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J. Svoboda et al.
those of classical Hodgkin lymphoma.11 Recent efforts using gene expression profiling have aimed at better defin- ing PMBCL at the molecular level and distinguishing it from other aggressive B-cell lymphomas with mediastinal presentation. In particular, the NanoString© based Lymph3Cx assay measures expression of 58 genes and allows precise identification of PMBCL cases.12
Presently, the optimal frontline management of patients with PMBCL remains controversial. Traditionally, PMBCL was included in clinical trials regarding aggressive B-cell lymphomas and regimens designed for DLBCL were found to be effective.13-17 Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) results in event-free survival rates of about 80% when followed by consolidative radiation therapy.14,16 In 2013, in a phase II trial by Dunleavy et al. including 51 PMBCL patients treated at the National Cancer Institute, dose-adjusted etoposide, prednisone, vincristine, cyclophos- phamide, and doxorubicin, plus rituximab (DA-EPOCH-R) without radiotherapy achieved an event-free survival of 93%.15 Many centers in the USA now use this dose-intense DA-EPOCH-R approach for frontline treatment of all PMBCL patients without considering any risk stratifica- tion.15 Some patients with r/r PMBCL, can be salvaged by high-dose chemotherapy with autologous stem cell trans- plant or radiation, but outcomes tend to be poor.18,19 Recently, pembrolizumab and axicabtagene ciloleucel were approved for the treatment of r/r PMBCL.20-22 While the activity of BV as monotherapy in r/r PMBCL has been dis- appointing, results of a phase II trial using nivolumab in combination with BV are very encouraging.23,24
To test the tolerability and make a preliminary assess- ment of the efficacy of BV in frontline treatment of B-cell lymphomas, we designed a phase I/II trial using BV in combination with rituximab, cyclophosphamide, doxoru- bicin, and prednisone (R-CHP) for the treatment of CD30+ PMBCL, DLBCL, and gray zone lymphoma (GZL) in adult patients (ClinicalTrials.gov identifier: NCT01994850).
Methods
Study design and patient eligibility
This multicenter, single arm, phase I/II study enrolled patients aged 18 years and over with untreated histologically confirmed CD30+ PMBCL, DLBCL, or GZL. Patients with any stage, measur- able disease, and an Eastern Cooperative Oncology Group Performance Status of 3 or less were eligible. The diagnostic biop- sy had to demonstrate at least 1% or higher expression of CD30 on the lymphoma B cells by immunohistochemistry and was assessed independently by two pathologists. Patients with active central nervous system involvement and uncontrolled systemic infections were excluded. Enrollment began in January 2014 and was completed in April 2017. The primary objective of the phase I portion was to determine the safety of the combination and the maximum tolerated dose of BV in combination with R-CHP using a de-escalation design. The primary objective of the phase II por- tion was the overall response rate at the end of systemic treatment as determined by investigator assessment using International Working Group response criteria for non-Hodgkin lymphoma.25 Secondary endpoints were 2-year progression-free survival and 2- year overall survival for all patients and by each lymphoma sub- type (PMBCL, DLBCL, and GZL).
With regard to the toxicity assessment, the study had 90% power to detect any unforeseen toxicity that occurred in 7% or
Table 1. The study regimen: brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BV-R-CHP).
Agent Route
Prednisone PO
(or equivalent) (or IV equivalent)
Rituximab IV Cyclophosphamide IV Doxorubicin IV
Dose
100 mg
375 mg/m2† 750 mg/m2 50 mg/m2
Cycle1 Cycles2-6
Days 1-5
Day 1 and 2† Day 2 Day 2
Days 1-5
Day 1
Day 1
Day 1
Day1
Brentuximabvedotin‡
IV
1.8mg/kgor1.2mg/kg Day2
Consolidative radiation following the end-of-treatment response assessment was permissible. †The rituximab dose was split into 100 mg/m2 and 275 mg/m2 on day 1 and day 2, respectively of cycle 1. ‡The maximum dose of brentuximab vedotin was 180 mg. PO: per os; IV: intravenous.
more of patients. The number of patients required for the trial was determined based on the following assumptions for an optimal two-stage design in order to detect and minimize enrollment if the overall response rate was not greater than 50% but also to mini- mize the likelihood of failing to reject the null hypothesis if the overall response rate was at least 70%. Sample size calculations for the stopping rules were based upon a type I error rate of 10% and type II error rate of 20%. The number of subjects enrolled and evaluable in the phase I cohort was defined as at least six and a maximum of 12. For the phase II cohort, using the null hypothesis of a 50% overall response rate, the study required a sample size of 20 patients. Since the phase I subjects were recruited, treated, and followed in the same way as the phase II subjects, the phase I sub- jects accrued at the phase II dose were included in the efficacy analysis.
The study was conducted in three academic centers in the USA and was run in accordance with the Declaration of Helsinki. Approval from the institutional review board of each center was obtained before initiating the study at each site. All patients signed a written informed consent form before enrollment into the trial.
Treatment protocol and response assessment
As shown in Table 1, the study treatment protocol consisted of six cycles of BV administered with the R-CHOP regimen without vincristine, including: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2 on day 1 and prednisone 100 mg (or equivalent) daily on days 1 through 5 of each 21-day cycle. For cycle 1, rituximab was split into two doses (100 mg/m2 on day 1 and 275 mg/m2 on day 2) to reduce risks of an infusion reaction to rituximab. We also aimed to separate the initial ritux- imab infusion from the first exposure to BV to avoid any potential confusion about attribution of infusion reactions. The rest of the agents were given on day 2 (cyclophosphamide, doxorubicin, BV). In cycles 2 through 6, rituximab was administered at a dose of 375 mg/m2 on day 1 together with the rest of the agents.
For phase I, the starting dose of BV was 1.8 mg/kg (maximum dose of 180 mg) with a 3+3 de-escalation design to 1.2 mg/kg (maximum dose of 120 mg) should dose-limiting toxicities occur during the first 21-day cycle. A dose-limiting toxicity was defined as any grade 3 or 4 non-hematologic toxicity requiring a dose delay over 14 days from the planned day 1 of cycle 2 or any hema- tologic toxicity not returning to baseline or ≤ grade 2 by 21 days from the planned day 1 of cycle 2. By protocol, at least six patients had to be enrolled and complete one cycle of dosing at the final recommended BV dose in phase I prior to beginning enrollment of patient in phase II. Dose modifications during cycle 2 through 6 for treatment-associated toxicity were specified in the protocol and based on the grade using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
The use of granulocyte-colony stimulating factor (G-CSF) was
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