Bortezomib, Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant For High-Risk Stage I or II Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01163357
First received: July 14, 2010
Last updated: October 9, 2014
Last verified: October 2014

July 14, 2010
October 9, 2014
January 2011
August 2015   (final data collection date for primary outcome measure)
  • Maximum tolerated dose of bortezomib as defined as the highest dose tested in which none or only one patient experiences dose limiting toxicity attributable to the study regimen [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: Yes ]
    Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicity will be defined using Bearman Scale for events that occur.
  • Feasibility of escalating doses of bortezomib with or without TMI in combination with FLU and MEL as preparative regimen for allogeneic hematopoietic stem cell transplant in patients with high risk multiple myeloma [ Time Frame: 5 years post transplant ] [ Designated as safety issue: No ]
  • Maximum tolerated dose [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: Yes ]
  • Feasibility [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Dose limiting toxicities [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01163357 on ClinicalTrials.gov Archive Site
  • Frequency of clinical response (i.e., complete, partial, or very good partial response) [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
    Response is evaluated based on a new International myeloma working group uniform response criteria.
  • Frequency of primary and secondary engraftment failure [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: No ]
  • Time to neutrophil and platelet engraftment [ Time Frame: 100 days post transplant ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: 4 years post transplant ] [ Designated as safety issue: No ]
    Time from day 0 of transplant to the first observation or relapse or death due to any cause, assessed up to 4 years
  • Incidence of acute and chronic graft-versus-host disease [ Time Frame: At 6 months and 1 year post transplant up to 4 years post transplant ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 4 years post transplant ] [ Designated as safety issue: No ]
    Time from first day of treatment to time of death due to any cause, assessed up to 4 years
  • Minimal residue disease [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Frequency of clinical response [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Frequency of primary and secondary engraftment failure [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: No ]
  • Time to neutrophil and platelet engraftment [ Time Frame: 6 weeks post transplant ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Incidence of acute and chronic graft-versus-host disease [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
  • Minimal residue disease [ Time Frame: At 6 months and 1 year post transplant ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Bortezomib, Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant For High-Risk Stage I or II Multiple Myeloma
Phase I Study of Bortezomib With or Without Total Marrow Irradiation (TMI) Using Intensity Modulated Radiation Therapy (IMRT) in Combination With Fludarabine (FLU) and Melphalan (MEL) as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation in Patients With High Risk Multiple Myeloma

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy drugs, such as fludarabine phosphate and melphalan, and total marrow irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps 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.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with fludarabine phosphate and melphalan with or without total marrow irradiation in treating patients undergoing donor peripheral blood stem cell transplant for high-risk stage I or II multiple myeloma.

PRIMARY OBJECTIVES:

I. To determine the feasibility of escalating doses of bortezomib with or without total marrow irradiation (TMI) at a fixed dose of 900 cGy in combination with fludarabine (FLU) and melphalan (MEL) as preparative regimen for allogeneic hematopoietic stem cell transplant in patients with high risk multiple myeloma who have human leukocyte antigen (HLA) matched donor (sibling or matched unrelated donor).

II. To describe toxicities, maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of this preparative regimen.

SECONDARY OBJECTIVES:

I. To evaluate the frequency of clinical response, i.e., complete response [CR], partial response [PR], very good partial response [VGPR]) at 6 month and 1 year post transplant.

II. To evaluate the frequency of primary and secondary engraftment failure.

III. To evaluate the time to neutrophil and platelet engraftment.

IV. To evaluate the incidence of acute and chronic graft-versus-host disease (GVHD).

V. To evaluate progression-free survival.

VI. To evaluate overall survival.

VII. To evaluate minimal residual disease (MRD) at 6 months and 1 year post transplant by flow cytometry in the bone marrow.

OUTLINE: This is a dose-escalation study of bortezomib. Patients are assigned to 1 of 2 treatment groups. GROUP I (patients eligible for TMI): Patients receive bortezomib intravenously (IV) on days -6 and -3 and undergo TMI twice daily (BID) on days -9 to -7. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. GROUP II (patients ineligible for TMI): Patients receive bortezomib IV on days -6, -3, 1, and 4. Patients also receive fludarabine phosphate IV and melphalan IV as in Group I.

TRANSPLANT: All patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

GVHD PROPHYLAXIS: All patients receive tacrolimus IV or orally (PO) and sirolimus PO beginning on day -3.

