Childhood Nodular Lymphocyte Predominant Hodgkin Lymphoma, Stage III Childhood Hodgkin Lymphoma, Stage IV Childhood Hodgkin Lymphoma
Conditions
Brief summary
This phase III trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed Hodgkin lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. To maintain the overall survival (as defined by 4-year second-event free survival) for subjects with high risk Hodgkin lymphoma at or above 95%. SECONDARY OBJECTIVES: I. To maintain 3-year event-free survival for subjects with high risk Hodgkin lymphoma at or above 93%. II. To maintain comparable overall survival (as defined by 4-year second-event free survival) between subjects with high risk Hodgkin lymphoma who have a rapid or slow response to the initial 2 cycles of ABVE-PC\* by intensifying therapy through the addition of 2 cycles of ifosfamide/vinorelbine in those with a slow early response. III. To investigate whether very early response assessment measured by FDG-PET after 1 cycle of chemotherapy identifies a subject cohort that can be studied in future trials and that is distinguishable from currently defined RER after 2 cycles. IV. To describe the patterns of relapse after ABVE-PC\* and risk-adapted radiotherapy. OUTLINE: This is a multicenter study. INDUCTION THERAPY (ABVE-PC): Patients receive doxorubicin hydrochloride IV over 1-120 minutes and cyclophosphamide IV over 30-60 minutes on days 1 and 2, bleomycin sulfate IV over at least 10 minutes or subcutaneously (SC) and vincristine sulfate IV on days 1 and 8, etoposide phosphate IV over 1-2 hours on days 1-3, oral prednisone twice daily on days 1-7, and filgrastim\* SC or IV daily beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity or disease progression. NOTE: \*Patients do not receive filgrastim on day 8. Patients undergo clinical restaging and response assessment after 2 courses of induction therapy. Patients with rapid early response (RER) or slow early response (SER) proceed to consolidation therapy. Patients with progressive disease go off study. CONSOLIDATION THERAPY: Patients are assigned to 1 of 2 consolidation therapy regimens based on response to induction therapy. Patients who develop progressive disease after induction are taken off protocol therapy. REGIMEN I (RER): Patients receive 2 more courses of ABVE-PC in the absence of unacceptable toxicity or disease progression. REGIMEN II (SER): Patients receive ifosfamide IV continuously on days 1-4, vinorelbine ditartrate IV over 6-30 minutes on days 1 and 5, and filgrastim SC or IV daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity or disease progression. Patients then receive 2 more courses of ABVE-PC in the absence of unacceptable toxicity or disease progression. Patients with a continued response after completion of consolidation therapy proceed to risk-adapted radiotherapy. RISK-ADAPTED RADIOTHERAPY: Beginning at 3 weeks after completion of consolidation chemotherapy, patients undergo radiotherapy once daily, 5 days a week, for 3 weeks (14 fractions) in the absence of unacceptable toxicity or disease progression. Patients classified as RER receive radiation therapy only to sites of bulky disease. Patients classified as SER receive radiation therapy to sites of bulky disease and areas that remain FDG-PET avid after induction therapy. After completion of study therapy, patients are followed up periodically for 10 years.
Interventions
BIOLOGICALbleomycin sulfate
Given IV or SC
DRUGdoxorubicin hydrochloride
Given IV
Given IV
DRUGvinorelbine tartrate
Given IV
DRUGcyclophosphamide
Given IV
DRUGetoposide phosphate
Given IV
DRUGprednisone
Given IV
BIOLOGICALfilgrastim
Given IV or SC
DRUGifosfamide
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed newly diagnosed Hodgkin lymphoma (HL) meeting one of the following criteria: * Classical disease * Nodular lymphocyte-predominant disease * Stage III or IV disease with B symptoms, as defined by ≥ 1 of the following: * Unexplained weight loss \> 10% within the past 6 months * Unexplained recurrent fever \> 38°C within the past month * Recurrent drenching night sweats within the past month * Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows: * 0.4 mg/dL (1 to 5 months) * 0.5 mg/dL (6 to 11 months) * 0.6 mg/dL (12 to 23 months) * 0.8 mg/dL (2 to 5 years) * 1 mg/dL (6 to 9 years) * 1.2 mg/dL (10 to 12 years) * 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to 15 years) * 1.7 mg/dL (males) or 1.4 mg/dL (females) (≥ 16 years) * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age * AST or ALT \< 2.5 times ULN for age * Shortening fraction ≥ 27% by ECHO OR ejection fraction ≥ 50% by MUGA (unless due to large mediastinal mass from HL) * FEV\_1/FVC \> 60% by pulmonary function tests (PFT) (unless due to large mediastinal mass fromHL) * For children who are unable to cooperate for PFTs, the criteria are: * No evidence of dyspnea at rest * No exercise intolerance * Pulse oximetry \> 92% on room air * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No pathologic prolongation of QTc interval (\> 450 milliseconds) on 12-lead ECG * No prior chemotherapy, biological response modifiers (e.g., monoclonal antibody therapy), or radiotherapy * At least 28 days since prior corticosteroids except for emergent treatment for respiratory distress or spinal cord compression, or for treatment of allergy to contrast agent required for CT scan * No other concurrent cancer chemotherapy or immunomodulating agents (including steroids) * Concurrent corticosteroid therapy as treatment or prophylaxis for anaphylactic reactions allowed * No concurrent pegfilgrastim
