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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

Primary Purpose

Autologous Hematopoietic Stem Cell Transplant Recipient, Loss of Chromosome 17p, Plasma Cell Leukemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
bortezomib
fludarabine phosphate
melphalan
total marrow irradiation
tacrolimus
sirolimus
peripheral blood stem cell transplantation
laboratory biomarker analysis
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autologous Hematopoietic Stem Cell Transplant Recipient

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • City of Hope

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group I (bortezomib, fludarabine phosphate, TMI, melphalan)

Group II (bortezomib, fludarabine phosphate, melphalan

Arm Description

Patients receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. Patients also undergo TMI BID on days -9 to -7. If no DLT is observed in the first cohort, bortezomib IV will be added on days -6 and -3 for subsequent cohorts.

Patients receive fludarabine phosphate IV and melphalan IV as in Stratum I. Patients also receive bortezomib IV on days -6, -3, 1, and 4.

Outcomes

Primary Outcome Measures

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
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

Secondary Outcome Measures

Frequency of clinical response (i.e., complete, partial, or very good partial response)
Response is evaluated based on a new International myeloma working group uniform response criteria.
Frequency of primary and secondary engraftment failure
Time to neutrophil and platelet engraftment
Progression-free survival
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
Overall survival
Time from first day of treatment to time of death due to any cause, assessed up to 4 years
Minimal residue disease
Assessed by flow cytometry

Full Information

First Posted
July 14, 2010
Last Updated
March 17, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01163357
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 28, 2011 (Actual)
Primary Completion Date
July 20, 2019 (Actual)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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 fludarabine phosphate intravenously (IV) on days -9 to -5 and melphalan IV on day -4. Patients also undergo TMI twice daily (BID) on days -9 to -7. If no DLT is observed in the first cohort, bortezomib IV will be added on days -6 and -3 for subsequent cohorts. GROUP II (patients ineligible for TMI): Patients receive fludarabine phosphate IV and melphalan IV as in Group I. Patients also receive bortezomib IV on days -6, -3, 1, and 4. 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 for up to 4 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autologous Hematopoietic Stem Cell Transplant Recipient, Loss of Chromosome 17p, Plasma Cell Leukemia, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group I (bortezomib, fludarabine phosphate, TMI, melphalan)
Arm Type
Experimental
Arm Description
Patients receive fludarabine phosphate IV on days -9 to -5 and melphalan IV on day -4. Patients also undergo TMI BID on days -9 to -7. If no DLT is observed in the first cohort, bortezomib IV will be added on days -6 and -3 for subsequent cohorts.
Arm Title
Group II (bortezomib, fludarabine phosphate, melphalan
Arm Type
Experimental
Arm Description
Patients receive fludarabine phosphate IV and melphalan IV as in Stratum I. Patients also receive bortezomib IV on days -6, -3, 1, and 4.
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, PS-341, VELCADE
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
melphalan
Other Intervention Name(s)
Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin, Melfalan
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
total marrow irradiation
Intervention Description
Undergo TMI
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
Advagraf, FK 506, Prograf, Protopic
Intervention Description
Given IV and orally
Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
AY 22989, RAPA, Rapamune, rapamycin, SILA 9268A, SLM
Intervention Description
Given orally
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
6 weeks post transplant
Title
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
Secondary Outcome Measure Information:
Title
Frequency of clinical response (i.e., complete, partial, or very good partial response)
Description
Response is evaluated based on a new International myeloma working group uniform response criteria.
Time Frame
At 6 months and 1 year post transplant
Title
Frequency of primary and secondary engraftment failure
Time Frame
6 weeks post transplant and 4 years post transplant
Title
Time to neutrophil and platelet engraftment
Time Frame
100 days post transplant
Title
Progression-free survival
Description
Time from day 0 of transplant to the first observation or relapse or death due to any cause, assessed up to 4 years
Time Frame
4 years post transplant
Title
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
Title
Overall survival
Description
Time from first day of treatment to time of death due to any cause, assessed up to 4 years
Time Frame
4 years post transplant
Title
Minimal residue disease
Description
Assessed by flow cytometry
Time Frame
At 6 months and 1 year post transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Firoozeh Sahebi, MD
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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