Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis

NCT ID: NCT03426969

Last Updated: 2020-10-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-31
• Study Completion Date: 2020-09-21

Brief Summary

This early phase I trial studies the side effects of combination chemotherapy, total body irradiation, and donor blood stem cell transplant in treating patients with primary or secondary myelofibrosis. Drugs used in chemotherapy, such as melphalan, fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil, and filgrastim work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving combination chemotherapy and total body irradiation before a donor blood stem cell transplant helps to stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of reduced-intensity (FM) haploidentical hematopoietic cell transplantation (Haplo-HCT) followed by post-transplant cyclophosphamide (PTCy) in patients with advanced myelofibrosis (MF), as assessed by the evaluation of toxicities, including type, frequency, severity, attribution, time course and duration.

SECONDARY OBJECTIVES:

I. To summarize and evaluate hematologic (neutrophil and platelet) recovery. II. To estimate graft failure-free survival (GFS) at 100-days post-transplant. III. To estimate overall survival (OS), progression-free survival (PFS) and cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year, and 2-year post transplant.

IV. To estimate the cumulative incidence of acute graft-versus-host disease (GvHD), grade II-IV, at 100-days post-transplant (per Keystone Consensus modification of the Glucksberg criteria).

V. To estimate the cumulative incidence of chronic GvHD at 1-year and 2-year post transplant (per National Institute of Health [NIH] Consensus Criteria).

VI. To characterize the severity and extent of acute and chronic GvHD.

OUTLINE:

Patients receive melphalan intravenously (IV) over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Patients undergo total body irradiation (TBI) on day -1 and hematopoietic stem cell transplant (HCT) on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously for approximately 2 weeks, then orally (PO) for 6 months followed by a taper, mycophenolate mofetil PO thrice daily (TID) until day 100, and filgrastim subcutaneously (SC) daily from day 7 until continued until absolute neutrophil count (ANC) > 1,500/mm^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 1, 3, 6, 9, 12 and 24 months.

Conditions

Primary Myelofibrosis; Secondary Myelofibrosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (combination chemotherapy, TBI, HCT)

Patients receive melphalan IV over 30 minutes on days -5, fludarabine phosphate IV over 1 hour on days -5 to -2. Patients undergo TBI on day -1 and HCT on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously for approximately 2 weeks, then PO for 6 months followed by a taper, mycophenolate mofetil PO TID until day 100, and filgrastim SC daily from day 7 until continued until ANC \> 1,500/mm\^3 for 3 consecutive days. Treatment continues in the absence of disease progression or unexpected toxicity.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Given IV

Filgrastim

Intervention Type: BIOLOGICAL

Given SC

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Hematopoietic Cell Transplantation

Intervention Type: PROCEDURE

Undergo HCT

Melphalan

Intervention Type: DRUG

Given IV

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO

Tacrolimus

Intervention Type: DRUG

IV or PO

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Interventions

Cyclophosphamide

Given IV

Intervention Type: DRUG

Filgrastim

Given SC

Intervention Type: BIOLOGICAL

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Hematopoietic Cell Transplantation

Undergo HCT

Intervention Type: PROCEDURE

Melphalan

Given IV

Intervention Type: DRUG

Mycophenolate Mofetil

Given PO

Intervention Type: DRUG

Tacrolimus

IV or PO

Intervention Type: DRUG

Total-Body Irradiation

Undergo TBI

Intervention Type: RADIATION

Other Intervention Names

(-)-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; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; G-CSF; Neupogen; r-metHuG-CSF; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; HCT; Hematopoietic Stem Cell Transplantation; HSCT; Stem Cell Transplant; stem cell transplantation; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine nitrogen mustard; Sarcoclorin; Sarkolysin; WR-19813; Cellcept; MMF; FK 506; Fujimycin; Hecoria; Prograf; Protopic; TBI; TOTAL BODY IRRADIATION; Whole Body Irradiation; Whole-Body Irradiation

Eligibility Criteria

Inclusion Criteria

• Diagnosis of primary or secondary Myelofibrosis with transplant indication by DIPSS-plus (> intermediate -1);
• Age 18-70; patients >/= age 50 must have an comorbidity score (HCT-CI) </= 4 (Sorror). The Principal Investigator is the final arbiter for comorbidity;
• Patients can be in chronic phase (CP) with BM blast count </= 10% or after progression to AML and achieved </= 5% BM blasts (morphologic CR prior to transplant);
• Lack of an HLA matched donor or need to proceed fast to transplantation when a patient does not have an immediately available matched unrelated donor (typed by high-resolution in the registry);
• Performance status >/=70% (Karnofsky); patients > 50 years should have adequate cognitive function; any concerns regarding cognitive function should be addressed by a Geriatrician/Neurologist;
• Adequate organ function: ALT/AST/billirubin </= 5X UNL, creatinine clearance > 50mls/min (calculated with Cockroft-Gault formula); LVEF >/= 50%, DLCOc >/= 50%;
• Prior treatment with JAK2 inhibitor therapy is not excluded. Patients on a JAK2 inhibitor may continue through conditioning until Day -3 then tapered at the discretion of the investigator.

Exclusion:

• Evidence of portal hypertension with varices, ascites, or hepatic encephalopathy;

->10% bone marrow blasts at transplant if no history of AML and >5% if had previous progression to AML;

• HIV positive; active hepatitis B or C;
• Patients with active infections. The PI is the final arbiter of the eligibility;
• Liver cirrhosis;
• Prior CNS involvement by tumor cells;
• Severe pulmonary hypertension (PHT) (On echo or right side cardiac catheterization);
• 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);
• Positive Beta HCG test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization;
• Noncompliance - Inability or unwillingness to comply with medical recommendations regarding therapy or follow-up, including smoking tobacco. Smoking cessation is a standard teaching practice prior to admission for all patients undergoing stem cell transplant. Any patient who refuses to stop smoking prior to transplant will not be eligible for this study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

M.D. Anderson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stefan O Ciurea

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Locations

M D Anderson Cancer Center

Houston, Texas, United States

Countries

United States

Related Links

http://www.mdanderson.org

University of Texas MD Anderson Cancer Center Website

Other Identifiers

NCI-2018-00910

Identifier Type: REGISTRY

Identifier Source: secondary_id

2017-0375

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA016672

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2017-0375

Identifier Type: -

Identifier Source: org_study_id