Clinical Trial: NCT03426969 - My Cancer Genome

NCT03426969

Description:

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.

Related Conditions:

Myelofibrosis

Recruiting Status:

Completed

Phase:

Early Phase 1

URL:

https://clinicaltrials.gov/show/NCT03426969

Trial Eligibility

Document

Title

Brief Title: Combination Chemotherapy, Total Body Irradiation, and Donor Blood Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis
Official Title: A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide in Patients With Advanced Myelofibrosis

Clinical Trial IDs

ORG STUDY ID: 2017-0375
SECONDARY ID: NCI-2018-00910
SECONDARY ID: 2017-0375
SECONDARY ID: P30CA016672
NCT ID: NCT03426969

Conditions

Primary Myelofibrosis
Secondary Myelofibrosis

Interventions

Drug	Synonyms	Arms
Cyclophosphamide	(-)-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	Treatment (combination chemotherapy, TBI, HCT)
Filgrastim	G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim	Treatment (combination chemotherapy, TBI, HCT)
Fludarabine Phosphate	2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586	Treatment (combination chemotherapy, TBI, HCT)
Melphalan	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	Treatment (combination chemotherapy, TBI, HCT)
Mycophenolate Mofetil	Cellcept, MMF	Treatment (combination chemotherapy, TBI, HCT)
Tacrolimus	FK 506, Fujimycin, Hecoria, Prograf, Protopic	Treatment (combination chemotherapy, TBI, HCT)

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Treatment (combination chemotherapy, TBI, HCT)	Experimental	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.	Cyclophosphamide Filgrastim Fludarabine Phosphate Melphalan Mycophenolate Mofetil Tacrolimus

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.

Maximum Eligible Age:	70 Years
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	Accepts Healthy Volunteers

Primary Outcome Measures

Measure:	Incidence of adverse events
Time Frame:	Up to day +100 post-hematopoietic cell transplantation (HCT)
Safety Issue:
Description:	Observed toxicities will be tabulated and summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome.

Secondary Outcome Measures

Measure:	Overall survival
Time Frame:	Up to 24 months
Safety Issue:
Description:	Estimated will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.

Measure:	Progression-free survival
Time Frame:	Up to 24 months
Safety Issue:
Description:	Estimated will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.

Measure:	Graft failure-free survival
Time Frame:	Up to 24 months
Safety Issue:
Description:	Estimates will be calculated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.

Measure:	Time to neutrophil recovery
Time Frame:	Up to 24 months
Safety Issue:
Description:	Will be estimated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.

Measure:	Time to platelet recovery
Time Frame:	Up to 24 months
Safety Issue:
Description:	Will be estimated using the Kaplan-Meier product-limit method. Distributions will be compared using the log-rank test. Cox proportional hazards regression will be used to assess the association between survival endpoints and clinical and disease covariates of interest.

Measure:	Non-relapse mortality (NRM)
Time Frame:	Up to 24 months
Safety Issue:
Description:	The cumulative incidence of relapse/progression with a competing risk of NRM will be estimated in a competing risks framework. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.

Measure:	Acute graft versus host disease (GvHD)
Time Frame:	Up to 24 months
Safety Issue:
Description:	Will be estimated in a competing risks framework with competing risks of relapse and NRM. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.

Measure:	Chronic GvHD
Time Frame:	Up to 24 months
Safety Issue:
Description:	Will be estimated in a competing risks framework with competing risks of relapse and NRM. Analyses to assess the association between the cumulative incidence of the above parameters and clinical and disease covariates of interest will be performed using the method of Fine and Gray.

Details

Phase:	Early Phase 1
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	M.D. Anderson Cancer Center

Last Updated

October 14, 2020

Clinical Trials /

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