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

NCT03128359 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 16419NCI-2017-00480
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Leukemia; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Graft Versus Host Disease; Hodgkin Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; Secondary Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Graft-Versus-Host Disease-Free, Relapse-Free Survival (GRFS) at 1 Year

  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.

  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 1 year.

Secondary Outcomes (2)

• Acute Graft Versus Host Disease (aGVHD) of Grades 2-4 According to the Consensus Grading

  Up to 100 days post-stem cell infusion

• Overall Survival (OS) at 1 Year

  From start of transplant to death, or last follow up, whichever occurs first, assessed for up to 1 year.

Study Arms (3)

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis)

EXPERIMENTAL

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; Drug: Fludarabine Phosphate; Procedure: Hematopoietic Cell Transplantation; Other: Laboratory Biomarker Analysis; Drug: Melphalan Hydrochloride; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Quality-of-Life Assessment; Drug: Tacrolimus

Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis)

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Procedure: Hematopoietic Cell Transplantation; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Quality-of-Life Assessment; Drug: Tacrolimus

Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

EXPERIMENTAL

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; Drug: Fludarabine Phosphate; Procedure: Hematopoietic Cell Transplantation; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Quality-of-Life Assessment; Drug: Tacrolimus; Radiation: Total-Body Irradiation

Interventions

Busulfan DRUG

Given IV

Also known as: 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508

Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Hematopoietic Cell Transplantation PROCEDURE

Undergo PBSC HCT

Also known as: HCT, Hematopoietic Stem Cell Transplantation, HSCT, stem cell transplantation

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Laboratory Biomarker Analysis OTHER

Correlative studies

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Melphalan Hydrochloride DRUG

Given IV

Also known as: Alkeran, Alkerana, Evomela

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis)

Mycophenolate Mofetil DRUG

Given IV or PO

Also known as: Cellcept, MMF

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo PBSC HCT

Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Tacrolimus DRUG

Given IV

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Regimen A (fludarabine, melphalan, PBSC HCT, GVHD prophylaxis); Regimen B (fludarabine, busulfan, PBSC HCT, GVHD prophylaxis); Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Regimen C (fludarabine, TBI, PBSC HCT, GVHD prophylaxis)

Eligibility Criteria

• Age: 5 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 10% blasts in the bone marrow
• 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
• 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
• High risk, or refractory and relapsed multiple myeloma
• No available human leukocyte antigen (HLA)-matched related donor
• Available matched unrelated donor
• Ejection fraction at rest \>= 50%
• Karnofsky performance status (KPS) \>= 70
• Measured creatinine clearance more than 60 mL/min. The updated Schwartz formula should be used for pediatric patients (\>=5 to 12 years old)
• Carbon monoxide diffusing capability test (DLCO) \>= 50% (adjusted for hemoglobin) and forced expiratory volume in 1 second (FEV1) \>= 50%
• 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
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 2.5 x the upper limit of normal
• Alkaline phosphatase \< 2.5 x the upper limit of normal
• 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
• 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

You may not qualify if:

• Prior allogeneic transplant
• Active central nervous system (CNS) involvement by malignant cells
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
• Patients with transformed lymphoma (e.g., Richter's transformation arising in follicular lymphoma or chronic lymphocytic leukemia)
• Patients seropositive for the human immunodeficiency virus (HIV)
• Patients with active hepatitis B or C determined by polymerase chain reaction (PCR)
• 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
• Female patients who are lactating or pregnant
• Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
• 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)
• Psychosocial issues: no appropriate caregivers identified, or non-compliant to medications
• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

Related Publications (1)

• Al Malki MM, Tsai NC, Palmer J, Mokhtari S, Tsai W, Cao T, Ali H, Salhotra A, Arslan S, Aldoss I, Karras N, Karanes C, Zain J, Khaled S, Stein A, Snyder D, Marcucci G, Forman SJ, Nakamura R. Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant. Blood Adv. 2021 Jun 22;5(12):2650-2659. doi: 10.1182/bloodadvances.2021004192.

  PMID: 34156440 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Graft vs Host Disease; Hodgkin Disease; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Myelodysplastic Syndromes; Myeloproliferative Disorders; Multiple Myeloma

Interventions

Busulfan; Cyclophosphamide; fludarabine phosphate; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Melphalan; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Tacrolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Bone Marrow Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Dr. Monzr M.Al Malki, MD
• Organization: City of Hope Medical Center

malmalki@coh.org

6263598111

Study Officials

• Monzr Al Malki, MD

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2017
• First Posted: April 25, 2017
• Study Start: May 30, 2017
• Primary Completion: August 1, 2020
• Study Completion: September 15, 2021
• Last Updated: January 9, 2024
• Results First Posted: June 9, 2023

Record last verified: 2024-01

Locations

US (1)