Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL)

Background:

Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts.

Methods:

Eligible pts were aged 5 to <18 years, with treatment-naïve stage III/IV cHL, a Lansky Play/Karnofsky Performance Status of ≥50, and bidimensional measurable disease by radiography. Pts received up to six 28-day cycles of 48 mg/m² brentuximab vedotin with AVD on days 1 and 15 of each cycle. RP2D was confirmed according to a modified 3+3 design; at least three pts were monitored for dose limiting toxicities (DLTs) during the evaluation period (cycle 1+28 days; from the first dose through study day 56), if 0/1 DLTs were observed, at least 3 additional pts were enrolled and monitored for DLTs. Toxicity was evaluated according to the NCI CTCAE, v4.03. The primary endpoints were to determine the RP2D of brentuximab vedotin in combination with AVD, and to assess treatment-emergent adverse events (AEs) and serious AEs (SAEs) from the first dose of treatment through 30 days after the last dose; pharmacokinetics (PK) was a secondary endpoint. G-CSF use was not permitted in the DLT-evaluation period.

Results:

Eight pts were enrolled (50% male), age range 6-17 years, with advanced stage cHL (stage III, n=5; IV, n=3) one of whom had bone marrow involvement. Four pts (50%) had two extra-nodal sites of involvement and four pts (50%) had no extranodal involvement. Two pts were not DLT-evaluable due to the administration of G-CSF under the original protocol. Of the six DLT-evaluable pts, all completed the 56-day DLT evaluation period with no DLTs reported. The RP2D of brentuximab vedotin was confirmed as 48 mg/m². All pts reported at least one treatment-emergent, treatment-related AE during the DLT-evaluation period. During the DLT-evaluation period, 10 grade 4 AEs were reported, all treatment-related: neutrophil count decrease or neutropenia (n=7) and white blood cell (WBC) count decrease (n=3). One pt reported a treatment-related SAE of grade 3 febrile neutropenia for a duration of 2 days. Fifteen additional grade 3 AEs included: vomiting (n=3), WBC decreased (n=4), neutrophil count decreased or neutropenia (n=7), mucositis (n=1), and headache (n=1, not treatment related). Treatment-related AEs in pts who were not DLT-evaluable included: grade 4 neutropenia (n=3), grade 3 neutrophil count decrease (n=4), and grade 3 WBC decreased (n=1); non treatment-related AEs (1 each; grade 3) were leukopenia, anemia, and aspartate aminotransferase increase. Dose delays during the DLT-evaluation period were due to neutrophil count decrease/neutropenia (n=6) and mucositis (n=1). Currently, 5 of the Phase 1 patients continue on treatment while 3 patients have completed all 6 cycles. Full Phase 1 AE data will be provided. PK concentrations were within target range and consistent with two prior brentuximab vedotin studies: Phase 3 ECHELON-1 study (C25003; NCT01712490) and C25002 pediatric study (NCT01492088).

Conclusions:

The safety, tolerability, and PK profile of brentuximab vedotin were consistent with its expected profile, and a dose of 48mg/m² was confirmed as the RP2D. Phase 2 is currently open for enrollment in the USA, Italy, Singapore, Taiwan, Hong Kong, Japan, and Brazil. Clinicaltrials.gov NCT02979522.