease in patients with hematological malignancies undergoing myeloablative or reduced intensity donor stem cell transplant. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft versus host disease). Giving high dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
| Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- To estimate the graft versus host disease (GVHD)-free relapse/progression-free survival (GRFS) at one-year post hematopoietic cell transplantation (HCT) and to evaluate the clinical activity of post-transplant high dose cyclophosphamide (PTCy).
SECONDARY OBJECTIVES:
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To summarize toxicities/complications/infections including type, frequency, severity, attribution, time course and duration through 100 days post-transplant.
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To estimate the cumulative incidence (CI) of acute and chronic GVHD. III. To characterize the time course of neutrophil and platelet recovery/engraftment.
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To estimate overall survival (OS), progression-free survival (PFS), CI of relapse/progression and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.
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To describe quality of life at 100 days, 6 months, 1 and 2 years. VI. To characterize immune cell reconstitution and T cell repertoire post high dose cyclophosphamide in mismatched donor HCT.
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To characterize quality of life.
OUTLINE:
CONDITIONING REGIMEN: Patients are assigned to 1 of 3 conditioning regimens at the discretion of the attending physician and principal investigator.
REGIMEN A (REDUCED INTENSITY CONDITIONING): Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -7 to -3 and melphalan hydrochloride IV over 20 minutes on day -2.
REGIMEN B (MYELOABLATIVE CONDITIONING [MAC]): Patients receive fludarabine phosphate IV over 1-3 hours and busulfan IV over 3 hour on days -5 to -2.
REGIMEN C (MAC): Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -5 and total body irradiation (TBI) twice daily (BID) on days -4 to -1.
TRANSPLANT: Patients undergo peripheral blood stem cell (PBSC) hematopoietic cell transplantation (HCT) on day 0.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or orally (PO) thrice daily (TID) beginning on day 5 and stopping on day 35 if no severe GVHD is present, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up twice weekly for 100 days, twice monthly for 6 months, monthly until no evidence of GVHD, and then yearly for up to 2 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis) Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -3 and melphalan hydrochloride IV over 20 minutes on day -2. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide Given IV
Other Names: Drug: Fludarabine Phosphate Given IV
Other Names: Procedure: Hematopoietic Cell Transplantation Undergo PBSC HCT
Other Names: Other: Laboratory Biomarker Analysis Correlative studies Drug: Melphalan Hydrochloride Given IV
Other Names: Drug: Mycophenolate Mofetil Given IV or PO
Other Names: Procedure: Peripheral Blood Stem Cell Transplantation Undergo PBSC HCT
Other Names: Other: Quality-of-Life Assessment Ancillary studies
Other Names: Drug: Tacrolimus Given IV
Other Names: |
| Experimental: Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis) Patients receive fludarabine phosphate IV over 1-3 hours and busulfan IV over 3 hour on days -5 to -2. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity. | Drug: Busulfan Given IV
Other Names: Drug: Cyclophosphamide Given IV
Other Names: Drug: Fludarabine Phosphate Given IV
Other Names: Procedure: Hematopoietic Cell Transplantation Undergo PBSC HCT
Other Names: Other: Laboratory Biomarker Analysis Correlative studies Drug: Mycophenolate Mofetil Given IV or PO
Other Names: Procedure: Peripheral Blood Stem Cell Transplantation Undergo PBSC HCT
Other Names: Other: Quality-of-Life Assessment Ancillary studies
Other Names: Drug: Tacrolimus Given IV
Other Names: |
| Experimental: Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis) Patients receive fludarabine phosphate IV over 60 minutes on days -7 to -5 and TBI BID on days -4 to -1. Patients undergo PBSC HCT on day 0. Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID beginning on days 5 and stopping on day 35 if no severe GVHD is present-35, and tacrolimus IV continuously on days 5-180 with a taper beginning on day 90 in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide Given IV
Other Names: Drug: Fludarabine Phosphate Given IV
Other Names: Procedure: Hematopoietic Cell Transplantation Undergo PBSC HCT
Other Names: Other: Laboratory Biomarker Analysis Correlative studies Drug: Mycophenolate Mofetil Given IV or PO
Other Names: Procedure: Peripheral Blood Stem Cell Transplantation Undergo PBSC HCT
Other Names: Other: Quality-of-Life Assessment Ancillary studies
Other Names: Drug: Tacrolimus Given IV
Other Names: Radiation: Total-Body Irradiation Undergo TBI
Other Names: |
Outcome Measures
Primary Outcome Measures
- GRFS [From stem cell infusion to grade 3-4 acute graft versus host disease (GVHD), moderate-severe chronic GVHD, relapse, progression or death (from any cause), whichever occurs first, assessed for up to 2 years]
Estimates will be calculated using the Kaplan-Meier method, Greenwood formula will be used to calculate standard error (SE), and log-log transformation method will be used to construct 95% confidence intervals. Graft versus host disease (GVHD, acute and chronic), disease status and vital status will be monitored per clinical standard operating procedure. For this endpoint failure is defined as the first occurrence of grade 3 or 4 acute GVHD, or moderate/severe chronic GVHD, or disease relapse (for patients in complete remission at the start of conditioning) or disease progression (for patients with active disease at the start of conditioning) or death (from any cause). Patients not experiencing any of these will be censored at his/her date of last contact.
Secondary Outcome Measures
- Acute graft versus host disease (aGVHD) of grades 2-4 and 3-4 graded according to the Consensus Grading [Up to 100 days post-stem cell infusion]
The first day of aGVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade. Relapse/death prior to onset will be considered competing events.
