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A Randomized Phase II Trial of Myeloablative Versus Non-Myeloablative Consolidation Chemotherapy for Newly Diagnosed Primary CNS B-cell Lymphoma


Phase 2
18 Years
70 Years
Open (Enrolling)
Both
Lymphoma

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Trial Information

A Randomized Phase II Trial of Myeloablative Versus Non-Myeloablative Consolidation Chemotherapy for Newly Diagnosed Primary CNS B-cell Lymphoma


OBJECTIVES:

Primary

- To compare the two-year progression-free survival (PFS) of patients treated with the
myeloablative consolidation treatment strategy of high-dose therapy (HDT)/autologous
stem cell transplant (ASCT) versus those treated with non-myeloablative consolidation
chemotherapy with cytarabine and etoposide.

Secondary

- To compare the two-year event-free survival (EFS) of patients treated with
consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting
of etoposide and cytarabine.

- To compare the overall survival (OS) of patients treated with the consolidation
HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide
and cytarabine.

- To assess the toxicities associated with consolidation HDT/ASCT versus consolidation
consisting of etoposide and cytarabine.

- To determine diffusion magnetic resonance imaging (MRI) metrics (ADC_mini, ADC_25%, and
ADC_mean) prior to induction chemotherapy, after one full induction chemotherapy cycle,
and at the end of induction chemotherapy as a predictor of response and outcome (CALGB
581101 Companion Study).

- To determine brain fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)
metrics (tumor SUV and tumor versus background SUV) prior to induction chemotherapy,
after one full induction chemotherapy cycle, and at the end of induction chemotherapy
as a predictor of response and outcome (CALGB 581101 Companion Study).

- To determine whether low baseline ADC measurements are associated with shorter PFS and
OS (CALGB 581101 Companion Study).

- To determine whether reduction in tumor SUV by > 25% on brain FDGPET/ CT after one
cycle of induction therapy is associated with improved PFS and OS (CALGB 581101
Companion Study).

- To determine which immunohistochemistry (IHC)-based biomarkers are predictive of an
adverse prognosis (CALGB 151113 Companion Study).

- To determine which IHC-based biomarkers are predictive of a favorable prognosis (CALGB
151113) for BCL6 (B-cell CLL/lymphoma 6), and STAT 6 (signal transducer and activator
of transcription 6, interleukin-4 induced). (Exploratory)

- To analyze tumor tissue for gene expression profiles, and to correlate these profiles
with treatment outcomes (CALGB 151113 Companion Study). (Exploratory)

- To determine whether cerebrospinal fluid (CSF) proteome is a predictor of outcomes
(prognostic marker) irrespective of treatment arm (CALGB 151113) for (IL-10
[interleukin-10] and C3 [complement component 3]). (Exploratory)

- To assess at the neurocognitive function of patients treated with consolidation
HDT/ASCT versus those treated with consolidation chemotherapy (etoposide and
cytarabine) as measured by serial administration of the International Primary Central
Nervous System Lymphoma (PCNSL) Collaborative Group (IPCG) neurocognitive battery at
and evaluate the long-term survivorship differences between the two arms (CALGB 71105
Companion Study).

- To assess the quality of life of patients treated with consolidation HDT/ASCT versus
those treated with consolidation etoposide and cytarabine as measured by the EORTC
Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QLQ30/BCM20), and
to evaluate the long-term survivorship differences between the two arms (CALGB 71105
Companion Study).

OUTLINE: This is a multicenter study. Patients are stratified according to age and Karnofsky
performance status (KPS) (age < 51 years vs age ≥ 51 years and KPS ≥ 70% vs age ≥ 51 years
and KPS < 70%).

Induction Chemotherapy: Patients receive methotrexate IV over 4 hours on days 1 and 15
(courses 1-4); leucovorin calcium IV every 6 hours beginning 24 hours after each
methotrexate dose (courses 1-4); rituximab IV on days 3, 10, 17, and 24 (course 1), and days
3 and 10 (course 2); temozolomide orally (PO) on days 7-11 (courses 1-4); and cytarabine IV
over 2 hours twice daily (BID) on days 1 and 2 (course 5 only). Treatment repeats every 28
days for 5 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving a complete response, complete response unconfirmed, partial response, or
stable disease proceed to consolidation therapy.

Consolidation therapy: Patients are randomized to 1 of 2 treatment arms.