After completion of study treatment, patients are followed up at day 100, 6 months, and then annually thereafter.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • PS-341
    • VELCADE
  • Drug: fludarabine phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • Beneflur
    • Fludara
  • Other: melphalan
    Given IV
    Other Names:
    • Alkeran
    • CB-3025
    • L-PAM
    • L-phenylalanine mustard
    • L-Sarcolysin
    • Melfalan
  • Radiation: total marrow irradiation
    Undergo TMI
  • Drug: tacrolimus
    Given IV and orally
    Other Names:
    • Advagraf
    • FK 506
    • Prograf
    • Protopic
  • Drug: sirolimus
    Given orally
    Other Names:
    • AY 22989
    • RAPA
    • Rapamune
    • rapamycin
    • SILA 9268A
    • SLM
  • Procedure: peripheral blood stem cell transplantation
    Undergo allogeneic PBSC transplant
    Other Names:
    • PBPC transplantation
    • PBSC transplantation
    • peripheral blood progenitor cell transplantation
    • transplantation, peripheral blood stem cell
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Group I (bortezomib, fludarabine phosphate, TMI, melphalan)
    Patients receive bortezomib IV on days -6 and -3 and undergo TMI BID on days -9 to -7. Patients also receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4.
    Interventions:
    • Drug: bortezomib
    • Drug: fludarabine phosphate
    • Other: melphalan
    • Radiation: total marrow irradiation
    • Drug: tacrolimus
    • Drug: sirolimus
    • Procedure: peripheral blood stem cell transplantation
    • Other: laboratory biomarker analysis
  • Experimental: Group II (bortezomib, fludarabine phosphate, melphalan
    Patients receive bortezomib IV on days -6, -3, 1, and 4. Patients also receive fludarabine phosphate IV and melphalan IV as in Group I.
    Interventions:
    • Drug: bortezomib
    • Drug: fludarabine phosphate
    • Other: melphalan
    • Drug: tacrolimus
    • Drug: sirolimus
    • Procedure: peripheral blood stem cell transplantation
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
27
Not Provided
August 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Recipient must have signed a voluntary, informed consent in accordance with institutional and federal guidelines
  • Recipients must have histopathologically confirmed diagnosis of multiple myeloma
  • Age:

    • Stratum I (TMI containing arm): 18-60 years of age
    • Stratum II (non TMI arm): 18-70 years of age
  • Patients with primary progressive disease on induction therapy with new targeted therapies
  • Relapsed/refractory disease on new targeted therapies, i.e. thalidomide, lenalidomide, bortezomib, or other new novel agents such as carfilzomib, pomalidomide
  • Patients with relapsed multiple myeloma following previous autologous stem cell transplant
  • Plasma cell leukemia at diagnosis
  • High-risk patients with presence of chromosome 17p deletion (> 60%) in the bone marrow by fluorescence in situ hybridization (FISH); patients are not required to have prior autologous stem cell transplant
  • Able to lie supine for approximately 60 minutes, the anticipated duration of each treatment session
  • Performance status evaluated by Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Scales (KPS) patients must have a score of 0-II (ECOG) or >= 70% (KPS)
  • Cardiac ejection fraction >= 50% by multiple gate acquisition (MUGA) scan and/or by echocardiogram
  • Forced expiratory volume in one second (FEV1) >= 50%
  • Diffusing lung capacity for carbon monoxide (DLCO) >= 50%
  • Creatinine clearance or glomerular filtration rate (GFR) >= 60 ml/min
  • Serum bilirubin =< 2.0 mg/dl
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) =< 2.5 times the institutional upper limits of normal
  • Pre-treatment tests must be performed within 30 days prior to enrollment
  • No other medical and or psychosocial problems, which in the opinion of the primary physician or principal investigator would place the patient at unacceptable risk from this regimen
  • Patients with no previous radiation or up to a maximum 2000 cGy to non thoracic-spine and rib bone lesions or < 20% of bone marrow are eligible for TMI conditioning regimen
  • Patients with previous history of irradiation at any dose to thoracic-spine, ribs or >= 20% of bone marrow cannot undergo TMI and will be eligible for bortezomib, fludarabine, and melphalan regimen

Stratum II); patients can be enrolled on stratum II at their physician's discretion or if patients decline radiation therapy

DONOR: Any matched sibling donor (matched at HLA A, B, C by intermediate resolution typing and HLA-DRB1 by high resolution typing), or unmatched unrelated donor (matched at HLA A, B, C, DRB1 by high resolution typing) will be considered a suitable donor

Exclusion Criteria:

  • Patients with peripheral neuropathy greater than grade II
  • Major medical or psychiatric disorders that would seriously compromise patient tolerance of this regimen
  • Human immunodeficiency virus (HIV) infection, active hepatitis B or C infection, or evidence of liver cirrhosis
  • Active viral, bacterial or fungal infection unless adequately treated. For fungal infection, patient should have completed full course of antifungal therapy with resolution of infection.
  • Patients with radiographic changes including pulmonary disease, including but not limited to: pulmonary nodules, infiltrates, pleural effusion are excluded unless cleared by pulmonary biopsy showing no evidence for pulmonary infection
  • Patients with renal insufficiency or cr clearance < 60 ml/min

DONOR: Donors will be excluded if for medical or psychological reasons they are unable to tolerate the procedure of peripheral stem cell donation

Both
18 Years to 70 Years
No
United States
 
NCT01163357
09171, NCI-2010-01610
Yes
City of Hope Medical Center
City of Hope Medical Center
National Cancer Institute (NCI)
Principal Investigator: Firoozeh Sahebi, MD Beckman Research Institute
City of Hope Medical Center
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP