OPTmizing Advanced Stage HodgkIn LymphoMa patIentS Therapy

Study Overview
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Brief Summary
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This is a prospective, multi-center, open-label, phase II clinical trial, aims to assess the effectiveness of the combination ACVD (Adriamycin, Cyclophosphamide, Vinblastine and Dacarbazine) and BV (Brentuximab Vedotin) in PET-2 positive advanced-stage HL patients, in order to improve the overall long-term disease control in the entire cohort of advanced-stage HL.

Detailed Description
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With the aim of reducing Blemoycin pulmonary injury (BPI) , Bleomycin was withdrawn and substituted with Cyclophosphamide (ACVD cycle) in patients with a PET-2 negative. All advanced stage HL patients will receive 2 cycles of the standard treatment ABVD and assessed with PET-2 scan. Knowing that Cyclophosphamide toxicities include cytopenias, amenorrhea and male infertility. These toxicities are mainly dependent on the total cumulative dose. Doses less than 4 g/m2 are not associated with sterility or major toxicity, doses higher than this can lead to azoospermia which was reversible in many cases therefore the cumulative dose will be used in this study is 3200 mg. Additionally, Brentuximab Vedotin has shown significant activity in relapsed refractory HL with minor toxicities. PET scan after 2 cycles of ABVD has proven to be an excellent tool to identify patients that will have long term PFS of 95% when it is negative and only progression-free survival (PFS) of less than 15% when it is positive. The primary endpoint of the study will be to assess the overall 3-Y PFS of the entire cohort of patients.

Official Title
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A Phase II, Multicenter, Open Label Study of Treatment Intensification With ACVD and Brentuximab-Vedotin in Advanced-stage Hodgkin Lymphoma Patients With a Positive Interim PET Scan After 2 ABVD Cycles

Conditions
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Classical Hodgkin Lymphoma, Hodgkin Lymphoma (Category), Hodgkin Disease, Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Adriamycin
* Drug: Cyclophosphamide
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Brentuximab Vedotin
* Drug: ABVD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All the following parameters should be met Newly diagnosed untreated ,histologically proven CD30 positive classical Hodgkin Lymphoma (cHL) Advanced stage (Stage IIB to IVB) as defined by Ann Arbor Staging System (Appendix 1) Age ≥ 14, < 60 years ECOG performance status 0-2 Written informed consent for the trial Adequate contraceptive precautions for all patients of childbearing potential All prognostic group Exclusion Criteria: Any of the following: Pregnant or lactating women. Presence of the following: Heart failure with LVEF <50% Liver enzymes, >2 ULN not attributed to Hodgkin Lymphoma. Another malignancy that is currently clinically significant or requires active intervention Early-stage disease (Stage I- IIA). Patients who are already participating to another clinical trial. Known history of HIV seropositive status ECOG performance status 3-4 Creatinin clearance <50 ml/min Prior treatment for Hodgkin Lymphoma excluding steroids Medical or psychiatric conditions compromising the patient's ability to give informed consent Patients with serious active infection Pre-existing peripheral neuropathy (grade 2 or more).

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 60 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients with PET-2 Negative Result<br>After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 negative patients will be treated with 4 cycles of ACVD (Adriamycin, Cyclophosphamide, Vinblastine And Dacarbazine) | Drug: Adriamycin<br>* 25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle.<br>* Other names: Doxorubicin;Drug: Cyclophosphamide<br>* 400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle<br>* Other names: Revimmune;Drug: Vinblastine<br>* 6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle<br>* Other names: Velbe ®;Drug: Dacarbazine<br>* 375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle<br>* Other names: DTIC;Drug: ABVD<br>* All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2)<br>* Other names: (Adriamycin, Bleomycin, Vinblastine and Dacarbazine );|
| Other: Patients with PET-2 Positive Result<br>After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 positive patients will be treated with 4 cycles of ACVD with addition of Brentuximab Vedotin | Drug: Adriamycin<br>* 25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle.<br>* Other names: Doxorubicin;Drug: Cyclophosphamide<br>* 400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle<br>* Other names: Revimmune;Drug: Vinblastine<br>* 6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle<br>* Other names: Velbe ®;Drug: Dacarbazine<br>* 375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle<br>* Other names: DTIC;Drug: Brentuximab Vedotin<br>* 1.2mg/kg Intravenous infusion, in days 1 and 15 of each 28 day cycle<br>* Other names: SGN-35;Drug: ABVD<br>* All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2)<br>* Other names: (Adriamycin, Bleomycin, Vinblastine and Dacarbazine );|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ]Progression Free Survival (PFS) | PFS is estimated from the date of diagnosis until the date of first disease progression or relapse, death for any cause. Superior overall 3 year progression-free survival of patients with PET 2 positive after 2 cycles of ABVD with ACVD and BV compared to historical control of ABVD treated patients and PET 2 negative patients with ACVD only after 2 cycles of ABVD. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Superior overall survival of PET 2 positive patients treated with ACVD + BV after 2 cycles of ABVD and PET 2 negative treated with ACVD after 2 cycles of ABVD. It is estimated from the date of diagnosis up to study completion or death, whichever came first, assessed up to 5 years. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage II B Classical Hodgkin Lymphoma, Stage III Classical Hodgkin Lymphoma, Stage IV Classical Hodgkin Lymphoma