Dose-Finding Study Of Nktr-102 In Combination With Cetuximab

e13503 Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types. [Table: see text]