Adcetris (Brentuximab Vedotin), Combination Chemotherapy, and Radiation Therapy in Treating Younger Patients With Stage IIB, IIIB and IV Hodgkin Lymphoma

Study Overview
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Brief Summary
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This pilot phase II trial studies how well giving brentuximab vedotin, combination chemotherapy, and radiation therapy works in treating younger patients with stage IIB, IIIB or IV Hodgkin lymphoma. Monoclonal antibodies, such as brentuximab vedotin, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer killing substances to them. Drugs used in chemotherapy, such as etoposide, prednisone, doxorubicin hydrochloride, cyclophosphamide, and dacarbazine, 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 brentuximab vedotin with combination chemotherapy may kill more cancer cells and reduce the need for radiation therapy.

Detailed Description
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PRIMARY OBJECTIVES: To evaluate the safety of brentuximab vedotin, etoposide, prednisone and doxorubicin hydrochloride (AEPA)/cyclophosphamide, brentuximab vedotin, prednisone and dacarbazine (CAPDac), as well as the efficacy (early complete response) after 2 cycles of AEPA chemotherapy in high risk patients with Hodgkin lymphoma (HL). To compare the event-free survival in high risk HL patients treated with AEPA/CAPDac to the historical control unfavorable risk 2 arm (UR2) of the St. Jude HOD99 study. SECONDARY OBJECTIVES: To estimate the number of patients with adequate response according to the definitions in the Euro-Net C1 after 2 cycles of AEPA. To evaluate the safety of Adcetris (brentuximab vedotin) in the AEPA/CAPDac regimen in children with high risk HL. To describe acute hematologic, neuropathic, and infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. To study the association between local failure and original lymph node region and volume of radiation (patterns of treatment failure). To assess patient-reported symptoms and health-related quality of life in children with high risk HL compared to those treated on the unfavorable treatment arm of the St. Jude HOD99 study. OUTLINE: AEPA REGIMEN: Patients receive brentuximab vedotin on days 1, 8, and 15, etoposide on days 1 to 5, prednisone three times daily (TID) on days 1 to 15, and doxorubicin hydrochloride on days 1 and 15. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. CAPDac REGIMEN: Patients receive cyclophosphamide on days 1 and 8, brentuximab vedotin days 1 and 8, prednisone TID on days 1 to 15, and dacarbazine on days 1 to 3. Treatment repeats every 21-28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Beginning 2-3 weeks after CAPDac chemotherapy, patients with lymph nodes that do not go into remission after 2 courses of AEPA chemotherapy undergo radiation therapy daily, 5 days a week for 3-4 weeks. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 2 years, and then annually for 5 years.

Official Title
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Adcetris (Brentuximab Vedotin), Substituting Vincristine in the OEPA/COPDac Regimen [Treatment Group 3 (TG3) of Euro-Net C1] With Involved Node Radiation Therapy for High Risk Pediatric Hodgkin Lymphoma (HL)

Conditions
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Stage III Childhood Hodgkin Lymphoma, Stage IV Childhood Hodgkin Lymphoma, Stage II Childhood Hodgkin Lymphoma

