Abstract 5587: Phase I study of PM00104 in combination with carboplatin in patients (pts) with advanced solid tumors
Authors: Calvo Emiliano , Gil Marta , Coronado Cinthya , Valer Anna , Duran Ignacio , Hidalgo Manuel , Pardo Beatriz , Calles Antonio , Garcia Margarita , Morelli Pia , Kahatt Carmen , Prados Raquel , Fernandez Carlos , Salazar Ramon 
Published: August 2012

Abstract
Background: PM00104 (Zalypsis®) is a synthetic alkaloid related to Jorumycin with a strong antitumor activity against a wide variety of tumor lines. In vivo data of synergism between PM00104 and a platinum compound against human gastric and bladder xenografts prompted this study. Objectives: To identify the maximum tolerated dose (MTD) and the recommended dose (RD) of C given on day (d) 1 followed by PM00104 as a 1-hour i.v. infusion on d1, every three weeks. Secondary objectives were safety and feasibility of the treatment, pharmacokinetic (PK) analysis and antitumor activity. Methods: 20 pts with metastatic or advanced solid tumors were enrolled in a 3+3 dose escalation study design. If a dose-limiting toxicity (DLT) was deemed associated with prior treatment, separate expansions into two cohorts of either heavily or mildly pretreated (HP or MP) patients were to be conducted at each dose level (DL). HP was defined as any of the following: &gt; 2 lines of chemotherapy, &gt; 6 cycles of an alkylating agent or of a C-based regimen, therapy with mitomycin-C, therapy with any nitrosourea, high-dose therapy, or irradiation of areas bearing &gt; 25% bone marrow. Results: Median age was 60 (34-73) years; male/female, 10:10; ECOG 0/1, 10:10. Most frequent cancers were colon and breast. After recruitment of 3 evaluable pts at DL1 (3 AUC C and 2 mg/m2 PM00104), 1 DLT was found in 1 HP pt. Thus, the stratification of each cohort was started. As one patient in the MP cohort also experienced a DLT, both cohorts had to be expanded to include 6 evaluable pts. No more DLTs emerged and it was decided to treat a new cohort of MP pts at DL2 (4 AUC C and 2 mg/m2 PM00104), while recruitment of HP pts was put on hold. Because 2 out of 6 MP pts at DL2 had DLTs, this dosing was declared the MTD and DL1 the RD. All 4 DLTs (HP, 1 out of 6 pt; MP, 3 out of 14 pts) consisted of grade 4 thrombocytopenia regardless of the intensity of the pretreatment. Grade 3-4 toxicities (including the aforementioned DLTs) were found in 11 pts and comprised mainly neutropenia (n=11), and thrombocytopenia (n=8), followed by nausea, vomiting, and diarrhea (all grade 3 in 1 pt), fatigue (n=1) and C-related hypersensitivity (n=1). Preliminary PK parameters showed similar characteristics to single-agent PM00104 (n=19): mean AUC, 80.53 h·ng/ml; Cmax, 29.84 ng/ml; CL, 47.80 L/h; Vdss, 630 L. Target AUC 3 (n=13) and 4 (n=6) for C were 2.6 and 3.7 mg/ml·min, respectively. No PK interactions were detected for PM00104 or for C. One pt with triple negative breast cancer achieved a partial response (time to progression, 11.6 months), and 3 pts had disease stabilizations &gt; 3 months (colorectal, head and neck, and tumor of unknown origin). Conclusion The intensity (heavy or mild) of prior antitumor treatment seems not to have a major impact in dose escalation. The RD for this schedule was 3 AUC C and 2 mg/m2 PM00104, however the combination suggests an overlapping toxicity that hampers dose escalation of either of the compounds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5587. doi:1538-7445.AM2012-5587