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Blood Stem Cell Transplant With Low Dose Chemotherapy for Relapsed Follicular Non-Hodgkin's Lymphoma (BMT CTN 0701)

Primary Purpose

Lymphoma, Non-Hodgkin

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Hematopoietic Stem Cell Transplant

About this trial

This is an interventional treatment trial for Lymphoma, Non-Hodgkin focused on measuring Follicular Non-Hodgkin's Lymphoma, Hematopoietic Stem Cell Transplant (HSCT), Non-Myeloablative Transplant (NST)

Eligibility Criteria

1 Year - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Must have confirmed CD20+ follicle center lymphoma that meets one of the following:
1. Histologically confirmed recurrent Revised European American Lymphoma (REAL) Classification CD20+ follicle center lymphoma, follicular grades I and II
2. Histologically confirmed World Health Organization (WHO) classification CD20+ follicular lymphoma grades 1, 2, or 3a.
  For either classification, the diffuse component of large cleaved cells (if present) cannot be greater than 50% of cellularity. Patients do not have to express t(14;18) to be eligible.
Any number of prior regimens (including autologous hematopoietic cell transplantation [HCT]); the most recent prior regimen must have occurred more than 28 days before study entry
Must demonstrate chemosensitive or radiosensitive disease to most recent prior regimen and meet one of the following criteria:
1. Patients in second or subsequent complete remission (CR)
2. Patients in first or subsequent partial remission (PR)
3. Patients experiencing a relapse that demonstrates a response, as defined as largest nodal mass less than or equal to 3 cm or greater than or equal to 50% reduction in estimated lymph node volume measured as a product of bi-dimensional measurements (see protocol for detailed definition).
4. Patients with stable follicular lymphoma are eligible if all lymph node masses are less than or equal to 3 cm and are smaller or unchanged in size to the most recent salvage regimen.
Patients with human leukocyte antigen (HLA)-matched donors that meet the following criteria:
1. 6/6 HLA-matched related donor. HLA typing must be performed by DNA methods for HLA-A and B at intermediate (or higher) resolution, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to individual transplant center criteria; or,
2. 8/8 HLA-matched unrelated donor. HLA typing must be performed by DNA methods for HLA-A, B, C, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (NMDP) criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to NMDP criteria.
Patients with adequate organ function, as measured by the following:
1. Heart: Left ventricular ejection fraction at rest greater than 45%
2. Lungs: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted (corrected for hemoglobin). For patients in whom pulse oximetry is performed, baseline O2 saturation greater than 85% (when lung function testing cannot be performed due to age restrictions)
3. Liver: Bilirubin less than two times the upper limit of normal for age as per local laboratory; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than three times the upper limit of normal as per local laboratory
4. Kidney: Calculated or measured creatinine clearance greater than or equal to 40 mL/min; if creatinine is greater than or equal to 1.5 mg/dL then 24-hour urine for measured creatinine clearance should be performed.

Exclusion Criteria:

Patients in first CR
Karnofsky performance score less than 70%
Patients with follicular lymphoma that demonstrates evidence of histologic transformation. In the presence of B symptoms, rapid growth of a single dominant site, or prolonged (> 2 yrs) interval since last tissue diagnosis, investigators are encouraged to consider re-biopsy of nodes prior to enrollment.
Uncontrolled hypertension
Uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication and progression of clinical symptoms)
Prior cancer, other than resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent less than 5 years will not be allowed unless approved by the medical monitor or protocol chair. Cancer treated with curative intent greater than 5 years will be allowed.
Pregnant or breastfeeding
Seropositive for human immunodeficiency virus (HIV)
Fertile men or women unwilling to use contraception from the time of initiation of conditioning until 6 months post-transplant
Prior allogeneic HSCT
Known anaphylactic reaction to rituximab
Seropositive for any of the following: HIV ab, hepatitis B sAg or polymerase chain reaction (PCR)+, or hepatitis C ab or PCR+

