Clinical trial NCT00118209: Rituximab and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma
Official title: Phase III Randomized Study of R-CHOP V. Dose-Adjusted EPOCH-R With Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Large B Cell Lymphoma
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-07-11
Enrollment: 524
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial studies rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell non-Hodgkin's lymphoma. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rituximab together with combination chemotherapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective when given with rituximab in treating diffuse large B-cell non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell lymphoma.

Detailed description: PRIMARY OBJECTIVES:

I. To compare the event-free survival of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (R-CHOP) versus dose-adjusted (DA-) etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, and rituximab (EPOCH-R) chemotherapy in untreated cluster of differentiation (CD)20 positive (+) diffuse large B-cell lymphomas.

II. To develop a molecular predictor of outcome of R-CHOP and DA-EPOCH-R chemotherapy using molecular profiling.

SECONDARY OBJECTIVES:

I. To compare the response rates, overall survival and toxicity of R-CHOP versus DA-EPOCH-R.

II. To define the pharmacogenomics of untreated diffuse large B-cell lymphoma (DLBCL) and correlate clinical parameters (toxicity, response, survival outcomes and laboratory results) with molecular profiling.

III. To assess the use of molecular profiling for pathological diagnosis. IV. To identify new therapeutic targets using molecular profiling. V. To perform a comprehensive analysis of somatic alterations to the tumor genome and to understand which genomic alterations are somatically acquired by the tumor and which are encoded in the germ line of the patient.

VI. To identify biomarkers of response to chemotherapy by fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging that are predictive of histopathologic remissions and survival in patients with stage I (mediastinal), II, III, or IV untreated DLBCL.

VII. To evaluate the use of semiquantitative measurements of FDG uptake in defining FDG-PET/CT based biomarkers of response to chemotherapy in patients with DLBCL.

VIII. To determine whether FDG-PET/CT measurements of tumor response after the second cycle of chemotherapy can predict clinical response.

IX. To establish a standardized protocol for FDG-PET/CT image acquisition. X. To determine additional FDG-PET/CT parameters (e.g., the ratio of tumor maximum standard uptake value \[SUVmax\] to liver SUVmean; SUVs corrected for body surface area and lean body mass; nuclear medicine physician's assessment) and evaluate their utility in refining FDG-PET/CT based biomarkers of response to therapy.

XI. To evaluate inter-institutional reproducibility of FDG-PET/CT measurements for this indication.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Eligibility criteria: 1. Histologically documented de novo CD20+ DLBCL with stage II, III or IV disease.

   * Stage I primary mediastinal (thymic) DLBCL is also eligible.
   * Patients with an underlying low-grade lymphoma, such as a transformed lymphoma or low-grade lymphoma in the bone marrow, are not eligible.
   * Diagnosis should be based on an adequate tissue sample, including open biopsy or core needle biopsy.
   * Needle aspiration for primary diagnosis is unacceptable.
   * Patients must have one of the following WHO classification subtypes:

     * Diffuse large B-cell lymphoma (includes morphological variants: centroblastic, immunoblastic, T-cell/histiocyte rich, and anaplastic)
     * Mediastinal (thymic) large B-cell lymphoma
     * Intravascular large B-cell lymphoma
   * Note: Failure to submit a pathology block within 60 days of patient registration will be considered a major protocol violation.

     * Fresh (frozen) tumor biopsy must be available or attempted. A frozen tumor biopsy equivalent to a minimum of four at least 16 gauge needle cores is an important component of this study.
     * Patients without adequate frozen material should have a biopsy performed to obtain material.
     * If a biopsy is performed and does not yield adequate material, the patient is still eligible for the study. If a biopsy cannot be done safely, the patient may still be eligible for the study if permission is granted.
   * Note: This study does not allow concurrent radiation unless a patient has a documented CNS treatment failure with no systemic failure.
2. No prior cytotoxic chemotherapy or rituximab. Patients may be entered if they have received prior limited field radiation therapy or a short course of glucocorticoids (\< 10 days) for an urgent local disease complication at diagnosis (e.g., cord compression, SVC syndrome). Patients who have received chemotherapy for prior malignancies are not eligible.
3. Age ≥ 18 years
4. ECOG Performance Status 0-2
5. No active ischemic heart disease or congestive heart failure. If there is suspicion of cardiac disease, a cardiac ejection fraction must show LVEF \> 45%, but the study is not required
6. No known lymphomatous involvement of the CNS. A lumbar puncture prior to study is not required in the absence of neurological symptoms
7. No known HIV disease. Patients with a history of intravenous drug abuse or any other behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible.
8. Non pregnant and non-nursing. Treatment would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective form of contraception.
9. Patients with active medical processes (e.g., uncontrolled bacterial or viral infection, bleeding) not related to their lymphoma should be excluded.
10. Required Initial Laboratory Values (unless non-Hodgkin lymphoma):