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Second-event-free Survival | At 4 years from enrollment | Second event here is defined as any relapse/progression of Hodgkin Lymphoma (HL) or a previously reported second malignant neoplasm (SMN), a new SMN, or death after a first event which can be relapse/progression of HL, SMN, biopsy-proven HL following completion of Consolidation for Slow Early Response (SER) patient, positive bilateral bone marrow biopsy following completion of Consolidation for Stage IV patient, or death. If death occurs as the 1st event, it also counts as the 2nd event. |
| Safety Analysis and Monitoring of Toxic Death | Within 30 days of protocol treatment at median follow-up of 48 months (range: 1 to 70 months). | The primary endpoint for safety analysis and monitoring is toxic death, which is death primarily attributable to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival for Rapid Early Response (RER) Positron Emission Tomography(PET)-1 Positive, RER PET-1 Negative | 3 years from enrollment | To investigate whether very early response assessment measured by Fluorodeoxyglucose-PET after 1 cycle of chemotherapy identifies a subject cohort that can be studied in future trials and that is distinguishable from currently defined RER after 2 cycles. |
| Relapse-free Survival | 3 years from enrollment | A description, survival to relapse, of patterns of relapse after Doxorubicin, Bleomycin, Vincristine, Etoposide - Prednisone, Cyclophosphamide (ABVE-PC) and risk-adapted radiotherapy. |
| Event Free Survival | At 3 years from enrollment | Survival from enrollment to first event: relapse/progression, second malignancy, or death. |
| Overall Survival | At 3 years from enrollment | Survival from enrollment to death. |
| Grade 3 and 4 Non-hematologic Toxicities During Protocol Therapy | During and after completion of study treatment. | The number of patients that experience Common Terminology Criteria (CTC) Version 4 grade 3 or higher non-hematologic toxicity at any time during protocol therapy. |
| Second-event-free Survival | At 4 years from enrollment | Second event here is defined as any relapse/progression of Hodgkin Lymphoma (HL) or a previously reported second malignant neoplasm (SMN), a new SMN, or death after a first event which can be relapse/progression of HL, SMN, biopsy-proven HL following completion of Consolidation for Slow Early Response (SER) patient, positive bilateral bone marrow biopsy following completion of Consolidation for Stage IV patient, or death. If death occurs as the 1st event, it also counts as the 2nd event. |
Countries
Australia, Canada, Israel, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| INDUCTION THERAPY (ABVE-PC) All Patients | 166 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Consolidation Maintenance | Death | 0 | 1 | 0 |
| Consolidation Maintenance | Lack of Efficacy | 0 | 1 | 1 |
| Consolidation Maintenance | Physician Decision | 0 | 2 | 7 |
| Consolidation Maintenance | Withdrawal by Subject | 0 | 2 | 6 |
| Induction | Death | 1 | 0 | 0 |
| Induction | Ineligible | 1 | 0 | 0 |
| Induction | Lack of Efficacy | 2 | 0 | 0 |
| Induction | Physician Decision | 12 | 0 | 0 |
| Induction | Withdrawal by Subject | 9 | 0 | 0 |
Baseline characteristics
| Characteristic | INDUCTION THERAPY (ABVE-PC) |
|---|---|
| Age, Categorical <=18 years | 156 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 15 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants |
| Race (NIH/OMB) White | 112 Participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Canada | 19 participants |
| Region of Enrollment Puerto Rico | 1 participants |
| Region of Enrollment United States | 143 participants |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 89 / 165 | 43 / 81 | 46 / 80 |
| serious Total, serious adverse events | 0 / 165 | 0 / 81 | 0 / 80 |
Outcome results
Primary
Safety Analysis and Monitoring of Toxic Death
The primary endpoint for safety analysis and monitoring is toxic death, which is death primarily attributable to treatment.
Time frame: Within 30 days of protocol treatment at median follow-up of 48 months (range: 1 to 70 months).