Sites / Locations

City of Hope National Medical Center
University of California, San Diego (UCSD) Medical Center
University of California, Davis Medical Center
Stanford Hospital and Clinics
University of Florida College of Medicine
H. Lee Moffitt Cancer Center
Rush University Medical Center
Dana-Farber Cancer Institute (DFCI)/Brigham & Women's Hospital
Dana-Farber Cancer Institute (DFCI)/Massachusetts General Hospital
University of Minnesota
University of Nebraska Medical Center
University of North Carolina Hospital at Chapel Hill
Wake Forest University Health Sciences
University Hospitals of Cleveland/Case Western
Ohio State/Arthur G. James Cancer Hospital
University of Oklahoma Medical Center
Vanderbilt University Medical Center
University of Texas, MD Anderson Cancer Research Center
West Virginia University
University of Wisconsin Hospital and Clinics
Medical College of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Hematopoietic Stem Cell Transplant

Arm Description

Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.

Outcomes

Primary Outcome Measures

Progression-Free Survival (PFS)

Patients are considered a failure for this endpoint if they die, or if they relapse/progress or receive anti-lymphoma therapy not including planned post-transplant radiation.

Secondary Outcome Measures

Graft Failure

Primary graft failure is defined as a donor peripheral blood T cell chimerism < 5% at Day +30 post-transplant. Secondary Graft Failure is defined as documented engraftment followed by loss of graft as defined by donor peripheral blood T cell chimerism < 5%.

Donor Cell Engraftment

Donor engraftment is defined as > 5% donor peripheral blood T cell chimerism by Day +30 post-transplant in the setting of Absolute Neutrophil Count (ANC) recovery (ANC >500/mm^3 for 3 consecutive days).

Time to Neutrophil Recovery

Neutrophil Recovery is defined as ANC > 500/mm^3 for 3 consecutive days.

Acute Graft-versus-Host Disease (GVHD)

The event is the incidence of grades II-IV acute GVHD from day of transplant, where grade IV is worst. The first day of acute GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that acute GVHD grade. GVHD should be monitored in accordance with BMT CTN manual of procedures guidelines. Acute GVHD grading was based on the consensus conference criteria (Przepiorka, et. al., 1994) and the Center for International Blood and Marrow Transplant Research (CIBMTR) grading criteria.

Chronic GVHD

The event is the incidence and severity of chronic GVHD from day of transplant, a cumulative incidence curve will be computed along with a 95% confidence interval at two years post-transplant. Death prior to occurrence of chronic GVHD will be considered as a competing risk.

Overall Survival

The event is death from any cause.

Treatment-related Mortality (TRM)

The event is death occurring in patients in continuous complete remission. The TRM distribution will be estimated by the Kaplan-Meier curve.

Infections

Quality of Life

Immunologic Reconstitution

Quantitative immunoglobulins (IgG)

Incidence of Toxicities

Number of participants that experiences at least one grade 3 - 5 toxicity during the first two years, where grade 5 is worst. Toxicity grades are based on the NCI CTCAE Version 3.0.

Serum Rituximab (RTX) Levels

RTX concentration levels within participants

Full Information

NCT ID

NCT00912223

First Posted

June 1, 2009

Last Updated

December 7, 2022

Sponsor

Medical College of Wisconsin

Collaborators

National Heart, Lung, and Blood Institute (NHLBI), Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program

1. Study Identification

Unique Protocol Identification Number

NCT00912223

Brief Title

Blood Stem Cell Transplant With Low Dose Chemotherapy for Relapsed Follicular Non-Hodgkin's Lymphoma (BMT CTN 0701)

Official Title

A Phase II Trial of Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation for Patients With Relapsed Follicular Non-Hodgkin's Lymphoma Beyond First Complete Response (BMT CTN #0701)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

April 2009 (undefined)

Primary Completion Date

November 2014 (Actual)

Study Completion Date

August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Medical College of Wisconsin

Collaborators

National Heart, Lung, and Blood Institute (NHLBI), Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Marrow Donor Program

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Blood stem cell transplants are one treatment option for people with lymphoma or other types of blood cancers. For this type of treatment, family members or unrelated donors with a similar tissue type usually donate their blood stem cells to the transplant patients. This study will evaluate the effectiveness of a type of blood stem cell transplant that uses lower doses of chemotherapy in people with relapsed follicular non-Hodgkin's lymphoma (NHL).