    * ANC ≥ 1000/μL
    * Platelets ≥ 100,000/μL
    * Creatinine≤ 1.5 mg/dL or creatinine clearance ≥ 50 cc/min
    * Total Bilirubin ≤ 2 mg/dL (unless a history of Gilbert's Disease)

Primary outcomes:
measure: Progression-Free Survival Rate at 2 and 5 Years
timeFrame: Up to 5 years post-registration
Secondary outcomes:
measure: Response Rate
timeFrame: Up to 5 years post-registration
measure: Overall Survival Rate at 2 and 5 Years
timeFrame: Up to 5 years post-registration
Other outcomes:
measure: Whether the Gene Expression Signatures That Were Previously Associated With Survival Following CHOP Therapy Are Associated With Survival in Either of the Treatment Arms of the Prospective Trial
timeFrame: Up to 5 years post-registration
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Mountain View
country: United States
facility: Camino Medical Group - Treatment Center
state: California
city: Palo Alto
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Saint Helena
country: United States
facility: Saint Helena Hospital
state: California
city: San Diego
country: United States
facility: Naval Medical Center - San Diego
state: California
city: Norwich
country: United States
facility: Eastern Connecticut Hematology and Oncology Associates
state: Connecticut
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Creticos Cancer Center at Advocate Illinois Masonic Medical Center
state: Illinois
city: Maywood
country: United States
facility: Cardinal Bernardin Cancer Center at Loyola University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
state: Maryland
city: Bethesda
country: United States
facility: National Naval Medical Center
state: Maryland
city: Bethesda
country: United States
facility: NIH - Warren Grant Magnuson Clinical Center
state: Maryland
city: Southfield
country: United States
facility: Providence Cancer Institute at Providence Hospital - Southfield Campus
state: Michigan
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Saint Louis
country: United States
facility: Christian Hospital Northeast-Northwest
state: Missouri
city: Concord
country: United States
facility: New Hampshire Oncology - Hematology, PA at Payson Center for Cancer Care
state: New Hampshire
city: Hooksett
country: United States
facility: New Hampshire Oncology - Hematology, PA - Hooksett
state: New Hampshire
city: Glens Falls
country: United States
facility: Charles R. Wood Cancer Center at Glens Falls Hospital
state: New York
city: New York
country: United States
facility: New York Weill Cornell Cancer Center at Cornell University
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Kinston
country: United States
facility: Kinston Medical Specialists
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Grand Forks
country: United States
facility: Altru Cancer Center at Altru Hospital
state: North Dakota
city: Canton
country: United States
facility: Mercy Cancer Center at Mercy Medical Center
state: Ohio
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
state: Ohio
city: Danville
country: United States
facility: Geisinger Cancer Institute at Geisinger Health
state: Pennsylvania
city: Easton
country: United States
facility: Easton Regional Cancer Center at Easton Hospital
state: Pennsylvania
city: Hazleton
country: United States
facility: Geisinger Hazleton Cancer Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
state: Pennsylvania
city: Berlin
country: United States
facility: Mountainview Medical
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Tacoma
country: United States
facility: Madigan Army Medical Center - Tacoma
state: Washington
city: Morgantown
country: United States
facility: Mary Babb Randolph Cancer Center at West Virginia University Hospitals
state: West Virginia
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Marshfield
country: United States
facility: Saint Joseph's Hospital
state: Wisconsin
city: Minocqua
country: United States
facility: Marshfield Clinic - Lakeland Center
state: Wisconsin
city: Rhinelander
country: United States
facility: Ministry Medical Group at Saint Mary's Hospital
state: Wisconsin
city: Rice Lake
country: United States
facility: Marshfield Clinic - Indianhead Center
state: Wisconsin
city: Stevens Point
country: United States
facility: Marshfield Clinic at Saint Michael's Hospital
state: Wisconsin
city: Stevens Point
country: United States
facility: Saint Michael's Hospital Cancer Center
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Clinic - Weston Center
state: Wisconsin
Study officials:
affiliation: National Cancer Institute (NCI)
name: Wyndham H. Wilson, MD, PhD
role: STUDY_CHAIR
affiliation: Memorial Sloan Kettering Cancer Center
name: Andrew D. Zelenetz, MD, PhD
role: STUDY_CHAIR
References:
citation: Schoder H, Polley MC, Knopp MV, Hall N, Kostakoglu L, Zhang J, Higley HR, Kelloff G, Liu H, Zelenetz AD, Cheson BD, Wagner-Johnston N, Kahl BS, Friedberg JW, Hsi ED, Leonard JP, Schwartz LH, Wilson WH, Bartlett NL. Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial. Blood. 2020 Jun 18;135(25):2224-2234. doi: 10.1182/blood.2019003277.
citation: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schoder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. doi: 10.1200/JCO.18.01994. Epub 2019 Apr 2.
citation: Barta SK, Lee JY, Kaplan LD, Noy A, Sparano JA. Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer. 2012 Aug 15;118(16):3977-83. doi: 10.1002/cncr.26723. Epub 2011 Dec 16.