Combination Chemotherapy in Treating Patients with Classical Hodgkin Lymphoma
This is a phase II study using risk and response-adapted therapy for low, intermediate and high risk classical Hodgkin lymphoma. Chemotherapy regimens will be based on risk group assignment. Low-risk and intermediate- risk patients will be treated with bendamustine, etoposide, Adriamycin (doxorubicin), bleomycin, Oncovin (vincristine), vinblastine, and prednisone (BEABOVP) chemotherapy. High-risk patients will receive Adcetris (brentuximab vedotin), etoposide, prednisone and Adriamycin (doxorubicin) (AEPA) and cyclophosphamide, Adcetris (brentuximab vedotin), prednisone and Dacarbazine (DTIC) (CAPDac) chemotherapy. Residual node radiotherapy will be given at the end of all chemotherapy only to involved nodes that do not have an adequate response (AR) after 2 cycles of therapy for all risk groups.
Inclusion Criteria
- Histologically confirmed, previously untreated CD30+ classical HL. (Participants are still eligible if they received limited emergent radiation therapy [RT] or steroid therapy - maximum of 7 days if within the last month or as approved by principal investigator [PI])
- Age =< 21 years at the time of diagnosis (i.e., participants are eligible until their 22nd birthday) for low-risk and intermediate-risk. Age =< 25 years at the time of diagnosis (i.e., participants are eligible until their 26th birthday) for high-risk
- All Ann Arbor stages * Low-risk: IA, IIA (excluding patients with “E” lesions or mediastinal bulk) * Intermediate-risk: IA or IIA with “E” lesions or bulky mediastinal adenopathy (mediastinal mass to thoracic cavity ratio 33% or greater by chest radiograph) and IB, IIIA * High-risk: IIB, IIIB, IV
- Adequate renal function based on glomerular filtration rate (GFR) >= 70 ml/min/1.73m^2 OR serum creatinine adjusted for age and gender as follows: * Age: Maximum Serum Creatinine (mg/dL) * 1 to < 2 years: 0.6 (male and female) * 2 to < 6 years: 0.8 (male and female) * 6 to < 10 years: 1 (male and female) * 10 to < 13 years: 1.2 (male and female) * 13 to < 16 years: 1.5 (male), 1.4 (female) * >= 16 years: 1.7 (male), 1.4 (female)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for age
- Absolute neutrophil count (ANC) >= 1000/uL (unless secondary to Hodgkin disease diagnosis)
- Platelets >= 75,000/uL (unless secondary to Hodgkin disease diagnosis)
- Shortening fraction of >= 27% by echocardiogram or multigated acquisition scan (MUGA), unless decreased function is due to large mediastinal mass or effusion related to HL
- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 92% on room air unless secondary to a large mediastinal mass or effusion related to HL
- 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 if they received limited emergent RT or steroid therapy - maximum of 7 days if within the last month or as approved by PI
- Inadequate organ function
- High-risk participants with a history of >= grade 2 peripheral neuropathy or any active neurologic disease that would impede the ability to assess neurologic toxicities
- Inability or unwillingness of research participant or legal guardian / representative to give written informed consent
Additional locations may be listed on ClinicalTrials.gov for NCT03755804.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To evaluate the efficacy (adequate response) after 2 cycles of bendamustine, etoposide, doxorubicin hydrochloride (adriamycin), bleomycin, vincristine sulfate (Oncovin), vinblastine, prednisone (BEABOVP) (bendamustine substitution for mechlorethamine in the original Stanford V chemotherapy backbone) in low-risk and intermediate-risk patients with classical Hodgkin lymphoma (cHL).
II. To estimate the event-free survival in high-risk patients with classical Hodgkin lymphoma (cHL).
SECONDARY OBJECTIVES:
I. To describe the acute hematologic and infectious toxicities of BEABOVP (bendamustine substitution for mechlorethamine in the original Stanford V chemotherapy backbone) in patients with low-risk and intermediate-risk cHL as they relate to transfusion requirements, hematopoietic growth factor support, episodes of febrile neutropenia and hospitalizations, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
II. To describe the acute hematologic, neuropathic, and infectious toxicities of brentuximab vedotin (Adcetris), etoposide, prednisone, adriamycin (AEPA)/cyclophosphamide, Adcetris, prednisone, dacarbazine (CAPDac) in patients with high-risk cHL as they relate to transfusion requirements, hematopoietic growth factor support, episodes of grade 3 and 4 sensory or motor neuropathy, episodes of febrile neutropenia and hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
III. To evaluate patterns of failure in irradiated and non-irradiated patients.
IV. To estimate the event-free survival (EFS) functions of low risk (LR) and intermediate risk (IR) patients, and compare with those in previously published studies.
