Phase II open-label study to assess efficacy and safety of lenalidomide in combination with cetuximab in KRAS-mutant metastatic colorectal cancer

Salvatore Siena, Eric Van Cutsem, Mingyu Li, Ulf Jungnelius, Alfredo Romano, Robert Beck, Katia Bencardino, Maria Elena Elez, Hans Prenen, Mireia Sanchis, Andrea Sartore-Bianchi, Sabine Tejpar, Anita Gandhi, Tao Shi, Josep Tabernero, Salvatore Siena, Eric Van Cutsem, Mingyu Li, Ulf Jungnelius, Alfredo Romano, Robert Beck, Katia Bencardino, Maria Elena Elez, Hans Prenen, Mireia Sanchis, Andrea Sartore-Bianchi, Sabine Tejpar, Anita Gandhi, Tao Shi, Josep Tabernero

Abstract

This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m(2) followed by weekly 250 mg/m(2)) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients.

Trial registration: Clinicaltrials.gov NCT01032291.

Conflict of interest statement

Competing Interests: Salvatore Siena is a member of advisory boards for Sanofi-Aventis, AstraZeneca, Roche, Genentech, and Amgen, and was supported by Oncologia Ca' Granda Onlus (OCGO) Fondazione. Eric Van Cutsem has received research funding from Merck-Serono, Roche and Sanofi-Aventis. Andrea Sartore-Bianchi received lecture fees from Merck Serono and Roche, is a member of advisory board for Amgen, and was supported by Oncologia Ca' Granda Onlus (OCGO) Fondazione. Josep Tabernero has participated in advisory boards for Amgen, Celgene, Genentech, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Symphogen. Katia Bencardino was supported by Oncologia Ca' Granda Onlus (OCGO) Fondazione. Mingyu Li, Ulf Jungnelius, Alfredo Romano, Robert Beck, Anita Gandhi, and Tao Shi are Celgene employees and stockholders. This study was funded by Celgene Corporation. Cetuximab was provided by Merck KGaA. Medical writing services were provided by Kim Grootscholten, MSc, of Excerpta Medica BV, funded by Celgene Corporation. Mingyu Li, Ulf Jungnelius, Alfredo Romano, Robert Beck, Anita Gandhi and Tao Shi are employed by Celgene Coporation. The Lenalidomide (Revlimid®) used in this study is a Celgene Corporation product. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Study design and enrollment in…
Figure 1. Study design and enrollment in patient groups.
Study was terminated before the expansion part of phase IIb. *One patient was randomized to the lenalidomide monotherapy group but discontinued before taking any study drug and was therefore excluded from the analyses. AE, adverse event; ITT, intention to treat; PD, progressive disease.
Figure 2. Reasons for discontinuation.
Figure 2. Reasons for discontinuation.
One patient in the lenalidomide monotherapy group of phase IIb discontinued on investigator's decision due to lack of efficacy, mentioned as “other” in the figure.

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