Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm

Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D.

The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to<18 years, with measurable disease, who were in their second or later relapse, had failed chemotherapy, and were ineligible for, refused, or previously received stem cell transplant, received brentuximab vedotin 1.8 mg/kg by IV infusion Q3wk for up to 16 cycles until progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses will be assessed both by the investigators and independent review facility per IWG revised response criteria for malignant lymphoma; investigator responses are reported here. Blood samples for PK analysis were collected on day 1 (all cycles) immediately before and 5 minutes after the infusion and on prespecified days during cycles 1, 2, and 8.

16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle.

Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL.

Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.