Non Hodgkin's LymphomaPhase 1RLINCT00909948

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

A Phase 1 study testing Fludarabine and total body irradiation and Total body irradiation in people with Non Hodgkin's Lymphoma and Hodgkin Disease, run by Massachusetts General Hospital at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 to 75 years
Conditions the study is for: Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma
What is being tested?: Fludarabine and total body irradiation and Total body irradiation
Type of treatment: Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 7 participants
Where: 1 siteUnited States
Study dates: Nov 2008to Aug 2012
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 75 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Show all 11Show fewer

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.

Who cannot join

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

Show all 10Show fewer

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

Trial locations and contacts

1 site in 1 country.

United States1 site

Massachusetts General Hospital
Boston, Massachusetts, 02114

Other trials in United States

About this study

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.

Conditions: Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma
Being tested: Fludarabine and total body irradiation, Total body irradiation
Keywords: Related stem cell transplant,, TBI,, Mismatched stem cell transplant, Fludarabine, Non-myeloablative, Lymphoma, Multiple myeloma
Medical subject headings: Lymphoma, Non-Hodgkin, Hodgkin Disease, Multiple Myeloma, Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Fludarabine and total body irradiationOther
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.
Total body irradiationRadiation
Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.

Study groups in NCT00909948
Study group	Role	What they receive
Fludarabine	Active comparator	The patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0. Receives: Other: Fludarabine and total body irradiation
TBI only	Active comparator	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. Receives: Radiation: Total body irradiation

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 100 days post transplant

Secondary outcomes (4)

To evaluate the incidence of acute and chronic GVHD
Measured: Up to 2 years post transplant
To evaluate the incidence of loss of donor grafts
Measured: Up to 2 years post transplant
To evaluate progression-free and overall survival
Measured: Up to 2 years post transplant
To evaluate antitumor responses following this transplant strategy
Measured: Up to 2 years post transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Nov 2008Aug 2012

First posted29 May 2009 (estimated)
Study startNov 2008
Primary completionAug 2012
Study completionAug 2012

Why it stopped: Slow Accrual

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (10)Papers the sponsor has linked to this study.
Other trials for Non Hodgkin's LymphomaStudies of the same condition, open and under way.
More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 7 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00909948
Sponsor's protocol ID: Protocol 07-068
Acronym: RLI
Status last verified: Mar 2018
First submitted: 27 May 2009
Last updated: 29 Mar 2018
Results posted: No
Data monitoring committee: Yes

Publications

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.
PubMed 4405359
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.
PubMed 9740354
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.
PubMed 12766882
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.
PubMed 2377601
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.
PubMed 12176915
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.
PubMed 12842706
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.
PubMed 10905768
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.
PubMed 12791660
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.
PubMed 12091334
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.
PubMed 9502295

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 29 Mar 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant
ClinicalTrials.gov ID: NCT00909948
Acronym / sponsor ID: RLI / Protocol 07-068
Conditions: Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma
Keywords: Related stem cell transplant,, TBI,, Mismatched stem cell transplant, Fludarabine, Non-myeloablative, Lymphoma, Multiple myeloma
Phase: Phase 1
Study type: Interventional
Recruitment status: TerminatedReason stopped: Slow Accrual
Enrolment: 7 participants (actual)
Lead sponsor: Massachusetts General HospitalUniversity, hospital or other
Study start: Nov 2008
Primary completion: Aug 2012 (actual)
Study completion: Aug 2012 (actual)
First posted: 29 May 2009 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Fludarabine	Active comparator	Other: Fludarabine and total body irradiationThe patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.
TBI only	Active comparator	Radiation: Total body irradiationPatients 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.

Who may qualify

Ages: 18 to 75 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (11 listed)

Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma.
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.

Key exclusion criteria (10 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Fludarabine and total body irradiationThe patients in the second cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.	Other	Fludarabine
Total body irradiationPatients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.	Radiation	TBI only

Primary outcome

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

4 secondary outcomes

To evaluate the incidence of acute and chronic GVHD
Time frame: Up to 2 years post transplant
To evaluate the incidence of loss of donor grafts
Time frame: Up to 2 years post transplant
To evaluate progression-free and overall survival
Time frame: Up to 2 years post transplant
To evaluate antitumor responses following this transplant strategy
Time frame: Up to 2 years post transplant

Results and safety

The study was stopped early (reason given: Slow Accrual). Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2018.
Background: PubMed 4405359Bortin 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.
Background: PubMed 9740354Hill 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.
Background: PubMed 12766882Dey 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.
Background: PubMed 2377601Sykes 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.
Background: PubMed 12176915Mapara 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.
Background: PubMed 12842706Kraus 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.
Background: PubMed 10905768Spitzer 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.
Background: PubMed 12791660Rubio 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.
Background: PubMed 12091334Ballen 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.
Background: PubMed 9502295Colby 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Bimalangshu R Dey, MD, PhD principal investigator

MGH

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 29 Mar 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Slow Accrual). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00909948, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2018.