NCIC IND.190: A phase I trial of MK-0646 in combination with cisplatin and etoposide in extensive-stage small cell lung cancer (ES SCLC).
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7093 Background: Increased serum levels of insulin like growth factor (IGF), plus overexpression of the IGF-receptor (IGFR) are implicated in SCLC cell growth and proliferation, making suppression of the IGFR a potential therapeutic target. MK-0646 is a monoclonal antibody directed against the IGFR. The aim of this study was to determine the recommended phase II dose (RP2D) of cisplatin, etoposide plus MK-0646. Methods: We conducted a phase I study of two dose levels of MK-0646 (DL1 5mg/kg, DL2 10mg/kg IV weekly) in combination with cisplatin (25mg/m2) and etoposide (100mg/m2) IV D1-3, q21d, for patients with chemotherapy-naive ES SCLC, PS 0-2. Patients with treated stable brain metastases were eligible. Patients completing 4-6 cycles of combination therapy could continue single agent MK-0646 until disease progression. Primary outcome was determination of the RP2D. Secondary outcomes included ORR (RECIST 1.1), and toxicity (CTCAEv3). Results: A total of 12 patients were treated (DL1 – 3, DL2 – 9). The median age was 63 years (48-70), with 6 males and 6 females. Most subjects were good ECOG PS (PS 1 – 8, PS 2 – 4) and had 4 or more sites of disease (n=8). No DLTs were observed in DL1 or DL2. In an expanded DL2 cohort, 1 patient died from neutropenic sepsis during cycle 1. The median number of treatment cycles of chemotherapy was 4 (DL1) or 5 (DL2) and MK-0646 was 6 (DL1&2). Dose delays were observed for chemotherapy (DL1 - 2, DL2 – 6) and MK-0646 (DL1 – 3, DL2 – 7). The confirmed ORR was 72.7% (PR 8, SD 2, PD 1, non-evaluable 1). Grade ≥3 toxicities (any cycle) occurring in more than 1 patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in 1 of 3 (DL1) and 5 of 9 (DL2). Eight SAEs were observed in 3 patients (thrombosis, febrile neutropenia, infection, syncope, fatigue 2, dyspnea, back pain). Conclusions: MK-0646 can be combined at full dose with standard doses of cisplatin and etoposide (25mg/m2 and 100mg/m2 D1-3) with a RP2D of MK-0646 10mg/kg/week. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which appears dose dependent.
