Clinical Trials /

Melphalan, Total Marrow Irradiation, and Autologous Stem Cell Transplantation in Treating Patients With High-Risk Multiple Myeloma

NCT03100877

Description:

This phase I/II trial studies the side effects and best dose of melphalan and total marrow irradiation and how well they work with autologous stem cell transplantation in treating patients with high-risk multiple myeloma. Drugs used in chemotherapy, such as melphalan, 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. Total marrow irradiation is a type of radiation therapy and a form of total body irradiation that may deliver focused radiation to the major marrow sites where cancer cells reside. Giving chemotherapy and total-body irradiation before a peripheral autologous blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Related Conditions:
  • Multiple Myeloma
  • Plasma Cell Leukemia
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Melphalan, Total Marrow Irradiation, and Autologous Stem Cell Transplantation in Treating Patients With High-Risk Multiple Myeloma
  • Official Title: Phase I-II Single Cycle Melphalan/Total Marrow Irradiation (TMI) and Autologous Stem Cell Transplantation (ASCT) Followed by Maintenance in Patients With High-Risk Myeloma and/or Poor Response to Induction Therapy Within 12 Months of Diagnosis

Clinical Trial IDs

  • ORG STUDY ID: 16464
  • SECONDARY ID: NCI-2017-00512
  • SECONDARY ID: 16464
  • NCT ID: NCT03100877

Conditions

  • Plasma Cell Leukemia in Remission
  • Plasma Cell Myeloma

Interventions

DrugSynonymsArms
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- 138719Treatment (mel/TMI, ASCT)
FilgrastimFilgrastim XM02, Filgrastim-sndz, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tbo-filgrastim, Tevagrastim, ZarxioTreatment (mel/TMI, ASCT)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (mel/TMI, ASCT)
MelphalanAlanine 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-19813Treatment (mel/TMI, ASCT)
PaliferminGrowth Factor, Recombinant Human Keratinocyte, Kepivance, Keratinocyte Growth Factor, Recombinant Human, Recombinant Human Keratinocyte Growth Factor, rhKGF, rhu Keratinocyte Growth FactorTreatment (mel/TMI, ASCT)

Purpose

This phase I/II trial studies the side effects and best dose of melphalan and total marrow irradiation and how well they work with autologous stem cell transplantation in treating patients with high-risk multiple myeloma. Drugs used in chemotherapy, such as melphalan, 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. Total marrow irradiation is a type of radiation therapy and a form of total body irradiation that may deliver focused radiation to the major marrow sites where cancer cells reside. Giving chemotherapy and total-body irradiation before a peripheral autologous blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and determine the maximum tolerated dose (MTD) of melphalan and
      fractionated total marrow irradiation (TMI) as conditioning regimen for autologous stem cell
      transplantation (ASCT) in patients with high-risk or treatment-insensitive multiple myeloma
      (MM). (Phase I) II. Evaluate the safety of the regimen at each dose level by assessing
      adverse events: type, frequency, severity, attribution, time course, duration.

      III. Evaluate the safety of the regimen at each dose level by assessing complication
      including: infection, delayed engraftment and secondary malignancy.

      IV. To assess complete response (CR) and minimal residual disease (MRD) rates at 100 days
      post ASCT in a phase II expanded cohort of patients treated at the MTD. (Phase II)

      SECONDARY OBJECTIVES:

      I. To assess the predictive value of high risk features inclusive of fluorescent in situ
      hybridization (FISH), lactate dehydrogenase (LDH), International Staging System (ISS) stage,
      gene expression profiling (GEP) for CR and minimal residual disease (MRD) for relapse free
      survival/progression free survival/overall survival (RFS/PFS/OS) after melphalan TMI
      (mel/TMI).

      II. To assess MRD by positron emission tomography (PET), next generation sequencing (NGS),
      and flow cytometry after mel/TMI, prior to maintenance and correlation with PFS and OS.

      III. To assess in a descriptive fashion PFS and OS following mel/TMI and ASCT. IV. Evaluate
      changes in fludeoxyglucose F-18 (FDG) PET pre and post TMI/melphalan.

      TERTIARY OBJECTIVES:

      I. Assessment of bone marrow residual damage. II. Assessment of immune recovery dynamics.
      III. To conduct genetic profiling of myeloma cells. IV. Multimodal imaging for non-invasive
      assessment of treatment effect on bone and marrow.

      OUTLINE: This is a phase I, dose-escalation study of melphalan and TMI followed by a phase II
      study.

      MOBILIZATION AND APHERESIS: Patients receive cyclophosphamide intravenously (IV) over 2
      hours. Beginning 24 hours after cyclophosphamide administration, patients receive filgrastim
      subcutaneously (SC) or IV. Patients also undergo apheresis over 4 hours on day 10.

