A phase I study of the safety and pharmacokinetics (PK) of XMT-1001 given as an intravenous (IV) infusion once every three weeks to patients with advanced solid tumors

Abstract

2574 Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro- drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 demonstrated an improved therapeutic window as compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT- 1001 administered as an IV infusion once every 3 weeks. The objectives of this phase I study are to determine the maximum tolerated dose and to assess safety and PK of XMT-1001. Initially 3 patients (pts) are entered at each dose level. The cohort is expanded to 6 pts if a patient experiences a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Thirty two pts with refractory solid tumors have received 82 cycles of XMT-1001 at 8 dose levels ranging from 1.0 to 20.5 mg CPT equivalents/m2. Two pts had Gr 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. After the introduction of new clinical trial material with an improved formulation, to date, no infusion reactions suggestive of hypersensitivity have occurred (11 patients, 22 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Myelosuppression was observed in 3 pts treated at 15.4 mg CPT equiv/m2 dose level. Stable disease was observed in 7 pts with the following tumor types and dose levels expressed in mg CPT equivalents/m2: NSCLC (1.0 mg/m2, 6 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), and colon (15.4 mg/m2, 6 wks). PK demonstrates dose proportional increases in plasma levels of XMT-1001 (conjugated CPT) and confirms the formation of its expected release products. To date, levels of free CPT in urine are low. Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease was observed in patients with refractory tumors. [Table: see text]