Intervention / Treatment
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* Drug: brentuximab vedotin
* Drug: etoposide
* Drug: prednisone
* Drug: doxorubicin
* Drug: cyclophosphamide
* Drug: Dacarbazine(R)
* Drug: filgrastim
* Other: quality of life assessment
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, previously untreated CD30+ classical Hodgkin Lymphoma (HL). (Participants receiving limited emergent radiation therapy (RT) or steroid therapy - maximum of 7 days - because of cardiopulmonary decompensation or spinal cord compression will be eligible for protocol enrollment). Age ≤ 18 years at the time of enrollment (i.e., participants are eligible until their 19th birthday). Ann Arbor stage IIB, IIIB, IVA, or IVB. Adequate renal function based on GFR ≥ 70 ml/min/1.73m^2 or serum creatinine adjusted for age and gender. Adequate hepatic function (total bilirubin < 1.5 x ULN for age, and SGOT/SGPT < 2.5 x ULN for age). Female participant who is post-menarchal must have a negative urine or serum pregnancy test. Female or male participant of reproductive potential must agree to use an effective contraceptive method throughout duration of study treatment. Exclusion Criteria: CD30 negative HL. Has received prior therapy for Hodgkin lymphoma, except as noted above. Inadequate organ function as described above. Inability or unwillingness of research participant or legal guardian / representative to give written informed consent.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Participants receive AEPA regimen (brentuximab vedotin, etoposide, prednisone, doxorubicin), and CAPDac regimen (cyclophosphamide, brentuximab vedotin, prednisone, dacarbazine(R)). Filgrastim may be given as clinically indicated. For those with lymph nodes that do not go into remission after 2 courses of AEPA chemotherapy, radiation therapy will be given. Some participants may volunteer to complete the quality of life assessment. | Drug: brentuximab vedotin<br>* Given intravenously (IV).<br>* Other names: Adcetris(R);Drug: etoposide<br>* Given IV.<br>* Other names: Vepesid(R);Drug: prednisone<br>* Given orally (PO).<br>* Other names: prednisolone;Drug: doxorubicin<br>* Given IV.<br>* Other names: Adriamycin(R);Drug: cyclophosphamide<br>* Given IV.<br>* Other names: Cytoxan(R);Drug: Dacarbazine(R)<br>* Given IV.<br>* Other names: Dimethyl Triazeno Imidazole Carboximide (DTIC);Drug: filgrastim<br>* Given subcutaneously (SQ) as clinically indicated.<br>* Other names: Neupogen(R);Other: quality of life assessment<br>* Quality of life assessment will be done at initial clinical visit, and during chemotherapy, completion of therapy, then at 1 year, 2 years and 5 years. It should take no more than 15-20 minutes to complete. Participation is voluntary by participating institution and by participant.<br>Radiation: radiation therapy<br>* At the end of chemotherapy and recovery of blood counts, radiotherapy will be given to any involved nodes (if any) that are not in complete remission.<br>* Other names: radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Initially Enrolled Patients That Have a Complete Response at Early Response Assessment Compared to Historical Control | To determine the efficacy of 2 cycles of AEPA chemotherapy, the response rate for the first 32 evaluable participants enrolled was evaluated. If it shown efficacy (detect 20% increase complete rate with 80% power and 5% type I error compared with the proportion of historical control of HOD99 (NCT00145600) unfavorable risk patients had complete rate at week 8 of 17% (24/141), the response results will be reported in a national/international meeting and the study will continue to enroll for a total of 77 patients. | After the first 2 cycles of chemotherapy (at approximately 2 months after enrollment) | 
| Percentage of Initially Enrolled Patients That Have a Complete Response at Early Response Assessment Compared to Historical Control | To determine the efficacy of 2 cycles of AEPA chemotherapy, the response rate for the first 32 evaluable participants enrolled was evaluated. If it shown efficacy (detect 20% increase complete rate with 80% power and 5% type I error compared with the proportion of historical control of HOD99 unfavorable risk patients had complete rate at week 8 of 17% (24/141), the response results will be reported in a national/international meeting and the study will continue to enroll for a total of 77 patients. | After the first 2 cycles of chemotherapy (at approximately 2 months after enrollment) | 
| Complete Response Rate Estimate for All Evaluable Participants | To evaluate the safety of AEPA/CAPDac, as well as the efficacy (early complete response) after 2 cycles of AEPA chemotherapy in high-risk patients with Hodgkin Lymphoma (HL). | After the first 2 cycles of chemotherapy (at 2 months from enrollment for each participant) | 
| Comparison of the Event-free (EFS) Survival in High Risk HL Patients Treated With AEPA/CAPDac to the Historical Control HOD99 Unfavorable Risk 2 Arm (UR2). | Event-free survival (EFS) is defined as the probability of survival between the date of study enrollment to the date of first event (relapsed or progressive disease, second malignancy, or death from any cause) or to last follow-up for patients without events. Under the proportional hazard model assumption, the two-sample log-rank test used to compare the EFS between HLHR13 and historical control of HOD99 unfavorable risk 2 arm (UR2). | From start of therapy to 2 years after completion of therapy (up to 3 years after study enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Failure Rate in High Risk HL Patients Treated With AEPA/CAPDac. | The local failure rate within the high-risk HL participants treated with AEPA/CAPDac will be estimated with a 95% confidence interval using appropriate methods (e.g., estimate cumulative incidence in the presence of competing risks). | From start of therapy to 2 years after completion of therapy (up to 3 years after study enrollment) | 
| Descriptive of Hematological Adverse Events | To describe acute hematologic, neuropathic, and infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | From enrollment to end of therapy (approximately 8 months) | 
| Descriptive of Infectious Adverse Events | To describe acute hematologic, neuropathic, and infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | From enrollment to end of therapy (approximately 8 months) | 