- Change in quality of life as assessed by SF-36, Functional Assessment of Cancer Therapy Bone Marrow Transplant questionnaire [Baseline up to 2 years]
- Change in quality of life as assessed by the MD Anderson Symptom Inventory questionnaire [Baseline up to 2 years]
- Change in quality of life as assessed by the PedsQL Stem Cell Transplant module [Baseline up to 2 years]
- Chronic graft versus host disease (cGVHD) graded according to the National Institutes of Health Consensus Staging [Day 100 post-stem cell infusion up to 2 years]
The first day of cGVHD onset at a certain grade will be used to calculate cumulative incidence curves. Relapse/death prior to onset will be considered competing events.
- Cumulative incidence of relapse/progression [From start of protocol therapy, assessed for up to 2 years]
Will be calculated as competing risks using the Gray method.
- Incidence of adverse events graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Toxicity Scale [Up to 100 days post-stem cell infusion]
Will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.
- Incidence of adverse events graded using the Berman Toxicity Scale [Up to 100 days post-stem cell infusion]
Will include the type and severity. Tables will be constructed to summarize the observed incidence by type of toxicity.
- Microbiologically documented infections [Up to 100 days post-stem cell infusion]
Will be reported by site of disease, date of onset, severity and resolution.
- Non-relapse Mortality (NRM) [From start of protocol therapy until non-disease related death, or last follow-up, whichever comes first, assessed for up to 2 years]
Will be calculated as competing risks using the Gray method.
- Overall Survival (OS) [From start of protocol therapy to death, or last follow up, whichever occurs first, assessed for up to 2 years]
Estimates will be calculated using the Kaplan-Meier method, Greenwood formula will be used to calculate SE, and log-log transformation method will be used to construct 95% confidence intervals. Each patient's vital status will be monitored per clinical standard operating procedure. For this endpoint failure is defined as death (from any cause). Patients not experiencing a death event will be censored at his/her date of last contact.
- Progression Free Survival (PFS) [From start of protocol therapy to death, relapse/progression, or last follow up, whichever occurs first, assessed for up to 2 years]
Estimates will be calculated using the Kaplan-Meier method, Greenwood formula will be used to calculate SE, and log-log transformation method will be used to construct 95% confidence intervals. Disease status and vital status will be monitored per clinical standard operating procedure. For this endpoint failure is defined as disease relapse (for patients in complete remission at the start of conditioning) or disease progression (for patients with active disease at the start of conditioning) or death (from any cause). Patients not experiencing any of these will be censored at his/her date of last contact.
- Time to hematological recovery in terms of neutrophil (absolute neutrophil count >= 500/ul, 1.0 x 10^3/ul) and platelet (20 x 10^3/ul and 100 x 10^3/ul) engraftment time [Up to 2 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 10% blasts in the bone marrow
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Patients with myelodysplastic syndrome (MDS) with intermediate-2 or high risk per International Prognostic Scoring System (IPSS) (or intermediate, high, very high risk by Revised International Prognostic Scoring System [IPSS-R]) or myeloproliferative neoplasm; primary or secondary if high-risk features or refractory disease
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Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin lymphoma, or mantle cell lymphoma with chemosensitive disease at time of transplantation; all types of lymphoma are eligible
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High risk, or refractory and relapsed multiple myeloma
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No available human leukocyte antigen (HLA)-matched related donor
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Available matched unrelated donor
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Ejection fraction at rest >= 50%
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Karnofsky performance status (KPS) >= 70
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Measured creatinine clearance more than 60 mL/min. The updated Schwartz formula should be used for pediatric patients (>=5 to 12 years old)
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Carbon monoxide diffusing capability test (DLCO) >= 50% (adjusted for hemoglobin) and forced expiratory volume in 1 second (FEV1) >= 50%
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Total bilirubin < 1.5 x the upper limit of normal; patients who have been diagnosed with Gilbert's disease are allowed to exceed the defined bilirubin value of 1.5 x the upper limit of normal
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Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper limit of normal
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Alkaline phosphatase < 2.5 x the upper limit of normal
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Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing of the informed consent through 12 months post-transplant
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Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception, or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant
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All subjects must have the ability to understand and the willingness to sign a written informed consent document
DONOR INCLUSION CRITERIA
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7 out of 8 at high resolution using deoxyribonucleic acid (DNA)-based typing with either antigen or allele mismatched HLA (-A, -B, -C, and -DR) or 8/8 HLA-mismatched with either double DQ mismatch (10/12) or combined DQ and DP mismatch
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Donor must be willing to donate peripheral blood stem cells
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Suitable donor
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Medically cleared to donate per National Marrow Donor Program (NMDP)
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Absence of donor-specific antibodies (DSA) to the mismatched HLA-locus
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Donor choices per matched unrelated donor (MUD) committee according to center standard operating procedure (SOP)
Exclusion Criteria:
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Prior allogeneic transplant
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Active central nervous system (CNS) involvement by malignant cells
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Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
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Patients with transformed lymphoma (e.g., Richter's transformation arising in follicular lymphoma or chronic lymphocytic leukemia)
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Patients seropositive for the human immunodeficiency virus (HIV)
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Patients with active hepatitis B or C determined by polymerase chain reaction (PCR)
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Myocardial infarction within 6 months prior to enrollment or 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 electrocardiography (ECG) abnormality at screening must be documented by the investigator as not medically relevant
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Female patients who are lactating or pregnant
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Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
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History of another primary malignancy that has not been in remission for at least 3 years (the following are exempt from the 3-year limit: non-melanoma skin cancer, fully excised melanoma in situ [Stage 0], curatively treated localized prostate cancer, and cervical or breast carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear)
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Psychosocial issues: no appropriate caregivers identified, or non-compliant to medications
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Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Monzr Al Malki, MD, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 16419
- NCI-2017-00480
- 16419