Detailed Description

Follicular NHL, a type of blood cancer, is the second most common type of non-Hodgkin's lymphoma, with approximately 15,000 new cases being diagnosed each year in the United States. Chemotherapy is a common treatment option for people with NHL, and at first most people achieve cancer remission with initial chemotherapy. However, after the initial chemotherapy, people with this disease typically experience a continuous pattern of relapse that results in progressively shorter remission durations. A blood stem cell transplant is another treatment option for people with follicular NHL. In a blood stem cell transplant procedure, healthy blood stem cells are taken from a donor and transplanted into the patient. The cells can be donated by a family member or an unrelated donor who has a similar tissue type. Typically, people who are undergoing a blood stem cell transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor stem cells. In this study, participants will undergo a type of stem cell transplant called a nonmyeloablative transplant, which involves a reduced intensity method of transplantation that does not require high doses of chemotherapy. The purpose of the study is to examine the effectiveness of a nonmyeloablative allogeneic blood stem cell transplant at improving survival rates in people with relapsed follicular NHL. This study will enroll people with relapsed follicular NHL. At a baseline study visit, participants will undergo a medical history review, physical examination, blood collection, lung function testing, computed tomography (CT) scans, a bone marrow biopsy, and questionnaires to assess quality of life. Participants will be admitted to the hospital and on various days in the 2 weeks before the transplant, they will receive fludarabine, cyclophosphamide, rituximab, which are cancer medications, and tacrolimus, a medication that will help prevent graft-versus-host disease (GVHD), which is an attack by the donor cells on the body's normal tissues. Participants will then undergo the blood stem cell transplant. At various times during the 2 weeks after the transplant, participants will receive rituximab and methotrexate, which is another medication to prevent GVHD. They will also receive tacrolimus for at least 6 months to help prevent GVHD. Participants will remain in the hospital for as long as necessary to recover from the transplant. Follow-up study visits will occur weekly for Weeks 1 to 14, and then at Months 6, 12, 18, and 24. At each study visit, select baseline procedures will be repeated.

6. Conditions and Keywords

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

Lymphoma, Non-Hodgkin

Keywords

Follicular Non-Hodgkin's Lymphoma, Hematopoietic Stem Cell Transplant (HSCT), Non-Myeloablative Transplant (NST)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

65 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hematopoietic Stem Cell Transplant

Arm Type

Experimental

Arm Description

Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.

Intervention Type

Biological

Intervention Name(s)

Hematopoietic Stem Cell Transplant

Intervention Description

NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant. The conditioning regimen will consist of the following: Rituxan 375 mg/m^2 on Day -13 Rituxan 1000 mg/m^2 on Days -6, +1, and +8 Fludarabine 30 mg/m^2 on Days -5 to -3 Cyclophosphamide 750 mg/m^2 on Days -5, -4, -3 Day 0 will be the day of the transplant. The GVHD prophylaxis will consist of the following: Tacrolimus .09 mg/kg/po (Day -2 thru Day +180). Doses will be adjusted to maintain blood levels of 5-15 ng/mL. Methotrexate 5 mg/m^2 (Days +1, +3, and +6). Unrelated donor recipients will receive a fourth dose on Day +11.

Primary Outcome Measure Information:

Title

Progression-Free Survival (PFS)

Description

Patients are considered a failure for this endpoint if they die, or if they relapse/progress or receive anti-lymphoma therapy not including planned post-transplant radiation.

