Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal Large B-cell Lymphoma, Burkitt Lymphoma, Anaplastic Large-Cell Lymphoma, Gray Zone Lymphoma
Conditions
Keywords
Primary Mediastinal B-Cell Lymphoma, CD20 +, Diffuse Large B-Cell Lymphoma, Anaplastic Large Cell Lymphoma, De Novo
Brief summary
5-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. Etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH): Etoposide, VP-16, NSC-141540; Prednisone, PRED, NSC-10023; Vincristine, VCR, NSC-67574; Cyclophosphamide, CTX, NSC-26271; Doxorubicin, DOX, NSC-123127; with Granulocyte Colony-Stimulating Factor (Amgen), Granulocyte colony-stimulating factor (G-CSF), NSC-614629.
Detailed description
Background: The treatment of the intermediate and aggressive non-Hodgkin's lymphomas in adults and children commonly induces complete responses in a sizable fraction of the treated population, and about 2/3 of the complete responders appear to have prolonged disease-free survival. The present study assesses the activity and tolerability in previously untreated patients of a regimen of etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH) infusional chemotherapy given intensively with granulocyte colony-stimulating factor (G-CSF) support. Objectives: Primary: Assess complete response (CR) and progression-free survival (PFS) of dose-adjusted EPOCH-Rituximab (DA-EPOCH-R) with G-CSF in aggressive B-cell lymphomas. Eligibility: Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma (MGZL) and primary mediastinal B cell lymphoma (PMBL). Patients greater than or equal to 12 years old. Any Stage for PMBL and MGZL. No prior systemic chemotherapy. Human immunodeficiency virus (HIV) negative. Design: This study will estimate the complete response rate of a group of previously untreated patients and the extent to which EPOCH infusional drug delivery accompanied by a hematopoietic growth factor can increase the dose intensity of treatment. Patients receive prednisone orally for 5 days, a 96-hour infusion of vincristine, doxorubicin, and etoposide, and a bolus of cyclophosphamide on day 5. Cycles are repeated every 21 days for a total of 6-8 cycles. Patients with cluster of differentiation 20 (CD20) expressing tumors (i.e., mature B-cell lymphomas) will also receive rituximab, the humanized monoclonal antibody against the CD20 receptor on day 1 of each cycle. A total of 348 patients will be enrolled on this protocol.
Interventions
DRUGEtoposide
Etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
BIOLOGICALRituximab
Rituximab given on Day 1 of combination chemotherapy (EPOCH-R) every 3 weeks for 6 cycles. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
DRUGPrednisone
Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
DRUGCyclophosphamide
Cyclophosphamide 750mg/m\^2 on day 5 every 21 days. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
DRUGVincristine
Vincristine 0.4mg/m\^2/day. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
DRUGDoxorubicin
Doxorubicin 10mg/m\^2/day. Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.
DIAGNOSTIC_TESTMRI
Baseline and/or on completion of therapy.
DIAGNOSTIC_TESTCT
Baseline and/or on completion of therapy.
PROCEDUREBiopsy
Baseline and/or on completion of therapy.
DIAGNOSTIC_TESTPET scan
As clinically indicated.
PROCEDURELaparotomy
As clinically indicated.
OTHEROndansetron
Nausea and/or vomiting.
OTHERProchlorperazine
Nausea and/or vomiting.
OTHEROmeprazole
Gastroesophageal reflux disease (GERD).
OTHERDocusate Sodium + Sennosides
Constipation.
OTHERLactulose
Constipation
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma and primary mediastinal B cell lymphoma. Diagnosis confirmed by staff of the Hematopathology Section, Laboratory of Pathology, National Cancer Institute (NCI). Tissue blocks from patients treated in extramural sites must be forwarded to the NCI for analysis of B-cell leukemia/lymphoma 2 (bcl-2) by immunohistochemistry (IHC) and other markers within 1 month of study entry. Patients greater than or equal to 12 years old. Stage and Prognosis of Patients: Any stage for mediastinal gray zone lymphoma (MGZL) and primary mediastinal B-cell lymphoma (PMBL). No prior systemic chemotherapy. Patients may be entered if they have had prior limited-field radiotherapy, a short course of glucocorticoids and/or cyclophosphamide for an urgent problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome). Human immunodeficiency virus (HIV) negative. Not pregnant or nursing. Adequate major organ function \[in adults: serum creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 60 ml/min; and in children serum creatinine (CR) less than or equal to age-adjusted normal (age 12 to 15 maximum serum creatinine 1.2 mg/dl and age greater than 15 maximum serum creatinine 1.5 mg/dl); bilirubin less than 1.5 mg/dl; absolute neutrophil count (ANC) greater than 1,000 and platelets greater than 100,000) unless impairment is due to organ involvement by lymphoma or immune-mediated mechanism caused by lymphoma. No active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If multi-gated acquisition (MUGA) is obtained, the left ventricular ejection fraction (LVEF) should exceed 40%. No other serious concomitant medical illnesses or uncontrolled active infection that would jeopardize the patient's ability to receive the regimen with reasonable safety. No history of unrelated (non-lymphomatous) neoplasms within past 5 years other than non-melanoma skin cancer or in-situ cancer. Ability to give informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response (Complete Response + Partial Response) | Time frame was from beginning of therapy until the end of therapy, an average of 6 months | Overall response defined as a Complete Response + Partial Response was measured by the Response Criteria. Complete Response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. Partial Response is 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a period of at least one month. |
| Progression Free Survival (PFS) | Progression free survival was calculated from study entry until progression or death from any cause. Median follow up of evaluable participants was 5 years (range 2-7 years) | The Dixon-Simon method will be used to determine whether large B-cell lymphomas expressing BCL-2 (+) participants may experience an improved progression free survival with Etoposide, VP-16, and Doxorubicin with Prednisone, Cyclophosphamide, and Rituximab (EPOCH-R) compared to EPOCH alone, and to obtain a concurrent, precisely determined measure of progression free survival. PFS is the time from start of treatment to documented evidence of disease progression. Progression is an increase of 25% or more in the sum of the products of the longest perpendicular diameters of all measured lesions, or the appearance of any new lesions measured by the Response Criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Therapy | Initiation of study drug until 30 days after treatment, an average of 6 months | Here is the proportion of participants with adverse events leading to discontinuation of therapy. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the participant and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | Time frame is from study entry until 30 days after completing study therapy, approximately 5 years. | Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) Subgroup 1 (SG1) - All participants who received combination Rituximab (EPOCH-R). Rituximab 375 mg/m\^2 intravenous (IV) on day 1, every 21 days, prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m\^2 on day 5 every 21 days. Doxorubicin 10mg/m\^2/day, vincristine 0.4mg/m\^2/day, and etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir. | 235 |
| EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) Subgroup 2 (SG2) - EPOCH alone: All participants who received Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m\^2 on day 5 every 21 days. Doxorubicin 10mg/m\^2/day, vincristine 0.4mg/m\^2/day, and etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir. | 112 |
| Enrolled But Not Treated Participant was enrolled but not treated. | 1 |
| Total | 348 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | 2nd malignancy | 1 | 0 | 0 |
| Overall Study | 2nd primary disease | 0 | 0 | 1 |
| Overall Study | Began other Tx | 1 | 0 | 0 |
| Overall Study | Death during follow up period | 9 | 4 | 0 |
| Overall Study | Death on study | 19 | 9 | 0 |
| Overall Study | Disease progression during follow-up period | 3 | 1 | 0 |
| Overall Study | Disease progression on study | 33 | 41 | 0 |
| Overall Study | Doesn't have NHL | 0 | 1 | 0 |
| Overall Study | Lost to further follow-up | 10 | 6 | 0 |
| Overall Study | Non protocol tx needed | 3 | 1 | 0 |
| Overall Study | Physician Decision | 3 | 1 | 0 |
| Overall Study | Protocol change | 1 | 0 | 0 |
| Overall Study | Refused further treatment | 2 | 1 | 0 |
| Overall Study | Switched to alternate treatment | 2 | 2 | 0 |
| Overall Study | Transfer to transplant | 0 | 1 | 0 |
| Overall Study | Treatment for second lymphoma | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) | EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) | Enrolled But Not Treated | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Age, Categorical >=65 years | 30 Participants | 10 Participants | 0 Participants | 40 Participants |
| Age, Categorical Between 18 and 65 years | 200 Participants | 102 Participants | 1 Participants | 303 Participants |
| Age, Continuous | 43.97 years STANDARD_DEVIATION 17.7 | 47.2 years STANDARD_DEVIATION 15.29 | 62.6 years STANDARD_DEVIATION 0 | 45.06 years STANDARD_DEVIATION 17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 1 Participants | 0 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 211 Participants | 108 Participants | 1 Participants | 320 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 3 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 6 Participants | 0 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 37 Participants | 13 Participants | 1 Participants | 51 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 2 Participants | 0 Participants | 19 Participants |
| Race (NIH/OMB) White | 169 Participants | 91 Participants | 0 Participants | 260 Participants |
| Region of Enrollment United States | 235 participants | 112 participants | 1 participants | 348 participants |
| Sex: Female, Male Female | 103 Participants | 50 Participants | 0 Participants | 153 Participants |
| Sex: Female, Male Male | 132 Participants | 62 Participants | 1 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 235 | 13 / 112 |
| other Total, other adverse events | 235 / 235 | 112 / 112 |
| serious Total, serious adverse events | 146 / 235 | 44 / 112 |
Outcome results
Primary
Overall Response (Complete Response + Partial Response)
Overall response defined as a Complete Response + Partial Response was measured by the Response Criteria. Complete Response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. Partial Response is 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a period of at least one month.
Time frame: Time frame was from beginning of therapy until the end of therapy, an average of 6 months
Population: 347/348 participants were analyzed because 1 was inevaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) | Overall Response (Complete Response + Partial Response) | 216 Participants |
| EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) | Overall Response (Complete Response + Partial Response) | 94 Participants |
Primary
Progression Free Survival (PFS)
The Dixon-Simon method will be used to determine whether large B-cell lymphomas expressing BCL-2 (+) participants may experience an improved progression free survival with Etoposide, VP-16, and Doxorubicin with Prednisone, Cyclophosphamide, and Rituximab (EPOCH-R) compared to EPOCH alone, and to obtain a concurrent, precisely determined measure of progression free survival. PFS is the time from start of treatment to documented evidence of disease progression. Progression is an increase of 25% or more in the sum of the products of the longest perpendicular diameters of all measured lesions, or the appearance of any new lesions measured by the Response Criteria.
Time frame: Progression free survival was calculated from study entry until progression or death from any cause. Median follow up of evaluable participants was 5 years (range 2-7 years)
Population: 347/348 participants were analyzed because 1 was inevaluable for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) | Progression Free Survival (PFS) | 73 Participants |
| EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) | Progression Free Survival (PFS) | 41 Participants |
Secondary
Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Therapy
Here is the proportion of participants with adverse events leading to discontinuation of therapy. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the participant and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Initiation of study drug until 30 days after treatment, an average of 6 months
Population: 347/348 participants were analyzed because one participant was enrolled and not treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) | Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Therapy | 0.03 proportion of participants |
| EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) | Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Therapy | 0.04 proportion of participants |
Other Pre-specified
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Time frame is from study entry until 30 days after completing study therapy, approximately 5 years.
Population: 347/348 participants were analyzed because one participant was enrolled and not treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab) | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 235 Participants |
| EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide) | Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) | 112 Participants |