- Arm I : Between 3-5 weeks after induction therapy patients undergo stem cell
mobilization per participating institution guidelines.

- Consolidation therapy: Beginning 2-4 weeks after stem cell mobilization, patients
receive high-dose therapy comprising carmustine IV over 2 hours on day -6 and
thiotepa IV over 2 hours on days -5 to -4. Beginning on day 4, patients also
receive filgrastim subcutaneously (SC) once a day and continuing until absolute
neutrophil count recovers.

- Stem cell rescue: Patients then undergo autologous peripheral blood stem cell
transplantation on day 0.

- Arm II: Beginning at least 8 weeks and no later than 16 weeks after day 1 of induction
course 5, patients receive cytarabine IV over 2 hours on days 1-4, and etoposide IV
continuously over 96 hours on days 1-4. Beginning on day 14, patients also receive
filgrastim SC once a day and continuing until absolute neutrophil count recovers.

Tumor tissue, cerebrospinal fluid, and vitreous fluid samples may be collected for banking
and correlative studies.

Patients may complete quality-of-life questionnaires at baseline and periodically during
study.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then yearly for 5 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Diagnosis of primary central nervous system (CNS) diffuse large B-cell lymphoma
confirmed by one of the following:

- Brain biopsy or resection

- Cerebrospinal fluid

- Vitreous fluid

- No evidence or history of non-Hodgkin lymphoma (NHL) outside of CNS

- No isolated ocular lymphoma or isolated leptomeningeal lymphoma

- At least one measurable, contrast-enhancing brain lesion (≥ 1 cm in length)

PATIENT CHARACTERISTICS:

- Karnofsky performance status ≥ 30% (≥ 50% for patients ages 60-70 years)

- Adequate cardiac function (left ventricular ejection fraction [LVEF] ≥ 50%) and
pulmonary function (corrected diffusion capacity of carbon monoxide [DLCO] ≥ 60%
predicted)

- Pregnant or nursing patients may not be enrolled; women of childbearing potential
must have a negative serum or urine pregnancy test 10-14 days prior to registration;
in addition, women and men of childbearing potential must commit to use an effective
form of contraception throughout their participation in this study due to the
teratogenic potential of the therapy utilized in this trial; appropriate methods of
birth control include abstinence, oral contraceptives, implantable hormonal
contraceptives, or double barrier method (diaphragm plus condom)

- Negative human immunodeficiency virus (HIV) serology

- Negative hepatitis B virus (HBV) and hepatitis C virus (HCV) serology (unless HBV
antibody [HBsAb]-positive patient has recently received HBV vaccine, in this case
HBcAb should be negative)

- Absolute neutrophil count (ANC) ≥ 1500/mcL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 times upper
limit of normal (ULN)

- Total bilirubin ≤ 3 mg/dL

- Creatinine clearance ≥ 50 mL/min

- Platelet count ≥ 100,000/mcL

PRIOR CONCURRENT THERAPY:

- No prior chemotherapy or radiation therapy for lymphoma

- No history of organ transplantation or ongoing immunosuppressant therapy

- No concurrent palliative radiotherapy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Two-year PFS

Safety Issue:

No

Principal Investigator

Tracy Batchelor, MD, MPH

Investigator Role:

Principal Investigator

Investigator Affiliation:

Massachusetts General Hospital

Authority:

Unspecified

Study ID:

CDR0000721927

NCT ID:

NCT01511562

Start Date:

September 2012

Completion Date:

Related Keywords:

  • Lymphoma
  • primary central nervous system non-Hodgkin lymphoma
  • contiguous stage II adult diffuse large cell lymphoma
  • noncontiguous stage II adult diffuse large cell lymphoma
  • stage I adult diffuse large cell lymphoma
  • stage III adult diffuse large cell lymphoma
  • stage IV adult diffuse large cell lymphoma
  • Lymphoma
  • Lymphoma, B-Cell

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
Natalie Warren Bryant Cancer Center at St. Francis HospitalTulsa, Oklahoma  74136
SUNY Upstate Medical University HospitalSyracuse, New York  13210
University Cancer Center at University of Washington Medical CenterSeattle, Washington  98195
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
UPMC Cancer CentersPittsburgh, Pennsylvania  15232
Massachusetts General HospitalBoston, Massachusetts  02114-2617
Seattle Cancer Care AllianceSeattle, Washington  98109
Dana-Farber/Brigham and Women's Cancer CenterBoston, Massachusetts  02115