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Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using TLI & ATG

Primary Purpose

Transplantation, Homologous, Transplantation, Autologous, Multiple Myeloma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Autologous peripheral blood stem cells (auto-PBSC) transplantation

Allogeneic peripheral blood stem cells (allo-PBSC) transplantation

Filgrastim

Cyclophosphamide

Melphalan

Cyclosporine

Total lymphoid irradiation

Rabbit anti-thymocyte globulin

Mycophenolate Mofetil 250mg

Solumedrol

Diphenhydramine

Acetaminophen

Hydrocortisone

About this trial

This is an interventional treatment trial for Transplantation, Homologous

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

PARTICIPANT INCLUSION CRITERIA

Stage II-III multiple myeloma or have progression after initial treatment of Stage I disease (Durie Salmon Staging). Patients with plasma cell leukemia are also included.
Multiple myeloma / plasma cell leukemia diagnosis confirmed by pathology reviewed at Stanford University Medical Center.
18 to ≤ 75 years of age
Karnofsky Performance Status > 70%.
Corrected Carbon monoxide diffusing capacity (Dlco) > 60%
Left ventricle ejection fraction (LVEF) > 50%.
Alanine aminotransferase (ALT) ≤ 2 x normal
Aspartate aminotransferase (AST) ≤ 2 x normal
Total bilirubin ≤ 2 mg/dL, unless hemolysis or Gilbert's disease.
Estimated creatinine clearance > 50 mL/min.
Identified related or unrelated Human leukocyte antigen (HLA)-identical donor or donor with one antigen/allele mismatch in (HLA-A, B, C or DRB1).
Signed informed consent.

DONOR INCLUSION CRITERIA

At least 17 years of age
HIV-seronegative
Must be capable of giving signed, informed consent
No contraindication to the administration of filgrastim
Willing to have a central venous catheter placed for apheresis if peripheral veins are inadequate

PARTICIPANT EXCLUSION CRITERIA

Prior allogeneic hematopoietic cell transplantation
Uncontrolled active infection
Uncontrolled congestive heart failure or angina
HIV-positive
Pregnant or nursing

DONOR EXCLUSION CRITERIA

Serious medical or psychological illness
Pregnant or lactating
Prior malignancies within the last 5 years except for non-melanoma skin cancers

Sites / Locations

Stanford University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Autologous-Allogeneic Peripheral Blood Stem Cell Transplant

Arm Description

Study treatment is a high-dose sequential chemotherapy approach to hematopoietic stem cell (HSC) transplant that uses an autologous peripheral blood stem cell (auto-PBSC) transplant followed by allogeneic peripheral blood stem cell (allo-PBSC) transplant to evaluate improved graft vs host disease (GvHD) control. Participant auto-PBSC are mobilized with cyclophosphamide (also to provide cytoreduction) and filgrastim, followed by melphalan as an auto-PBSC conditioning agent, then auto-PBSC infusion. For the allo-PBSC transplant, donors are mobilized with filgrastim, and participants receive a regimen of total lymphoid irradiation and anti-thymocyte globulin (TLI/ATG), followed by infusion of donor allo-PBSC. Solumedrol, diphenhydramine, acetaminophen, and hydrocortisone are administered as premedications, and rabbit anti-thymocyte globulin (ATG) plus mycophenolate mofetil (MMF) are administered for post-allo-PBSC immunosuppression.

Outcomes

Primary Outcome Measures

Incidence of Graft Versus Host Disease (GvHD)

To evaluate the incidence acute GvHD of this tandem autologous/allogeneic transplant setting

Secondary Outcome Measures

Median Time to Engraftment After Auto-PBSC Transplant

Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia

Median Time to Engraftment After Allo-PBSC Transplant

Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia

Overall Response Rate (ORR)

Overall response rate (ORR) = Complete Response Rate (CRR) + Partial Response Rate (PRR)

Complete Response Rate (CRR)

Complete response rate (CRR) was assessed as all of: Negative immunoflixation on the serum and urine Disappearance of any soft tissue plasmacytomas < 5% plasma cells in bone marrow

Partial Response Rate (PRR)

Partial response rate (PRR) was assessed as > 50% reduction in serum M-protein plus urine M-protein reduction by 90% or < 200 mg/24 hr If serum M-protein is not measurable, then > 50% reduction in the involved serum free light chain If involved serum free light chain is not measurable, then > 50% reduction in the bone marrow plasma cell percentage + > 50% reduction in the size of any soft tissue plasmacytoma.