| Descriptive of Neuropathic Adverse Events | To describe acute hematologic, neuropathic, and infectious toxicities as they relate to transfusion requirements, growth factor support, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | From enrollment to end of therapy (approximately 8 months) | 
| To Assess the Patient Reported Symptoms and Health-related Quality of Life in Children With High Risk HL Compared to Those Treated on the Unfavorable HOD99 Treatment Arm (UR2) at Multiple Time Points. (PedsQL v.3.0) | Assess and compare the patient reported quality of life and symptom distress to that of patients treated on the HOD99 unfavorable risk 2 arm (UR2) using the Peds Quality of Life version 3. The QL scoring is a 5-point Likert scale from 0 (never) to 4 (almost always). Scores are transformed on a scale from 0 to 100. Items are reverse scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. Total score is the sum of all items over the number of items answered on all scales. For both the total score and subscales the range is 0-100. The total score is the sum of all items from each subscale, over the number of items answered on the scale. The total score is the sum of all items on the scale over the number of items answer. If >50% of the items are missing the score should not be computed. If >50% are completed, impute the mean of the completed items in a scale. The Higher the score the better quality of life. | At Diagnosis (baseline) (T1), completion of 2 cycles of chemotherapy (approximately 2 months) (T2), completion of 4 cycles of chemotherapy (approximately 4 months) (T3), completion of radiation (approximately 8 months) (T4) | 
| To Assess the Patient Reported Symptoms and Health-related Quality of Life in Children With High Risk HL Compared to Those Treated on the Unfavorable HOD99 Treatment Arm (UR2) at Multiple Time Points. (PedsQL v.4.0) | Assess and compare the patient reported quality of life and symptom distress to that of patients treated on the HOD99 unfavorable risk 2 arm (UR2) using the Peds Quality of Life version 4. The QL scoring is a 5-point Likert scale from 0 (never) to 4 (almost always). Scores are transformed on a scale from 0 to 100. Items are reverse scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. Total score is the sum of all items over the number of items answered on all scales. For both the total score and subscales the range is 0-100. The total score is the sum of all items from each subscale, over the number of items answered on the scale. The total score is the sum of all items on the scale over the number of items answer. If >50% of the items are missing the score should not be computed. If >50% are completed, impute the mean of the completed items in a scale. The Higher the score the better quality of life. | At Diagnosis (baseline) (T1), completion of 2 cycles of chemotherapy (approximately 2 months) (T2), completion of 4 cycles of chemotherapy (approximately 4 months) (T3), completion of radiation (approximately 8 months) (T4) | 
| Response Rate | Response compared to the Euro-Net C1 after 2 cycles of AEPA. | after the first 2 cycles of chemotherapy (at approximately 2 months after enrollment) | 
| Patient Quality of Life (QoL) | Patient QOL will be measured at multiple time points to assess the patient's physical emotional, social, and school functioning. Time references below are to the approximate time of measurement after start of therapy (baseline). Each course is approximately 1 month: At Diagnosis (baseline) (T1), Course 1 Day 8 (T2), Course 1 Day 15 (T3), Course 2 Day 1 (T4), Course 2 Day 15 (T5), Course 3 Day 1 (T6) Course 3 Day 8 (T7), Course 6 Day 1 (T8) and Course 6 Day 8 (T9), 4-6 weeks after chemotherapy (approximately 7-8 months) for those without radiation (T10), 4-6 weeks after radiation (approximately 9-10 months) (T11), 1 year off therapy (approximately 1 year and 8 months (T12), 2 years off therapy (approximately 2 years and 8 months) (T13), and 5 years off therapy (approximately 5 years and 8 months) (T14). | At various time points from diagnosis through 5 years off therapy. (up to approximately 6 years from enrollment) | 
| Parent Proxy Quality of Life (QoL) | Parent's assessment of child's physical, emotional, social and school functioning over multiple time points. Time references below are to the approximate time of measurement after start of therapy (baseline). Each course is approximately 1 month: At Diagnosis (baseline) (T1), Course 1 Day 8 (T2), Course 1 Day 15 (T3), Course 2 Day 1 (T4), Course 2 Day 15 (T5), Course 3 Day 1 (T6) Course 3 Day 8 (T7), Course 6 Day 1 (T8) and Course 6 Day 8 (T9), 4-6 weeks after chemotherapy (approximately 7-8 months) for those without radiation (T10), 4-6 weeks after radiation (approximately 9-10 months) (T11), 1 year off therapy (approximately 1 year and 8 months (T12), 2 years off therapy (approximately 2 years and 8 months) (T13), and 5 years off therapy (approximately 5 years and 8 months) (T14). | At various time points from diagnosis through 5 years off therapy. (up to approximately 6 years from enrollment) | 
| Correlation of Agreement Between Patient QoL and Parent Proxy QoL at Multiple Time Points | Assess and compare the patient reported and parent proxy quality of life across multiple time points. Time references below are to the approximate time of measurement after start of therapy (baseline). Each course is approximately 1 month: At Diagnosis (baseline) (T1), Course 1 Day 8 (T2), Course 1 Day 15 (T3), Course 2 Day 1 (T4), Course 2 Day 15 (T5), Course 3 Day 1 (T6) Course 3 Day 8 (T7), Course 6 Day 1 (T8) and Course 6 Day 8 (T9), 4-6 weeks after chemotherapy (approximately 7-8 months) for those without radiation (T10), 4-6 weeks after radiation (approximately 9-10 months) (T11), 1 year off therapy (approximately 1 year and 8 months (T12), 2 years off therapy (approximately 2 years and 8 months) (T13), and 5 years off therapy (approximately 5 years and 8 months) (T14). | At various time points from diagnosis through 5 years off therapy. (up to approximately 6 years from enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric cancer, Hodgkin lymphoma, Targeted therapy, Frontline therapy, Brentuximab vedotin, Quality of Life, OEPA/COPDac