Time Frame

Year 2

Secondary Outcome Measure Information:

Title

Graft Failure

Description

Time Frame

Day 30

Title

Donor Cell Engraftment

Description

Time Frame

Days 30 and 100

Title

Time to Neutrophil Recovery

Description

Neutrophil Recovery is defined as ANC > 500/mm^3 for 3 consecutive days.

Time Frame

Day 60

Title

Acute Graft-versus-Host Disease (GVHD)

Description

Time Frame

Day 100

Title

Chronic GVHD

Description

Time Frame

Year 2

Title

Overall Survival

Description

The event is death from any cause.

Time Frame

Years 2 and 3

Title

Treatment-related Mortality (TRM)

Description

The event is death occurring in patients in continuous complete remission. The TRM distribution will be estimated by the Kaplan-Meier curve.

Time Frame

Year 3

Title

Infections

Time Frame

Year 2

Title

Quality of Life

Time Frame

Year 2

Title

Immunologic Reconstitution

Description

Quantitative immunoglobulins (IgG)

Time Frame

Year 1

Title

Incidence of Toxicities

Description

Number of participants that experiences at least one grade 3 - 5 toxicity during the first two years, where grade 5 is worst. Toxicity grades are based on the NCI CTCAE Version 3.0.

Time Frame

Year 2

Title

Serum Rituximab (RTX) Levels

Description

RTX concentration levels within participants

Time Frame

Baseline, Days 28 and 365

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Must have confirmed CD20+ follicle center lymphoma that meets one of the following: Histologically confirmed recurrent Revised European American Lymphoma (REAL) Classification CD20+ follicle center lymphoma, follicular grades I and II Histologically confirmed World Health Organization (WHO) classification CD20+ follicular lymphoma grades 1, 2, or 3a. For either classification, the diffuse component of large cleaved cells (if present) cannot be greater than 50% of cellularity. Patients do not have to express t(14;18) to be eligible. Any number of prior regimens (including autologous hematopoietic cell transplantation [HCT]); the most recent prior regimen must have occurred more than 28 days before study entry Must demonstrate chemosensitive or radiosensitive disease to most recent prior regimen and meet one of the following criteria: Patients in second or subsequent complete remission (CR) Patients in first or subsequent partial remission (PR) Patients experiencing a relapse that demonstrates a response, as defined as largest nodal mass less than or equal to 3 cm or greater than or equal to 50% reduction in estimated lymph node volume measured as a product of bi-dimensional measurements (see protocol for detailed definition). Patients with stable follicular lymphoma are eligible if all lymph node masses are less than or equal to 3 cm and are smaller or unchanged in size to the most recent salvage regimen. Patients with human leukocyte antigen (HLA)-matched donors that meet the following criteria: 6/6 HLA-matched related donor. HLA typing must be performed by DNA methods for HLA-A and B at intermediate (or higher) resolution, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to individual transplant center criteria; or, 8/8 HLA-matched unrelated donor. HLA typing must be performed by DNA methods for HLA-A, B, C, and DRB1 at high resolution. The donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (NMDP) criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to NMDP criteria. Patients with adequate organ function, as measured by the following: Heart: Left ventricular ejection fraction at rest greater than 45% Lungs: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted (corrected for hemoglobin). For patients in whom pulse oximetry is performed, baseline O2 saturation greater than 85% (when lung function testing cannot be performed due to age restrictions) Liver: Bilirubin less than two times the upper limit of normal for age as per local laboratory; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than three times the upper limit of normal as per local laboratory Kidney: Calculated or measured creatinine clearance greater than or equal to 40 mL/min; if creatinine is greater than or equal to 1.5 mg/dL then 24-hour urine for measured creatinine clearance should be performed. Exclusion Criteria: Patients in first CR Karnofsky performance score less than 70% Patients with follicular lymphoma that demonstrates evidence of histologic transformation. In the presence of B symptoms, rapid growth of a single dominant site, or prolonged (> 2 yrs) interval since last tissue diagnosis, investigators are encouraged to consider re-biopsy of nodes prior to enrollment. Uncontrolled hypertension Uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication and progression of clinical symptoms) Prior cancer, other than resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent less than 5 years will not be allowed unless approved by the medical monitor or protocol chair. Cancer treated with curative intent greater than 5 years will be allowed. Pregnant or breastfeeding Seropositive for human immunodeficiency virus (HIV) Fertile men or women unwilling to use contraception from the time of initiation of conditioning until 6 months post-transplant Prior allogeneic HSCT Known anaphylactic reaction to rituximab Seropositive for any of the following: HIV ab, hepatitis B sAg or polymerase chain reaction (PCR)+, or hepatitis C ab or PCR+

