Phase I trial of docetaxel, carboplatin and lenalidomide in patients with advanced solid tumors

Abstract

13027 Lenalidomide (LEN) is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and different toxicity. It may interfere with the expression of angiogenic factors (TNF-alpha & IL-6), vascular endothelial growth factor (VEGF) and induce apoptosis in resistant cell lines. In preclinical trials it has shown synergy with chemotherapy. Primary objective of this study was to determine the maximum tolerated doses (MTD) of docetaxel (D) and carboplatin (Cb), combined with oral LEN. Secondary objectives were toxicity and activity. Eligibility included pathologically proven solid tumors, ≤ 2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function. Patients (Pts) with active brain metastases, or prior treatment with D, Cb, or LEN, were excluded. Treatment was continued for a maximum of 6 cycles, followed by optional continuation of LEN until disease progression or toxicity. MTD was defined as the dose level (dl) immediately lower than that producing dose limiting toxicity (DLT) during cycle 1 in ≥ 2 of 3–6 pts. DLT were ≥ grade (G) 3 non-hematological, or G 4 hematological toxicity. No growth factors were used during cycle 1. Four pts were treated at dl I, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 10 mg orally daily for 14 of a 21d cycle. Dose de-escalation was done following the first cohort due to DLT. 10 pts were treated at lower dl -1, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 of a 21d cycle. 3 of 14 pts had prior chemotherapy. Tumors included non small cell lung cancer (NSCLC) (9), and one each with thymic, rectal, apocrine carcinoma, angiosarcoma and unknown primary. The median number of cycles was 4 (range 1–6). DLTs occurred in 3 of 4 pts at dl I (G 3 electrolyte (E) (2), G 4 neutropenia (N) (1) and 1 of 10 pts at dl-1 (G 4 N). Overall G 3/4 toxicities were: N (7), thrombocytopenia (2), and E (2). There were no treatment-related deaths or irreversible toxicities. Of the evaluable pts, 5 had a partial response (5/9 NSCLC), & 5 had stable disease. D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 days of a 21 d cycle is the MTD without use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted. [Table: see text]