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Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant (RLI)

Primary Purpose

Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Fludarabine and total body irradiation

Total body irradiation

About this trial

This is an interventional treatment trial for Non Hodgkin's Lymphoma focused on measuring Related stem cell transplant,, TBI,, Mismatched stem cell transplant, Fludarabine, Non-myeloablative, Lymphoma, Multiple myeloma

Eligibility Criteria

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

Inclusion Criteria:

Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma.
Criteria for consideration of enrollment will include:
1. primary refractory or refractory relapsed disease for which autologous HCT is unlikely to be beneficial;
2. relapse after autologous HCT
3. ineligibility for standard myeloablative or nonmyeloablative allo-HCT because of either lack of a donor or patient considerations
Non Hodgkin's lymphoma, or Hodgkin's lymphoma: primary refractory or refractory relapse
Multiple myeloma; primary refractory or refractory relapse
Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant.
An estimated disease-free survival of less than one year.
Age 18 to age < 75 years
ECOG performance status of 0, 1, or 2.

Exclusion Criteria:

Patients whose life expectancy is limited by diseases other than their malignancy
Patients who have a 5/6 or better matched related donor or a 4/6 or better umbilical cord blood donor and who are medically eligible for conventional myeloablative or non-myeloablative transplant will be excluded
Cardiac disease: symptomatic congestive heart failure or RVG or echocardiogram determined LVEF ogf< 30%, active angina pectoris or uncontrolled hypertension
Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive lung disease, or corrected DLCO < 40% of predicted
Renal disease: serum creatinine > 3.0 mg/dl.
Hepatic disease: serum bilirubin > 3.0 mg/dl or alkaline phosphatase, SGOT or SGPT > 3 x ULN
Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation (pervious CNS malignancy presently in CR is not an exclusion)
Uncontrolled infection.
Recipient leukocyte infusion (RLI) might involve the infusion of circulating tumor cells to the patients. To minimize this risk patients who have evidence of circulating tumor cells by light microscopy and flow cytometry will be excluded
Patients with acute leukemia will be excluded because they will likely have much greater circulating tumor burden, which would increase the risk of infusion of clonal tumor cells

Sites / Locations

Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Fludarabine

TBI only

Arm Description

The patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.

Patients will be given 200 centiGray (cGy) total body irradiation (TBI) in one fraction. TBI will be given on day 0, 4 to 6 hours prior to HCT.

Outcomes

Primary Outcome Measures

To determine the safety at ≤100 days of a non myeloablative mismatched related HCT when followed by recipient leukocyte infusion to induce deliberate rejection of the donor graft.

Secondary Outcome Measures

To evaluate the incidence of acute and chronic GVHD

To evaluate the incidence of loss of donor grafts

To evaluate progression-free and overall survival

To evaluate antitumor responses following this transplant strategy

Full Information

NCT ID

NCT00909948

First Posted

May 27, 2009

Last Updated

March 26, 2018

Sponsor

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT00909948

Brief Title

Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant

Acronym

RLI

Official Title

Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant

Study Type

Interventional

2. Study Status

Record Verification Date

March 2018

Overall Recruitment Status

Terminated

Why Stopped

Slow Accrual

Study Start Date

November 2008 (undefined)

Primary Completion Date

August 2012 (Actual)

Study Completion Date

August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed study is based on our observation of paradoxical tumor regression after rejection of the donor graft in conjunction with the results of our murine experiments. We hypothesize that clinically meaningful responses can be achieved in patients with advanced malignancies with a transplant strategy using nonmyeloablative conditioning and related mismatched donor stem cell transplant where the intention will be to initially achieve mixed chimerism which will be followed by recipient lymphocyte infusion (RLI) in an attempt to deliberately reject the donor graft. This will lead to the development of novel transplant strategies for achieving antitumor effects without the risk of graft versus host disease (GVHD). This proposed protocol is a Pilot Study that will evaluate the safety of this outpatient transplant strategy, i.e., establishment of initial mixed chimerism followed by RLI for donor graft rejection, in patients with advanced lymphomas, and multiple myeloma. In addition, because RLI have been reported to reverse ongoing GVHD, this approach might potentially reverse GVHD while achieving antitumor responses if this complication unexpectedly occurs.

6. Conditions and Keywords

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

Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma

Keywords

Related stem cell transplant,, TBI,, Mismatched stem cell transplant, Fludarabine, Non-myeloablative, Lymphoma, Multiple myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Fludarabine

Arm Type

Active Comparator

Arm Description

The patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.

Arm Title

TBI only

Arm Type

Active Comparator

Arm Description

Patients will be given 200 centiGray (cGy) total body irradiation (TBI) in one fraction. TBI will be given on day 0, 4 to 6 hours prior to HCT.

Intervention Type

Other

Intervention Name(s)

Fludarabine and total body irradiation

Intervention Description

The patients in the second cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.

Intervention Type

Radiation

Intervention Name(s)

Total body irradiation

Intervention Description

Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.

Primary Outcome Measure Information:

Title

To determine the safety at ≤100 days of a non myeloablative mismatched related HCT when followed by recipient leukocyte infusion to induce deliberate rejection of the donor graft.