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mary Horowitz, MD, MS

Organizational Affiliation

Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Official's Role

Study Director

Facility Information:

Facility Name

City of Hope National Medical Center

City

Duarte

State/Province

California

ZIP/Postal Code

91010-3000

Country

United States

Facility Name

University of California, San Diego (UCSD) Medical Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92093

Country

United States

Facility Name

University of California, Davis Medical Center

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Facility Name

Stanford Hospital and Clinics

City

Stanford

State/Province

California

ZIP/Postal Code

94305

Country

United States

Facility Name

University of Florida College of Medicine

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610-0277

Country

United States

Facility Name

H. Lee Moffitt Cancer Center

City

Tampa

State/Province

Florida

ZIP/Postal Code

33624

Country

United States

Facility Name

Rush University Medical Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60612

Country

United States

Facility Name

Dana-Farber Cancer Institute (DFCI)/Brigham & Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Dana-Farber Cancer Institute (DFCI)/Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Facility Name

University of Nebraska Medical Center

City

Omaha

State/Province

Nebraska

ZIP/Postal Code

68198-7680

Country

United States

Facility Name

University of North Carolina Hospital at Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599-7305

Country

United States

Facility Name

Wake Forest University Health Sciences

City

Winston-Salem

State/Province

North Carolina

ZIP/Postal Code

27157

Country

United States

Facility Name

University Hospitals of Cleveland/Case Western

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106-5061

Country

United States

Facility Name

Ohio State/Arthur G. James Cancer Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

University of Oklahoma Medical Center

City

Oklahoma City

State/Province

Oklahoma

ZIP/Postal Code

73104

Country

United States

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232-8210

Country

United States

Facility Name

University of Texas, MD Anderson Cancer Research Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

West Virginia University

City

Morgantown

State/Province

West Virginia

ZIP/Postal Code

26506-9162

Country

United States

Facility Name

University of Wisconsin Hospital and Clinics

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53792-5156

Country

United States

Facility Name

Medical College of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53211

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Findings will be published in a manuscript.

IPD Sharing Time Frame

Within 6 months of official study closure at participating sites.

IPD Sharing Access Criteria

Available to the public.

IPD Sharing URL

https://biolincc.nhlbi.nih.gov/home/

Citations:

PubMed Identifier

27118571

Citation

Laport GG, Wu J, Logan B, Bachanova V, Hosing C, Fenske T, Longo W, Devine SM, Nademanee A, Gersten I, Horowitz M, Lazarus HM, Riches ML; Blood and Marrow Transplant Clinical Trials Network. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant. 2016 Aug;22(8):1440-1448. doi: 10.1016/j.bbmt.2016.04.014. Epub 2016 Apr 23.

Results Reference

result

Links:

URL

https://bethematch.org/

Description

National Marrow Donor Program

Learn more about this trial

Blood Stem Cell Transplant With Low Dose Chemotherapy for Relapsed Follicular Non-Hodgkin's Lymphoma (BMT CTN 0701)

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