SWOG-9704 Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma

• ClinicalTrials.gov Identifier: NCT00004031
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: February 2, 2021
• Last Update Posted: February 2, 2021
• Sponsor: SWOG Cancer Research Network
• Collaborators: National Cancer Institute (NCI); Cancer and Leukemia Group B; Eastern Cooperative Oncology Group; NCIC Clinical Trials Group
• Information provided by (Responsible Party): SWOG Cancer Research Network

Tracking Information

• First Submitted Date: December 10, 1999
• First Posted Date: January 27, 2003
• Results First Submitted Date: November 18, 2020
• Results First Posted Date: February 2, 2021
• Last Update Posted Date: February 2, 2021
• Study Start Date: July 1997
• Actual Primary Completion Date: June 1, 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2021)

• 2-year Overall Survival Rates [ Time Frame: up to 2 years post registration ]
  Percentage of participants surviving 2 years post registration
• 2 Year Progression-free Survival [ Time Frame: From registration until death ]
  Percentage of participants without disease progression up to 2 years post-registration.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: January 29, 2021)

Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 3 years post registration ]

Adverse Events (AEs) are reported by CTCAE Version 2.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. Higher grades indicate higher severity of adverse events.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: SWOG-9704 Chemoradiotherapy and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Non-Hodgkin's Lymphoma
• Official Title: SWOG-9704 A Randomized Phase III Trial Comparing Early High Dose Chemoradiotherapy and an Autologous Stem Cell Transplant to Conventional Dose CHOP Chemotherapy Plus Rituximab for CD20+ B Cell Lymphomas (With Possible Late Autologous Stem Cell Transplant) for Patients With Diffuse Aggressive Non-Hodgkin's Lymphoma in the High-Intermediate and High Risk International Classification Prognostic Groups

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation and kill more cancer cells. It is not yet known whether chemoradiotherapy plus peripheral stem cell transplantation is more effective than combination chemotherapy alone in treating non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying chemoradiotherapy and peripheral stem cell transplantation to see how well they work compared to combination chemotherapy in treating patients with stage II, stage III, or stage IV non-Hodgkin's lymphoma.

Detailed Description

OBJECTIVES:

• Compare the overall survival and progression-free survival of patients with intermediate- or high-grade non-Hodgkin's lymphoma treated with high-dose chemoradiotherapy and autologous peripheral blood stem cell transplantation (APBSCT) vs conventional dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (or CHOP plus rituximab for CD20+ disease) with possible late APBSCT.
• Compare the toxic effects of these regimens in this patient population.

OUTLINE: This is a randomized study. Patients are stratified according to disease risk (intermediate-high vs high).

Patients receive CHOP chemotherapy comprising cyclophosphamide IV over 15 minutes, doxorubicin IV, and vincristine IV on day 1 and oral prednisone on days 1-5. Patients with CD20-positive disease also receive rituximab IV on day 1 (or day 0 during course 1 only). Treatment repeats every 3 weeks for 5 courses in the absence of disease progression or unacceptable toxicity.

Within 35 days of completing the fifth course, patients with partial or complete response are randomized to one of two treatment arms.

• Arm I: Patients receive CHOP (or CHOP plus rituximab [CHOP-R]) as above. Treatment repeats every 3 weeks for 3 additional courses. After completion of chemotherapy, patients are encouraged to undergo harvest of peripheral blood stem cells (PBSC) for possible use at time of relapse. After completion of 8 courses, patients receive no additional therapy until disease progression or biopsy-proven disease.
• Arm II: Patients receive one additional course of CHOP/CHOP-R followed by filgrastim (G-CSF), sargramostim (GM-CSF), or other colony-stimulating factors used singly or in combination according to center preference. PBSC are harvested and selected for CD34+ cells. Patients under age 61 receive one of two preparative regimens: a total body irradiation (TBI)-based regimen comprising irradiation administered twice daily on days -8 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on day -2 OR carmustine IV over 2 hours on days -6 to -4 and etoposide and cyclophosphamide as in the TBI-based regimen. Patients age 61 to 65 receive the augmented regimen comprising carmustine, etoposide, and cyclophosphamide as above. Patients receive involved field radiotherapy prior to the preparative regimen only if there is biopsy-proven residual bulk disease and at the discretion of the center. PBSC are reinfused 36-48 hours after completion of cyclophosphamide. If both bone marrow and PBSC are harvested, bone marrow is reinfused on day 0 and then PBSC are reinfused either the same day or the following day.