      CONDITIONING REGIMEN: Patients receive palifermin IV on days -8, to -6, undergo TMI on days
      -5 to -2, and receive melphalan IV over 30 minutes on day -1. Patients then undergo ASCT IV
      on day 0, receive palifermin IV on days 1-3, and receive filgrastim SC or IV on day 5.

      MAINTENANCE THERAPY: Beginning 30 days after ASCT, patients receive lenalidomide orally (PO)
      daily.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (mel/TMI, ASCT)ExperimentalMOBILIZATION AND APHERESIS: Patients receive cyclophosphamide IV over 2 hours. Beginning 24 hours after cyclophosphamide administration, patients receive filgrastim SC or IV. Patients also undergo apheresis over 4 hours on day 10. CONDITIONING REGIMEN: Patients receive palifermin IV on days -8, to -6, undergo TMI on days -5 to -2, and receive melphalan IV over 30 minutes on day -1. Patients then undergo ASCT IV on day 0, receive palifermin IV on days 1-3, and receive filgrastim SC or IV on day 5. MAINTENANCE THERAPY: Beginning 30 days after ASCT, patients receive lenalidomide PO daily.
  • Cyclophosphamide
  • Filgrastim
  • Lenalidomide
  • Melphalan
  • Palifermin

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with will be eligible if they are either in partial response, or have stable
             disease after no more than two attempts of induction therapy

          -  Patients with high-risk cytogenetics, t(4:14); t(14;16), t(14:20), deletion p17, gain
             in 1q, are eligible

          -  Patients with plasma cell leukemia in >= partial remission are eligible

          -  Patients with non-quantifiable monoclonal proteins are eligible provided they meet
             other criteria for multiple myeloma and they have evaluable or measurable disease by
             other (radiographic, magnetic resonance imaging [MRI], computed tomography [CT], lytic
             measurable lesion on x-ray,) means

          -  Karnofsky performance status (KPS) >= 70%

          -  Less than 12 months since diagnosis

          -  No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by
             apheresis

          -  Bilirubin =< 1.5 mg/dl

          -  Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
             transaminase (SGPT) < 2.5 x upper limits of normal

          -  Creatinine of measured or calculated creatinine clearance of >= 50 cc/min

          -  Absolute neutrophil count of > 1000/ul

          -  Platelet count of > 100,000/ul

          -  Cardiac ejection fraction >= 50% by multi-gated acquisition (MUGA) scan and/or by
             echocardiogram

          -  Forced expiratory volume in 1 second (FEV1) > 60% and diffusion capacity of the lung
             for carbon monoxide (DLCO) > 50% of predicted lower limit

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control or abstinence) prior to study entry and
             for six months following duration of study participation; should a woman become
             pregnant or suspect that she is pregnant while participating on the trial, she should
             inform her treating physician immediately; patients must be fully aware of the
             teratogenic potential of immunomodulatory drugs (ImIDs) and agree to fully comply with
             the mandated guidelines regarding contraception as stated in the informed consent and
             the patient warning document attached to the consent form; women of childbearing
             potential must have a negative pregnancy test performed within 24 hours prior to
             beginning thalidomide, except for woman who have been postmenopausal for at least 2
             years, or underwent hysterectomy; use of effective means of contraceptive should be
             started at least 2 weeks prior to initiating lenalidomide

          -  All subjects must have the ability to understand and the willingness to sign a written
             informed consent; they are to give voluntary written informed consent before
             performance of any study-related procedure not part of normal medical care, with the
             understanding that consent may be withdrawn by the subject at any time without
             prejudice to future medical care

          -  Patients should have finished their prior systemic therapy or radiation therapy, at
             least 3 weeks before cyclophosphamide or granulocyte colony-stimulating factor
             (G-CSF)/plerixafor mobilization, and should have finished dexamethasone at least 7
             days prior to Plerixafor priming; administration of bisphosphonates needs to be
             completed at least 2 weeks before cyclophosphamide priming; bisphosphonates can be
             resumed or started after day 30

        Exclusion Criteria:

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy

          -  Known hypersensitivity to filgrastim or to Escherichia coli (E. coli) derived proteins

          -  Inability to lie supine in a full body cast for approximately 30 minutes, the
             anticipated duration of each treatment session

          -  Previous radiation therapy to more than 20% of bone marrow containing areas, or to any
             area exceeding 2000 cGy, is an exclusion

          -  Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
             (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core
             antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
             (PCR) result before enrollment; those who are PCR positive will be excluded

          -  No other medical, or psychosocial problems, which in the opinion of the primary
             physician or principal investigator would place the patient at unacceptably high risk
             from this treatment regimen
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response (CR) post-Autologous Stem Cell Transplantation (ASCT) (Phase II)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized both by pooling across dose levels and by dose level.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:City of Hope Medical Center

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