Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial

Abstract

Background: Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse.

Methods: In this Children's Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m² intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662.

Findings: Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m². 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths.

Interpretation: Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials.

Funding: National Institutes of Health and the St. Baldrick's Foundation.

Figure 1.. Trial Diagram.

Outcome for all patients enrolled on study. Subjects in both the Phase 1 (dose finding) and Phase 2 (complete response rate) portions are included. Subjects were treated at either dose level 1 (1.4 mg/kg/dose of Brentuximab vedotin) or dose level 2 (1.8 mg/kg/dose of Brentuximab vedotin). Results of primary outcomes and clinical outcomes are indicated.

Figure 2.. Maximum tumor volume reduction after treatment with Brentuximab vedotin and gemcitabine.

Thirty-five of 42 patients treated at the recommended phase 2 dose had centrally reviewed CT measurements of all target lesions at baseline and following the last cycle of therapy. The maximum change in tumor volume, estimated by the change from baseline in the sum of the product of the perpendicular diameters, is shown in this waterfall plot. For seven patients, tumor volume reduction could not be accurately calculated for one or more of the following reasons: Pretreatment target lesion(s) included FDG-avid non-measurable extranodal sites; pre-or post-treatment target lesions were too small to accurately measure in 2 dimensions on CT; or post treatment progression was diagnosed by clinical symptoms, physical examination, and FDG-PET scan without CT measurement.

Figure 3.. Change in serum TARC after treatment with Brentuximab vedotin and gemcitabine.

A. Serum TARC decreases significantly from baseline, within one cycle of therapy. Each circle represents an individual patient. Solid bars indicate the median value. The dotted green line indicates the upper limit of serum TARC among healthy controls, 470 pg/mL. ****, P<0·0001, compared to baseline. B. Serum TARC after treatment with Brentuximab vedotin and gemcitabine among individual patients who experienced a complete response (yellow circles) vs. remaining patients (progressive disease, partial response, stable disease; blue squares). Solid lines indicate the nonlinear fit of serum TARC data for each group. The dotted gray line indicates the upper limit of serum TARC among healthy controls, 470 pg/mL. C. Change in serum TARC after treatment with Brentuximab vedotin and gemcitabine, shown as % of baseline (100 × serum TARC at the indicated timepoint divided by baseline TARC) among patients with a complete response (open white circles) vs. remaining patients (progressive disease, partial response, stable disease; shaded squares). Lower values indicate a greater reduction from baseline. Values above 100 indicate an increase in serum TARC from baseline. Bold horizontal bars indicate median values. The dotted horizontal line indicates 10% of baseline, i.e. a 90% reduction with therapy.