Patients are followed every 6 months for 2 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 360 patients (at least 135 per treatment arm) will be accrued for this study within 5 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma

Intervention

• Biological: rituximab
  375 mg/m2 IV every 21 days
• Drug: CHOP regimen
• Drug: carmustine
• Drug: cyclophosphamide
• Drug: doxorubicin hydrochloride
• Drug: etoposide
• Drug: prednisone
• Drug: vincristine sulfate
• Procedure: bone marrow ablation with stem cell support
• Procedure: peripheral blood stem cell transplantation
• Radiation: radiation therapy

Study Arms

• Active Comparator: CHOP/CHOP-R x 3
  Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Prednisone 100 mg/day PO Days 1-5 Vincristine 1.4 mg/m2 IV Day 1 Rituximab 375 mg/m2 IV Day 1 This regimen is repeated every 21 days for 8 cycles
  Interventions:

  • Biological: rituximab
  • Drug: CHOP regimen
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Procedure: bone marrow ablation with stem cell support
• Experimental: CHOP/CHOP-R x 1 + Autologous Stem Cell Transplant
  Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Prednisone 100 mg/day PO Days 1-5 Vincristine 1.4 mg/m2 IV Day 1 Rituximab 375 mg/m2 IV Day 1 This regimen is repeated every 21 days for 6 cycles followed by autologous stem cell transplant.
  Interventions:

  • Biological: rituximab
  • Drug: CHOP regimen
  • Drug: carmustine
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: prednisone
  • Drug: vincristine sulfate
  • Procedure: bone marrow ablation with stem cell support
  • Procedure: peripheral blood stem cell transplantation
  • Radiation: radiation therapy

Publications *

• Stiff PJ, Unger JM, Cook J, et al.: Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP ± R for eight cycles to CHOP ± R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL). [Abstract] J Clin Oncol 29 (Suppl 15): A-8001, 2011.
• Cook JR, Goldman B, Tubbs RR, Rimsza L, Leblanc M, Stiff P, Fisher R. Clinical significance of MYC expression and/or "high-grade" morphology in non-Burkitt, diffuse aggressive B-cell lymphomas: a SWOG S9704 correlative study. Am J Surg Pathol. 2014 Apr;38(4):494-501. doi: 10.1097/PAS.0000000000000147.
• Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. doi: 10.1056/NEJMoa1301077.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 22, 2013): 397
• Original Enrollment: Not Provided
• Actual Study Completion Date: October 31, 2013
• Actual Primary Completion Date: June 1, 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically proven intermediate- or high-grade non-Hodgkin's lymphoma
• Ann Arbor classification of "bulky" stage II, III, or IV
• Must be classified as high-intermediate or high-risk according to International Age Adjusted Index
• Bidimensionally measurable disease
• No lymphoblastic, transformed, or mantle cell lymphomas
• No CNS involvement by lymphoma
• CD20 status confirmed by immunocytochemistry or flow cytometry
• Must have either bilateral or unilateral bone marrow aspiration and biopsy ≥ 42 days before first course of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (or CHOP plus rituximab [CHOP-R] for CD20+ disease) OR within 42 days prior to registration if CHOP/CHOP-R therapy has not begun

• Must have bilateral bone marrow aspiration and biopsy within 28 days of randomization

  • Bone marrow involvement with lymphoma is allowed, provided there is an improvement of at least 50% if used as an evaluable site of disease
• No prior lymphoma, Hodgkin's lymphoma, myelodysplastic syndromes, or leukemia NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age:

• 15 to 65

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• No nonlymphoma-related hepatic dysfunction

Renal:

• Creatinine no greater than 2 times ULN
• Creatinine clearance at least 60 mL/min
• No nonlymphoma-related renal dysfunction
• No history of grade 3 hemorrhagic cystitis due to cyclophosphamide

Cardiovascular:

• No coronary artery disease, cardiomyopathy, congestive heart failure, or dysrhythmia requiring therapy
• MUGA scan or 2-D echocardiogram required if patient's history is questionable
• Ejection fraction normal

Pulmonary:

• DLCO or FEV_1 at least 60% of predicted

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No allergy to etoposide
• No active bacterial, fungal, or viral infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior monoclonal antibody therapy for lymphoma except if included in a single course of CHOP/CHOP-R

Chemotherapy:

• No prior chemotherapy for lymphoma except for a single course of CHOP/CHOP-R* NOTE: *Prednisone or other corticosteroids not considered prior chemotherapy

Endocrine therapy:

• See Chemotherapy
• Prior corticosteroids allowed

Radiotherapy:

• No prior radiotherapy for lymphoma
• No prior thoracic radiotherapy or radiotherapy greater than 2,000 cGy to any other site

Surgery:

• Not specified

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00004031
• Other Study ID Numbers: CDR0000065658; S9704 ( Other Identifier: SWOG ); U10CA032102 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: SWOG Cancer Research Network
• Original Responsible Party: Not Provided
• Current Study Sponsor: SWOG Cancer Research Network
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• Cancer and Leukemia Group B
• Eastern Cooperative Oncology Group
• NCIC Clinical Trials Group

Investigators

• Study Chair: Patrick J. Stiff, MD; Loyola University
• Study Chair: Thomas C. Shea, MD; UNC Lineberger Comprehensive Cancer Center
• Study Chair: David P. Schenkein, MD; Tufts Medical Center Cancer Center
• Study Chair: Stephen Couban, MD; Cancer Care Nova Scotia

• PRS Account: SWOG Cancer Research Network
• Verification Date: January 2021