Event-free Survival (EFS)

To evaluate the graft versus myeloma effect by monitoring rate of event-free survival (EFS)

Overall Survival (OS)

To evaluate the graft versus myeloma effect by monitoring rate of overall survival (OS)

Full Information

NCT ID

NCT00899847

First Posted

May 8, 2009

Last Updated

September 19, 2017

Sponsor

Stanford University

1. Study Identification

Unique Protocol Identification Number

NCT00899847

Brief Title

Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using TLI & ATG

Official Title

A Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Antithymocyte Globulin (ATG) in Multiple Myeloma Patients

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Completed

Study Start Date

May 2009 (undefined)

Primary Completion Date

April 2014 (Actual)

Study Completion Date

December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

To evaluate the toxicity and tolerability of this tandem autologous/allogeneic transplant approach for patients with advanced stage multiple myeloma.

Detailed Description

Development of cell-based immunotherapy from allogeneic hematopoietic cell transplantation (HCT) is dependent upon stable T-cell engraftment and the success of this therapeutic approach is likely to be greatest when directed against a minimal rather than gross tumor burden. To this end, tandem transplants with high dose therapy and autologous hematopoietic cell transplantation (AHCT) for tumor cytoreduction followed by non-myeloablative allotransplant have been conducted. In myeloma, this tandem approach results in greater efficacy compared to conventional AHCT.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Transplantation, Homologous, Transplantation, Autologous, Multiple Myeloma, Blood and Marrow Transplant (BMT)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Autologous-Allogeneic Peripheral Blood Stem Cell Transplant

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Autologous peripheral blood stem cells (auto-PBSC) transplantation

Other Intervention Name(s)

auto-PBPC, Autologous peripheral blood progenitor cells (auto-PBPC) transplantation

Intervention Description

Auto-PBSC ≥ 2 to 3 x 10e6 CD34+ cells/kg are intravenously (IV) infused as part of the combination stem cell therapy. and allogeneic stem cells are administered intravenous (IV) infusion to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective

Intervention Type

Procedure

Intervention Name(s)

Allogeneic peripheral blood stem cells (allo-PBSC) transplantation

Other Intervention Name(s)

allo-PBSC, Allogeneic peripheral blood progenitor cells (allo-PBPC) transplantation

Intervention Description

Allo-PBSC (target collection ≥ 5 x 10e6 CD34+ cells/kg) are intravenously (IV) infused as part of the combination stem cell therapy.

Intervention Type

Drug

Intervention Name(s)

Filgrastim

Other Intervention Name(s)

Neupogen, Granulocyte colony-stimulating factor (G-CSF), r-metHuG-CSF

Intervention Description

Filgrastim is administered subcutaneously (SC) at 10 µg/kg/day for auto-PBSC mobilization starting day 2 of mobilization until the last day of apheresis. Filgrastim is administered SC at 5 µg/kg/day from Day 6 after auto-PBSC infusion to hematologic recovery. Filgrastim is administered SC at 16 µg/kg/day for donor allo-PBSC mobilization at from Day - 4 to Day 0, prior to allo-PBSC collection.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Ciclofosfamida, Ciclofosfamide, Claphene, CP monohydrate (CPM), CSP

Intervention Description

Cyclophosphamide is administered intravenously (IV) at 4 g/m2 on Day 1 of the auto-PBSC mobilization regimen.

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

L-Sarcolysin, L-phenylalanine mustard (L-PAM), L-Sarcolysin phenylalanine mustard, L-sarcolysine

Intervention Description

Melphalan is administered after CSP at 200 mg/m2 intravenously (IV) on Day -2 before auto-PBSC infusion.

Intervention Type

Drug

Intervention Name(s)

Cyclosporine

Other Intervention Name(s)

Cyclosporin, Cyclosporin A, Ciclosporin, CSP

Intervention Description

Cyclosporine is administered by mouth (PO) for allo-PBSC graft vs host disease (GvHD) prophylaxis at 5 mg/kg from Day -3 through Bay +56. Tacrolimus may substituted.

Intervention Type

Radiation

Intervention Name(s)

Total lymphoid irradiation

Other Intervention Name(s)

TLI

Intervention Description

Total lymphoid irradiation is administered at 80 centigrey (cGy) on Day -11 to -7; and Day -4 to -2 before alllo-PBSC infusion. TLI is also administered at 80 centigrey (cGy) x 2 on Day -1 before alllo-PBSC infusion.

Intervention Type

Biological

Intervention Name(s)

Rabbit anti-thymocyte globulin

Other Intervention Name(s)

Thymoglobulin, ATG

Intervention Description

ATG 1.5 mg/kg is administered intravenously (IV) on Day -11 to -7 before allo-PBSC infusion.