Population: The six patients who received induction and reported death. The analysis here examines whether their death is primarily attributable to treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Safety Analysis and Monitoring of Toxic Death | 0 participants |
Primary
Second-event-free Survival
Second event here is defined as any relapse/progression of Hodgkin Lymphoma (HL) or a previously reported second malignant neoplasm (SMN), a new SMN, or death after a first event which can be relapse/progression of HL, SMN, biopsy-proven HL following completion of Consolidation for Slow Early Response (SER) patient, positive bilateral bone marrow biopsy following completion of Consolidation for Stage IV patient, or death. If death occurs as the 1st event, it also counts as the 2nd event.
Time frame: At 4 years from enrollment
Population: This analysis excludes n=20 patients who had protocol early terminations or deviations (n=4 Regimen I, n=12 Regimen II, and n=4 Induction only).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Second-event-free Survival | 0.91 Probability of survival |
Secondary
Event Free Survival
Survival from enrollment to first event: relapse/progression, second malignancy, or death.
Time frame: At 3 years from enrollment
Population: 164 Group 1 All Patients received induction therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Event Free Survival | 0.81 Probability of survival |
Secondary
Event Free Survival
Survival from enrollment to first event: relapse/progression, second malignancy, or death.
Time frame: At 3 years from enrollment
Population: 161 patients began consolidation therapy: 81 Group 2 Regimen I and 80 Group 3 Regimen II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Event Free Survival | 0.83 Probability of survival |
| Group 3 | Event Free Survival | 0.78 Probability of survival |
Secondary
Event-free Survival for Rapid Early Response (RER) Positron Emission Tomography(PET)-1 Positive, RER PET-1 Negative
To investigate whether very early response assessment measured by Fluorodeoxyglucose-PET after 1 cycle of chemotherapy identifies a subject cohort that can be studied in future trials and that is distinguishable from currently defined RER after 2 cycles.
Time frame: 3 years from enrollment
Population: RER with positive PET-1, Event-Free Survival for RER PET-1 positive patients is compared to that of RER with negative PET-1: n=57 PET-1 positive RER patients, compared to 2 events among n=20 PET-1 negative RER patients. Two PET-1 equivocal RER patients (1 with relapse and 1 censored) are not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Event-free Survival for Rapid Early Response (RER) Positron Emission Tomography(PET)-1 Positive, RER PET-1 Negative | 0.84 Probability of survival |
| Group 3 | Event-free Survival for Rapid Early Response (RER) Positron Emission Tomography(PET)-1 Positive, RER PET-1 Negative | 0.82 Probability of survival |
| Group 5 | Event-free Survival for Rapid Early Response (RER) Positron Emission Tomography(PET)-1 Positive, RER PET-1 Negative | 0.90 Probability of survival |
Secondary
Grade 3 and 4 Non-hematologic Toxicities During Protocol Therapy
The number of patients that experience Common Terminology Criteria (CTC) Version 4 grade 3 or higher non-hematologic toxicity at any time during protocol therapy.
Time frame: During and after completion of study treatment.
Population: 165 eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Grade 3 and 4 Non-hematologic Toxicities During Protocol Therapy | 72 participants |
Secondary
Overall Survival
Survival from enrollment to death.
Time frame: At 3 years from enrollment
Population: 164 Group 1 All Patients received induction therapy. 161 patients began consolidation therapy: 81 Group 2 Regimen I and 80 Group 3 Regimen II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Overall Survival | 0.97 Probability of survival |
| Group 3 | Overall Survival | 0.97 Probability of survival |
| Group 5 | Overall Survival | 0.97 Probability of survival |
Secondary
Relapse-free Survival
A description, survival to relapse, of patterns of relapse after Doxorubicin, Bleomycin, Vincristine, Etoposide - Prednisone, Cyclophosphamide (ABVE-PC) and risk-adapted radiotherapy.
Time frame: 3 years from enrollment
Population: 161 patients began consolidation therapy: 126 patients received risk-adapted radiotherapy after consolidation therapy ABVE-PC and 35 did not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Relapse-free Survival | 0.82 Probability of survival |
| Group 3 | Relapse-free Survival | 0.83 Probability of survival |
| Group 5 | Relapse-free Survival | 0.79 Probability of survival |
Secondary
Second-event-free Survival
Second event here is defined as any relapse/progression of Hodgkin Lymphoma (HL) or a previously reported second malignant neoplasm (SMN), a new SMN, or death after a first event which can be relapse/progression of HL, SMN, biopsy-proven HL following completion of Consolidation for Slow Early Response (SER) patient, positive bilateral bone marrow biopsy following completion of Consolidation for Stage IV patient, or death. If death occurs as the 1st event, it also counts as the 2nd event.
Time frame: At 4 years from enrollment
Population: This analysis excludes n=20 patients who had protocol early terminations or deviations (n=4 Regimen I, n=12 Regimen II, and n=4 Induction only).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Second-event-free Survival | 0.94 Probability of survival |
| Group 3 | Second-event-free Survival | 0.88 Probability of survival |