Targeted Beacopp Variants In Patients With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Interim Results Of a Randomized Phase II Study

BEACOPP_escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has substantially improved the outcome for patients with advanced stage Hodgkin Lymphoma (HL) achieving an overall survival of 95% at five years. Although this certainly is the most important endpoint for these mainly young patients, there still is concern about the toxicities of this intensified chemotherapy regimen. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in HL. We aimed at improving the toxicity profile of BEACOPP_escalated while maintaining its efficacy by introducing BV (targeted BEACOPP).

Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), we replaced vincristine by BV and omitted bleomycin. In the more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) we additionally replaced procarbazine by dacarbazine to reduce gonadal toxicity, reduced the dose of etoposide to decrease risk of second acute myeloid leukemia while slightly increasing the dose of doxorubicin to maintain efficacy, and introduced dexamethasone (day 1-4) substituting for prednisone (day 1-14) to avoid immunosuppressive steroid treatment during neutropenia (please see table 1). Both regimens are administered q21d for 6 cycles. This is an ongoing randomized phase II study with the combined primary endpoint being the PET-based complete response rate after chemotherapy and the complete remission rate at final restaging including early follow-up. Here we report on the first 48 patients (planned n=100).

The study started in October 2012. 48 patients have been enrolled by June 2013 and are included in this analysis. Median age is 29 years (range 19-60 years), 60% are male, and 83% have Ann-Arbor stage III or IV disease. 14 patients have been staged after 6 cycles of chemotherapy, 6 in the BrECAPP and 8 in the BrECADD arm. Four of these patients have not reached a complete response. The 95% confidence interval for the number of treatment successes is 42% to 92% and contains both the margin for failure (65%) as well as the margin for success (85%). Regarding feasibility, 6 of 15 patients (60%) with 6 cycles of chemotherapy required no dose reductions of etoposide, cyclophosphamide or doxorubicin during the entire treatment period (corresponding number for 6 cycles of BEACOPP_escalated in the HD15 study: 50%). Hematological toxicity grade 3 or 4 of the targeted BEACOPP variants was documented in 26 of 32 patients (81%) with at least 1 cycle of chemotherapy documented (corresponding number for 4-6 cycles of BEACOPP_escalated in the GHSG HD15 study: 91.7%), and grade 3 or 4 organ toxicity in 1 patient (3%, GHSG HD15 study: 14.1%). Four patients reported symptoms of peripheral sensory neuropathy so far (grade 1 n=2; grade 2 n=2). BV was not given in the 6^th cycle in two of these patients.

These ongoing phase II trial results indicate that anti-CD30 targeted BEACOPP variants may be well feasible without compromising the efficacy associated with BEACOPP_escalated. Enrollment is ongoing and updated results will be presented.

Borchmann:Takeda: Honoraria, Research Funding. Off Label Use: Brentuximab vedotin first line Treatment of Hodgkin´s Lymphoma. Diehl:Takeda: Membership on an entity’s Board of Directors or advisory committees. Engert:Takeda: Consultancy.