V. To estimate the response rate in high risk (HR) patients and compare with historical and literature rates.
VI. To compare response rates in LR and IR patients with historical and literature rates.
VII. To compare the EFS function of HR patients with that in previously published studies.
EXPLORATORY OBJECTIVES:
I. To evaluate the plasma pharmacokinetics of bendamustine along with predictors of its variability when used as part of BEABOVP regimen for pediatric classical Hodgkin lymphoma (HL) patients.
II. To explore the patterns and dynamics of T-cell clonality in classical Hodgkin lymphoma.
III. To explore the association between thymus and activation regulated chemokine (TARC), total metabolic tumor volume, stage, risk group and treatment response.
IV. To establish next generation sequencing of circulating tumor deoxyribonucleic acid (ctDNA) as a reliable method of non-invasively profiling tumor-associated mutations in pediatric patients with HL.
V. To determine if the kinetics of ctDNA in patients with pediatric HL during treatment are predictive of outcome.
VI. To obtain baseline testing by St. Jude Lifetime Study (SJLIFE) to allow for enhanced survivorship follow-up:
VIa. Neurologic testing.
VIb. Neurocognitive testing.
VIc. Quantitative brain imaging.
VId. Polysomnography.
VIe. Cardiovascular testing (valvular testing, arterial elasticity, carotid-femoral pulse wave velocity, orthostatic hypotension, heart rate variability).
VIf. Neuropathy screening.
VIg. Changes in body mass index composition during therapy.
OUTLINE: Patients are assigned to 1 of 3 arms.
ARM I (LOW-RISK): Patients receive BEABOVP regimen consisting of bendamustine intravenously (IV) on day 1, etoposide IV on day 15, doxorubicin hydrochloride IV on days 1 and 15, bleomycin IV on days 8 and 22, vincristine sulfate IV on days 8 and 22, vinblastine IV on days 1 and 15, and prednisone orally (PO) two or three times per day every other day of each cycle for a total of 14 days of steroids. Treatment repeats every 28 days for 2 cycles. Patients with involved nodes that do not have an adequate response (AR) after 2 cycles of therapy undergo radiation at the end of 2 cycles of chemotherapy for 3-4 weeks.
ARM II (INTERMEDIATE-RISK): Patients receive BEABOVP regimen consisting of bendamustine IV on day 1, etoposide IV on day 15, doxorubicin hydrochloride IV on days 1 and 15, bleomycin IV on days 8 and 22, vincristine sulfate IV on days 8 and 22, vinblastine IV on days 1 and 15, and prednisone orally (PO) two or three times per day every other day of each cycle for a total of 14 days of steroids for 3 cycles. However, patients with an AR at early response assessment (ERA) do not continue prednisone in cycle 3. Treatment repeats every 28 days for 3 cycles. Patients with involved nodes that do not have an AR after 2 cycles of therapy undergo radiation at the end of all chemotherapy for 3-4 weeks.
ARM III (HIGH-RISK): Patents receive AEPA regimen consisting of brentuximab vedotin IV on days 1, 8 and 15, etoposide IV on days 1-5, prednisone PO BID or TID on days 1-15, and doxorubicin hydrochloride IV on days 1 and 15. Treatment repeats every 28 days for 2 cycles. Patients then receive CAPDac regimen consisting of cyclophosphamide IV on days 1 and 8, brentuximab vedotin IV on days 1 and 8, prednisone PO BID or TID on days 1-15, and dacarbazine IV on days 1-3. Prednisone will be eliminated for cycles 3-6 in patients with an AR after ERA. Treatment repeats every 21 days for up to 4 cycles. Patients with involved nodes that do not have an AR after 2 cycles of therapy undergo radiation at the end of all chemotherapy therapy for 3-4 weeks.
In all arms, patients may receive filgrastim subcutaneously (SC) or IV if they become neutropenic until absolute neutrophil count (ANC) is acceptable. Patients may also receive dexrazoxane at the discretion of the treating investigator.
After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, then annually thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorMatthew J. Ehrhardt
- Primary IDcHOD17
- Secondary IDsNCI-2018-02924
- ClinicalTrials.gov IDNCT03755804