Anna Franklin1, Marco Zecca2, Flavio Augusto Luisi3, Gregory Song4, Ajit Suri4, E. Jane Leonard4, Franco Locatelli5
1Children's Hospital Colorado, Aurora, USA,2Fondazione IRCCS Policlinico San Matteo, Pavia, Italy,3Grupo de Apoio ao Adolescente e à Criança com Câncer, São Paulo, Brazil,4Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA,5Ospedale Pediatrico Bambino Gesù, Rome, Italy
Background: Pediatric patients (pts) with classical Hodgkin lymphoma (cHL) have improved outcomes compared with adult pts. However, many combination regimens used in treatment result in significant morbidity, including secondary malignancies, cardiovascular disease, and infections. Furthermore, serious sequelae of radiation and alkylating chemotherapy (chemo) are pronounced in younger pts, in whom growth and development are particularly active when therapy is administered. Including brentuximab vedotin (Adcetris [A]) as a component of multi-agent chemo for pediatric pts may provide clinical benefit by decreasing the need for radiotherapy following chemo, and reducing the risks of late effects associated with radiotherapy.
This phase 1/2, open-label, multicenter study will assess the feasibility of A in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in pediatric pts with advanced stage, newly diagnosed, CD30+ cHL.
Methods: Eligible pts are 5 to <18 years of age, with stage III or IV cHL, Lansky Play/Karnofsky Performance Status ≥50, and bidimensional measurable disease by radiography.
In the phase 1 portion of the study, up to 6 DLT-evaluable pts will be enrolled into a dose-confirming cohort (48 mg/m^2) with a dose-reduction cohort (36 mg/m^2) available if needed, to determine the recommended phase 2 dose (RP2D) of A using a modified 3+3 design. Forty-nine additional pts at the RP2D will then be enrolled to phase 2. A+AVD will be administered on days 1 and 15 of each 28-day cycle for up to 6 cycles.
Phase 1 primary objectives are to assess safety and tolerability, and determine RP2D. Phase 2 primary objectives include overall, complete, and partial response rates, the proportion of pts PET-negative after 2 cycles, and the proportion of pts who complete 6 cycles of therapy at RP2D. Secondary phase 2 objectives include evaluation of progression-free, event-free, and overall survival (PFS, EFS, OS), duration of response, immunogenicity, pharmacokinetics, safety, and immune reconstitution.
Response to treatment includes assessment by CT, MRI, and PET after cycle 2 day 25 and between 3–7 weeks after last dose (end of treatment). Follow-up for PFS and OS will be performed every 12 weeks for 12 months, then every 24 weeks thereafter for a maximum of 2 years from date of last pt enrolled. Phase 2 is currently open for enrollment in the USA, Italy, Singapore, Taiwan, Hong Kong, Japan, and Brazil. Clinicaltrials.gov NCT02979522.