A Phase I Trial of Brentuximab Vedotin in Combination with Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background:

The addition of rituximab to CHOP has improved the overall survival of patients with diffuse large B-cell lymphoma (DLBCL); however, approximately 30% of patients will relapse.  Stem cell transplantation (SCT) provides a second chance at cure, but the prognosis for patients who are not candidates for SCT or who have refractory disease is poor, and new treatments with novel agents are needed.

Brentuximab vedotin (BV), an antibody-drug conjugate that combines an anti-CD30 monoclonal antibody and the microtubule disrupting agent MMAE, has a single agent response rate (RR) of 44% (CR 17%) in CD30 (+) (Jacobsen, Blood 2015) and 27% (CR 3.7%) in CD30 (-) relapsed/refractory (rel/ref) DLBCL (Bartlett, ASH 2014). Lenalidomide (Len), an immunomodulator with multiple described mechanisms of action, has a single agent RR of 28% (CR 7%) in rel/ref DLBCL (Witzig, Ann Oncol 2011).  Notably, the Len RR was 52.9% in the subset of patients with non-germinal center-like (non-GCB) DLBCL, compared to 8.7% in GCB DLBCL (Hernandez-Ilizaliturri, Cancer 2011).  Given that both compounds have single agent activity in DLBCL and favorable, non-overlapping toxicity profiles, we hypothesized that the combination of BV and Len would be an effective and tolerable regimen in rel/ref DLBCL.

Methods:

This investigator initiated, phase I/dose expansion trial is ongoing to identify the safety and maximum tolerated dose (MTD) of the combination of BV and Len (Clinical Trials.gov NCT02086604).  Eligible patients have rel/ref de novo or transformed DLBCL after at least one prior systemic therapy and have previously received or are ineligible for SCT.  Response assessments are performed after cycles 2, 4, 6, 9 and then every six months for two years by PET/CT scan and response determined per the Revised International Working Group Response Criteria for Malignant Lymphoma 2007.  The study is in two parts, a dose-escalation portion using a 3+3 design to determine the MTD, followed by a dose-expansion cohort enrolling patients with either CD30 (+) or CD30 (-) DLBCL assessed by visual assessment using routine IHC per local laboratory.  BV is administered every 21 days and Len is dosed continuously for a maximum of 16 cycles until disease progression or unacceptable toxicity.

Results:

Eighteen patients have been enrolled to date.  The median age is 61 years (range 51-79), with 83% having an ECOG performance status of 0-1.  Median number of prior therapies is 2 (range 1-6), with 39% undergoing a previous autoSCT, and one patient a previous alloSCT. 72% of patients were refractory to their last regimen.  13 patients have CD30 (-) and 5 CD30 (+) DLBCL.  Treatment-related adverse events (AEs) occurring in >20% of patients include anemia (50%), elevated ALT (28%), hypocalcemia (22%), peripheral neuropathy (22%), neutropenia (28%), thrombocytopenia (33%), and hypokalemia (28%).  Anemia, febrile neutropenia, thrombocytopenia, and hypokalemia were the only grade 3/4 related AEs observed in >10% of patients.  Growth factors were not given during cycle 1 but were administered in 11 patients with subsequent cycles.  One patient came off study for thrombocytopenia after completing 8 cycles, while in a CR. 47% have required at least one dose reduction.   The DLTs per dose cohort are summarized in the table. The MTD of the combination is 1.2 mg/kg of BV Q21d with 20 mg Len given continuously. 

At the time of this analysis, 17 patients (1 too early) have had restaging evaluations; 7 CR (41%), 2 PR, 3 SD, and 5 PD, for an overall RR of 53%.   Five CRs occurred after C2, 1 after C6 and 1 after C8.  All responses are ongoing with a range of 5 to 35 wks.  Among the 7 CRs, 2 patients have CD30 (+) and 5 patients CD30 (-) DLBCL, 4 pts were GCB and 3 non-GCB.  Of the four patients with CD30 (-) disease categorized as GCB, two achieved a CR.

Conclusions:

This Phase I study of BV plus Len identified the MTD of the combination at BV 1.2 mg/kg Q21d with Len 20 mg/d continuously. Dose expansion cohorts of 15 patients each for CD30 (-) and CD30(+) DLBCL are currently accruing.  The predominant toxicity of the study regimen is related to cytopenias, consistent with prior experience. Although patient numbers are small, the high CR rate is intriguing.  Updated results will be presented at the meeting.

# Patients	Assigned BV Dose	Assigned Len Dose	# of DLT	DLT Toxicity
9	1.2mg/kg	20mg	1	Neutropenia
6	1.2mg/kg	25mg	2	Neutropenia, DVT
3	1.8mg/kg	25mg	2	Fatigue, Neutropenia