Intervention Type

Drug

Intervention Name(s)

Mycophenolate Mofetil 250mg

Other Intervention Name(s)

CellCept, MMF

Intervention Description

MMF is administered at 15 mg/kg 3x/day by mouth (PO) after allo-PBSC through Day 40, followed by 10% dose reduction weekly (dose taper) through day 96, and adjusted if there is evidence of MMF-related GI toxicity or excessive myelosuppression

Intervention Type

Drug

Intervention Name(s)

Solumedrol

Other Intervention Name(s)

Solumedin, Soludecadron

Intervention Description

Solumedrol 1 mg/kg is administered intravenously (IV) on Day -11 to -7 as a premedication for ATG and allo-PBSC infusion

Intervention Type

Drug

Intervention Name(s)

Diphenhydramine

Other Intervention Name(s)

Benadryl

Intervention Description

Diphenhydramine 25 to 50 mg is administered as a premedication for the ATG; allo-PBSC; and DLI infusions.

Intervention Type

Drug

Intervention Name(s)

Acetaminophen

Other Intervention Name(s)

Tylenol

Intervention Description

Acetaminophen 650 mg is administered as a premedication for the ATG and allo-PBSC infusions.

Intervention Type

Drug

Intervention Name(s)

Hydrocortisone

Intervention Description

Hydrocortisone 100 mg is administered intravenously (IV) is a premedication for the allo-PBSC and DLI infusions.

Primary Outcome Measure Information:

Title

Incidence of Graft Versus Host Disease (GvHD)

Description

To evaluate the incidence acute GvHD of this tandem autologous/allogeneic transplant setting

Time Frame

2 years after the last participant is enrolled.

Secondary Outcome Measure Information:

Title

Median Time to Engraftment After Auto-PBSC Transplant

Description

Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia

Time Frame

1 month

Title

Median Time to Engraftment After Allo-PBSC Transplant

Description

Engraftment is assessed as: Neutrophil engraftment is > 0.5 x 10⁹/L after cytopenia Platelet engraftment is > 20 x 10⁹/L after cytopenia

Time Frame

1 month

Title

Overall Response Rate (ORR)

Description

Overall response rate (ORR) = Complete Response Rate (CRR) + Partial Response Rate (PRR)

Time Frame

1 year

Title

Complete Response Rate (CRR)

Description

Complete response rate (CRR) was assessed as all of: Negative immunoflixation on the serum and urine Disappearance of any soft tissue plasmacytomas < 5% plasma cells in bone marrow

Time Frame

1 year

Title

Partial Response Rate (PRR)

Description

Time Frame

1 year

Title

Event-free Survival (EFS)

Description

To evaluate the graft versus myeloma effect by monitoring rate of event-free survival (EFS)

Time Frame

2 years after the last participant is enrolled

Title

Overall Survival (OS)

Description

To evaluate the graft versus myeloma effect by monitoring rate of overall survival (OS)

Time Frame

2 years after the last participant is enrolled

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

PARTICIPANT INCLUSION CRITERIA Stage II-III multiple myeloma or have progression after initial treatment of Stage I disease (Durie Salmon Staging). Patients with plasma cell leukemia are also included. Multiple myeloma / plasma cell leukemia diagnosis confirmed by pathology reviewed at Stanford University Medical Center. 18 to ≤ 75 years of age Karnofsky Performance Status > 70%. Corrected Carbon monoxide diffusing capacity (Dlco) > 60% Left ventricle ejection fraction (LVEF) > 50%. Alanine aminotransferase (ALT) ≤ 2 x normal Aspartate aminotransferase (AST) ≤ 2 x normal Total bilirubin ≤ 2 mg/dL, unless hemolysis or Gilbert's disease. Estimated creatinine clearance > 50 mL/min. Identified related or unrelated Human leukocyte antigen (HLA)-identical donor or donor with one antigen/allele mismatch in (HLA-A, B, C or DRB1). Signed informed consent. DONOR INCLUSION CRITERIA At least 17 years of age HIV-seronegative Must be capable of giving signed, informed consent No contraindication to the administration of filgrastim Willing to have a central venous catheter placed for apheresis if peripheral veins are inadequate PARTICIPANT EXCLUSION CRITERIA Prior allogeneic hematopoietic cell transplantation Uncontrolled active infection Uncontrolled congestive heart failure or angina HIV-positive Pregnant or nursing DONOR EXCLUSION CRITERIA Serious medical or psychological illness Pregnant or lactating Prior malignancies within the last 5 years except for non-melanoma skin cancers

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wen-Kai Weng

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Stanford University School of Medicine

City

Stanford

State/Province

California

ZIP/Postal Code

94305

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using TLI & ATG

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