Time Frame

100 days post transplant

Secondary Outcome Measure Information:

Title

To evaluate the incidence of acute and chronic GVHD

Time Frame

Up to 2 years post transplant

Title

To evaluate the incidence of loss of donor grafts

Time Frame

Up to 2 years post transplant

Title

To evaluate progression-free and overall survival

Time Frame

Up to 2 years post transplant

Title

To evaluate antitumor responses following this transplant strategy

Time Frame

Up to 2 years post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma. Criteria for consideration of enrollment will include: primary refractory or refractory relapsed disease for which autologous HCT is unlikely to be beneficial; relapse after autologous HCT ineligibility for standard myeloablative or nonmyeloablative allo-HCT because of either lack of a donor or patient considerations Non Hodgkin's lymphoma, or Hodgkin's lymphoma: primary refractory or refractory relapse Multiple myeloma; primary refractory or refractory relapse Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant. An estimated disease-free survival of less than one year. Age 18 to age < 75 years ECOG performance status of 0, 1, or 2. Exclusion Criteria: Patients whose life expectancy is limited by diseases other than their malignancy Patients who have a 5/6 or better matched related donor or a 4/6 or better umbilical cord blood donor and who are medically eligible for conventional myeloablative or non-myeloablative transplant will be excluded Cardiac disease: symptomatic congestive heart failure or RVG or echocardiogram determined LVEF ogf< 30%, active angina pectoris or uncontrolled hypertension Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive lung disease, or corrected DLCO < 40% of predicted Renal disease: serum creatinine > 3.0 mg/dl. Hepatic disease: serum bilirubin > 3.0 mg/dl or alkaline phosphatase, SGOT or SGPT > 3 x ULN Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation (pervious CNS malignancy presently in CR is not an exclusion) Uncontrolled infection. Recipient leukocyte infusion (RLI) might involve the infusion of circulating tumor cells to the patients. To minimize this risk patients who have evidence of circulating tumor cells by light microscopy and flow cytometry will be excluded Patients with acute leukemia will be excluded because they will likely have much greater circulating tumor burden, which would increase the risk of infusion of clonal tumor cells

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bimalangshu R Dey, MD, PhD

Organizational Affiliation

MGH

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

4405359

Citation

Bortin MM, Rimm AA, Saltzstein EC. Graft versus leukemia: quantification of adoptive immunotherapy in murine leukemia. Science. 1973 Feb 23;179(4075):811-3. doi: 10.1126/science.179.4075.811.

Results Reference

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PubMed Identifier

9740354

Citation

Hill GR, Krenger W, Ferrara JL. The role of cytokines in acute graft-versus-host disease. Cytokines Cell Mol Ther. 1997 Dec;3(4):257-66.

Results Reference

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PubMed Identifier

12766882

Citation

Dey BR, McAfee S, Colby C, Sackstein R, Saidman S, Tarbell N, Sachs DH, Sykes M, Spitzer TR. Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2003 May;9(5):320-9. doi: 10.1016/s1083-8791(03)00077-6.

Results Reference

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PubMed Identifier

2377601

Citation

Sykes M, Romick ML, Sachs DH. Interleukin 2 prevents graft-versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5633-7. doi: 10.1073/pnas.87.15.5633.

Results Reference

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PubMed Identifier

12176915

Citation

Mapara MY, Kim YM, Wang SP, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood. 2002 Sep 1;100(5):1903-9. doi: 10.1182/blood-2002-01-0023.

Results Reference

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PubMed Identifier

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Citation

Kraus AB, Shaffer J, Toh HC, Preffer F, Dombkowski D, Saidman S, Colby C, George R, McAfee S, Sackstein R, Dey B, Spitzer TR, Sykes M. Early host CD8 T-cell recovery and sensitized anti-donor interleukin-2-producing and cytotoxic T-cell responses associated with marrow graft rejection following nonmyeloablative allogeneic bone marrow transplantation. Exp Hematol. 2003 Jul;31(7):609-21. doi: 10.1016/s0301-472x(03)00082-1.

Results Reference

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PubMed Identifier

10905768

Citation

Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, Saidman S, Weyouth DW, Preffer F, Poliquin C, Foley A, Cox B, Andrews D, Sachs DH, Sykes M. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant. 2000;6(3A):309-20. doi: 10.1016/s1083-8791(00)70056-5.

Results Reference

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PubMed Identifier

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Citation

Rubio MT, Kim YM, Sachs T, Mapara M, Zhao G, Sykes M. Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-gamma. Blood. 2003 Sep 15;102(6):2300-7. doi: 10.1182/blood-2002-12-3949. Epub 2003 Jun 5.

Results Reference

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PubMed Identifier

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Citation

Ballen KK, Becker PS, Emmons RV, Fitzgerald TJ, Hsieh CC, Liu Q, Heyes C, Clark Y, Levy W, Lambert JF, Chiafari F, Szymanski I, Rososhansky S, Popovsky MA, Stewart FM, Quesenberry PJ. Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy. Blood. 2002 Jul 15;100(2):442-50. doi: 10.1182/blood.v100.2.442.

Results Reference

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Citation

Colby C, Sykes M, Sachs DH, Spitzer TR. Cellular modulation of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1997 Dec;3(6):287-93.

Results Reference

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Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant

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