Clinical Trial: NCT01824693 - My Cancer Genome

NCT01824693

Description:

This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant works in treating younger patients with juvenile myelomonocytic leukemia. Giving chemotherapy before a donor hematopoietic 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 the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before a donor stem cell transplant is more effective in treating juvenile myelomonocytic leukemia.

Related Conditions:

Juvenile Myelomonocytic Leukemia

Recruiting Status:

Completed

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT01824693

Trial Eligibility

Document

Title

Brief Title: Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia
Official Title: A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)

Clinical Trial IDs

ORG STUDY ID: ASCT1221
SECONDARY ID: NCI-2013-00738
SECONDARY ID: COG-ASCT1221
SECONDARY ID: ASCT1221
SECONDARY ID: ASCT1221
SECONDARY ID: ASCT1221
SECONDARY ID: U10CA180886
SECONDARY ID: U10CA098543
NCT ID: NCT01824693

Conditions

Juvenile Myelomonocytic Leukemia

Interventions

Drug	Synonyms	Arms
Busulfan	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	Arm I (busulfan, cyclophosphamide, melphalan)
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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719	Arm I (busulfan, cyclophosphamide, melphalan)
Fludarabine Phosphate	2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586	Arm II (busulfan, fludarabine phosphate)
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	Arm I (busulfan, cyclophosphamide, melphalan)
Mycophenolate Mofetil	Cellcept, MMF	Arm I (busulfan, cyclophosphamide, melphalan)
Tacrolimus	FK 506, Fujimycin, Hecoria, Prograf, Protopic	Arm I (busulfan, cyclophosphamide, melphalan)

Purpose

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare ? in a randomized fashion ? the day 100 treatment related mortality (TRM)
      incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine
      phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to
      hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia
      (JMML), in order to determine the preferred regimen for future trials.

      II. To compare ? in a randomized fashion ? the 18-month event-free survival (EFS) following
      two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for
      children with JMML, in order to determine the preferred regimen for future trials.

      SECONDARY OBJECTIVES:

      I. To determine the 18-month relapse incidence (RI) following two different myeloablative
      conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

      II. To determine the graft failure rates following two different myeloablative conditioning
      regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

      TERTIARY OBJECTIVES:

      I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the
      two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL).

      II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host
      disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs. BU-CY-MEL)
      in children with JMML.

      III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future
      patients.

      IV. To determine the feasibility of assessing post-transplant disease burden by donor
      chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear and
      sorted cell subsets.

      V. To validate gene expression and methylation classifiers predictive of relapse in patients
      with JMML.

      VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML
      who are treated on this transplant protocol.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I:

      CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) over 2-3 hours once daily
      (QD), every 12 hours, or every 6 hours on days -8 to -5, cyclophosphamide IV over 60 minutes
      QD on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.

      TRANSPLANT: Patients undergo allogeneic HCT on day 0.

      Patients receive tacrolimus IV or orally (PO) on days -1 to 98 (related donor) or 180
      (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30
      (related donor) or 45 (unrelated donor).

      ARM II:

      CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over
      30-60 minutes on days -5 to -2.

      TRANSPLANT: Patients undergo allogeneic HCT as in Arm I.

      Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated
      donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related
      donor) or 45 (unrelated donor).

      After completion of study treatment, patients are followed up for 5 years.

Trial Arms

Name	Type	Description	Interventions
Arm I (busulfan, cyclophosphamide, melphalan)	Experimental	CONDITIONING REGIMEN: Patients receive busulfan IV QD, every 12 hours, or every 6 hours over 2-3 hours on days -8 to -5, cyclophosphamide IV QD over 60 minutes on days -4 and -3, and melphalan IV over 15-30 minutes on day -1. TRANSPLANT: Patients undergo allogeneic HCT no sooner than 24 hours after the last dose of chemotherapy. Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).	Busulfan Cyclophosphamide Melphalan Mycophenolate Mofetil Tacrolimus
Arm II (busulfan, fludarabine phosphate)	Experimental	CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 1 hour on days -5 to -2. TRANSPLANT: Patients undergo allogeneic HCT as in Arm I. Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor).	Busulfan Fludarabine Phosphate Mycophenolate Mofetil Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a strong clinical suspicion of JMML, based on a modified category 1
             of the revised diagnostic criteria; specifically, eligible patients must have all of
             the following:

               -  Splenomegaly

               -  Absolute monocyte count (AMC) > 1000/uL

               -  Blasts in peripheral blood (PB)/bone marrow (BM) < 20%

          -  For the 7-10% of patients without splenomegaly, the diagnostic entry criteria must
             include all other features described above and at least 2 of the following criteria:

               -  Circulating myeloid precursors

               -  White blood cell (WBC) > 10,000/uL

               -  Increased fetal hemoglobin (HgbF) for age

               -  Sargramostim (GM-CSF) hypersensitivity OR, patients must have been previously
                  diagnosed with JMML

          -  Patients must be previously untreated with HCT

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  Patients with a known germline mutation of PTPN11 (Noonan?s Syndrome) are not eligible

          -  Patients with a known history of NF1 (Neurofibromatosis Type 1) and either

               -  A history of a tumor of the central nervous system (astrocytoma or optic glioma),
                  or

               -  A malignant peripheral nerve sheath tumor with a complete remission of < 1 year
                  are not eligible

          -  Human immunodeficiency virus (HIV) positive patients are not eligible

Maximum Eligible Age:	18 Years
Minimum Eligible Age:	3 Months
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Percent Probability of Event-free Survival (EFS)
Time Frame:	From transplant up to 18 months
Safety Issue:
Description:	Probability of Event-free Survival (EFS) for Patients after 18 months. An event is either treatment related mortality (TRM), primary or secondary graft failure, or relapse/non-response (as defined in protocol section 10). Time to event is time from transplant with patients who die between the start of the conditioning regimen and transplant given a time to event of zero.

Secondary Outcome Measures

Measure:	Percentage of Participants Who Experience Primary Graft Failure Event Between Arms
Time Frame:	Day 0 - day 540 (18 months) following completion of stem cell transplant
Safety Issue:
Description:	Primary Graft failure is defined as the failure to achieve an ANC >= 500/uL after 42 days, determined by 3 consecutive measurements on different days; OR < 5% donor cells in blood or bone marrow by day +42 (as demonstrated by a chimerism assay), without evidence of Juvenile Myelomonocytic Leukemia (JMML).

Measure:	Percent Probability of 18 Months-relapse Event Between Arms
Time Frame:	From transplant up to 18 months
Safety Issue:
Description:	Probability of patients relapsing at 18 months. A relapse event is defined in protocol section 10.2.3. Time to relapse/non-response is defined as time from transplant to when all criteria of section 10.2.3 are met.

Details

Phase:	Phase 2
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	Children's Oncology Group

Last Updated

December 5, 2018

Clinical Trials /

Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia