Lymphoma
Conditions
Keywords
anaplastic large cell lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known if combination chemotherapy with vinblastine is more effective than combination chemotherapy with vincristine in treating advanced anaplastic large cell lymphoma. PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens with either vinblastine or vincristine in treating patients who have newly diagnosed advanced anaplastic large cell lymphoma.
Detailed description
OBJECTIVES: * Compare the efficacy of a consolidation chemotherapy regimen comprising doxorubicin and prednisone in combination with vincristine vs vinblastine, in terms of event-free survival, in patients with advanced anaplastic large cell lymphoma. * Compare overall survival of patients treated with these regimens. * Compare the toxic effects of these regimens in these patients. * Correlate biological tumor characteristics and outcome in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are randomized at enrollment to receive either Standard APO regimen or a consolidation regimen including vinblastine (VBL). * Induction therapy: All Patients receive doxorubicin IV over 15 minutes on days 1 and 22; vincristine IV on days 1, 8, 15, 22, and 29; oral prednisone 3 times daily on days 1-28; and intrathecal (IT) methotrexate on days 1, 8, and 22 (patients with central nervous system (CNS) disease at diagnosis receive additional methotrexate IT on days 15, 29, and 36). Patients undergo restaging after Induction such that consolidation therapy is started on day 43. All patients with complete response (CR), complete response unconfirmed (CRu) or partial response (PR) proceed to Consolidation based on CT or MRI scans at the end of induction (week 6). All other patients will be removed from protocol therapy and will be followed until they meet the criteria for off study. Follow-up data will be required unless consent is withdrawn. * Standard APO (Arm I): Patients receive course-specific regimens without vinblastine. * Courses 1-3: Patients receive doxorubicin IV over 15 minutes, vincristine IV, and methotrexate IT on day 1 and oral prednisone three times daily and oral mercaptopurine once daily on days 1-5. * Courses 4-5: Patients receive doxorubicin, vincristine, prednisone, and mercaptopurine as in courses 1-3. * Courses 6-15: Patients receive vincristine, prednisone, and mercaptopurine as in courses 1-3 and methotrexate IV on day 1. * Consolidation with vinblastine (Arm II): Patients receive course-specific regimens including vinblastine. * Courses 1-3: Patients receive doxorubicin, methotrexate IT, prednisone, and mercaptopurine as in arm I and vinblastine IV over 1 minute on days 1, 8, and 15. * Courses 4-5: Patients receive doxorubicin, prednisone, and mercaptopurine as in arm I and vinblastine as in arm II (courses 1-3). * Courses 6-15: Patients receive prednisone and mercaptopurine as in arm I, vinblastine as in arm II (courses 1-3), and methotrexate IV on day 1. In both arms and all courses, treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. Patients are followed monthly for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter. PROJECTED ACCRUAL: A total of 200-250 patients (100-125 per treatment arm) will be accrued for this study within 5 years.
Interventions
DRUGdoxorubicin hydrochloride
Given IV
DRUGmercaptopurine
Given by mouth
DRUGmethotrexate
Given IV and intrathecally
DRUGprednisone
Given by mouth
DRUGvinblastine sulfate
Given IV
DRUGvincristine sulfate
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Newly diagnosed advanced anaplastic large cell lymphoma * Cluster of differentiation antigen 30 (CD30+) * Murphy stage III or IV * No B-cell large cell lymphoma * No disease limited to the skin (regardless of how wide-spread) PATIENT CHARACTERISTICS: Age * Under 21 Performance status * Not specified Life expectancy * Not specified Hematopoietic * Not specified Hepatic * Bilirubin no greater than 1.5 times upper limit of normal (ULN) * Aspartate aminotransferase (AST) or alanine transaminase (ALT) less than 2.5 times ULN (unless due to lymphoma) Renal * Not specified Cardiovascular * Shortening fraction (SF) at least 27% by echocardiogram OR * Ejection fraction (EF) at least 50% by radionuclide angiogram Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * Not specified Endocrine therapy * Prior steroids for management of a mediastinal mass allowed Radiotherapy * Prior limited-dose radiotherapy for a mediastinal mass allowed Surgery * Not specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | From first enrollment up to 3 years. | Percentage of EFS patients. This is measured as the time from study entry until disease progression, disease recurrence, occurrence of a second malignant neoplasm, or death from any cause. To measure Event Free Survival, repeated one-sided logrank tests will be performed The upper critical values are based on the one-sided alpha-spending functions of t2 (alpha=0.05) and the lower critical values are based on testing the alternative hypothesis at 0.005 level. |
Countries
Australia, Canada, Puerto Rico, Switzerland, United States
Participant flow
Recruitment details
This is a multi-center, phase III, randomized trial for newly diagnosed children with advanced-stage anaplastic large cell lymphoma (ALCL). The study was activated on November 3, 2003 and the first date of enrollment was January 13, 2004.
Pre-assignment details
Randomization occurs at the time of enrollment with all participants receiving Standard Induction of Doxorubicin, Prednisone and Vincristine (APO) and are evaluated at week 6 for continuation therapy.
Participants by arm
| Arm | Count |
|---|---|
| Standard (APO) With Vincristine (Arm I) In courses 1-3, patients receive doxorubicin hydrochloride (30 mg/m2) IV over 15 minutes, vincristine sulfate (1.5 mg/m2 (maximum dose 2 mg)) IV, and methotrexate intrathecally (age-adjusted dosing) (IT) on day 1 and oral prednisone (40 mg/m2/day) three times daily and oral mercaptopurine (225 mg/m2) once daily on days 1-5. In courses 4 and 5, patients receive doxorubicin (30 mg/m2), vincristine sulfate (1.5 mg/m2 (Maximum dose 2 mg)), prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in courses 1-3. In courses 6-15, patients receive vincristine sulfate (1.5 mg/m2), prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in courses 1-3 and methotrexate (60 mg/m2) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. | 65 |
| Consolidation (Includes Vinblastine) (Arm II) In courses 1-3, patients receive doxorubicin hydrochloride (30 mg/m2) IV, methotrexate (age adjusted dosing) IT, prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in arm I and vinblastine sulfate (4 mg/m2) IV over 1 minute on days 1, 8, and 15. In courses 4 and 5, patients receive doxorubicin hydrochloride (30 mg/m2) IV, prednisone (120 mg/m2/day), and mercaptopurine (225 mg/m2) as in arm I and vinblastine sulfate (4 mg/m2) as in arm II (courses 1-3). In courses 6-15, patients receive prednisone (120 mg/m2/day) and mercaptopurine (225 mg/m2) as in arm I, vinblastine sulfate (4 mg/m2) IV as in arm II (courses 1-3), and methotrexate (60 mg/m2) IV on day 1. Treatment repeats every 21 days for up to 15 courses in the absence of disease progression or unacceptable toxicity. | 64 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Ineligible | 1 | 3 |
| Overall Study | Lack of Efficacy | 6 | 5 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Standard (APO) With Vincristine (Arm I) | Total | Consolidation (Includes Vinblastine) (Arm II) |
|---|---|---|---|
| Age, Categorical <=18 years | 62 Participants | 124 Participants | 62 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 18 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 107 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 19 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) White | 47 Participants | 89 Participants | 42 Participants |
| Region of Enrollment Australia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Canada | 3 participants | 12 participants | 9 participants |
| Region of Enrollment Switzerland | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United States | 59 participants | 111 participants | 52 participants |
| Sex: Female, Male Female | 24 Participants | 51 Participants | 27 Participants |
| Sex: Female, Male Male | 41 Participants | 78 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 47 / 64 | 52 / 61 |
| serious Total, serious adverse events | 2 / 64 | 4 / 61 |
Outcome results
Primary
Event-free Survival (EFS)
Percentage of EFS patients. This is measured as the time from study entry until disease progression, disease recurrence, occurrence of a second malignant neoplasm, or death from any cause. To measure Event Free Survival, repeated one-sided logrank tests will be performed The upper critical values are based on the one-sided alpha-spending functions of t2 (alpha=0.05) and the lower critical values are based on testing the alternative hypothesis at 0.005 level.
Time frame: From first enrollment up to 3 years.
Population: 64 patients from Arm I were analyzed for this outcome measure, one patient was deemed ineligible. 61 patients from Arm II were analyzed for this outcome measure, three patients were deemed ineligible.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard (APO) With Vincristine (Arm I) | Event-free Survival (EFS) | 74 percentage of participants |
| Consolidation (Includes Vinblastine) (Arm II) | Event-free Survival (EFS) | 79 percentage of participants |