*.- In vitro, tiene actividad contra los tumores sólidos, especialmente de mama, colon, líneas de células tumorales renales y de ovario.
*.- In vivo, la actividad fuerte se ha encontrado en contra de mama murino xenoinjertado, colon, gástrico, cáncer de pulmón no microcítico (CPNM), de próstata, renal y los tumores de ovario.
*********************************************
M. Hidalgo(1), V. Boni(1), A. Tolcher(2), L. Smith(2), A. Cubillo(1), D. Rasco(2), E. Calvo(1), A. Amaya(1), E. Ordoñez(1), A. Patnaik(2), S. Cerda(1), C. Coronado(3), S. Fudio(3), B. Miguel-Lillo(3), R. Prados(3), O. Ortega(3), A. Soto-Matos(3), K.P. Papadopoulos(2)
(1)START Madrid-CIOCC, Oncology, Madrid, Spain
(2)South Texas Accelerated Research Therapeutics START, Oncology, Texas, USA
(3)PharmaMar SAU, Clinical Oncology, Colmenar Viejo, Madrid, Spain
Background:
PM060184 is a new chemical entity that inhibits tubulin polymerization, causing microtubular fragmentation and mitotic arrest.
*.- In vitro, it has activity against solid tumors, especially breast, colon, renal and ovarian tumor cell lines.
*.- In vivo, strong activity has been found against murine xenografted breast, colon, gastric, non-small cell lung cancer (NSCLC), prostate, renal and ovarian tumors. Xenograft experiments have shown that schedules with fractioned daily doses maintain antitumor activity at similar or lower total doses compared to weekly schedules.
*.- In the clinical setting, weekly schedules have shown activity in solid tumors but the main dose-limiting toxicity (DLT) peripheral sensory neuropathy (PSN) occurred soon after the first infusion of Cycle 1, preventing dose escalation. Changing the schedule might overcome this toxicity.
Material and Methods:
Patients (pts) with advanced solid tumors were enrolled in a phase I, open-label, 3+3 dose-escalating clinical and pharmacokinetic (PK) study of intravenous (i.v.) PM060184 given over 10 min on 3 consecutive days repeated fortnightly (Day 1–3 and 15–17) every 28 days. Response was determined after 2 cycles by RECIST.
Results:
20 pts were distributed in 2 dose levels (DLs). Median age was 59y (range: 35–75y), 65% were female. ECOG PS was 0 in 60% (r: 0–2). Most common tumors were breast (25%), NSCLC (20%) and urothelial (20%). Median number of prior lines was 4 (r: 1–8). Pts received a median of 2 PM060184 cycles (r: 1–21). The starting DL (DL1) was 4mg/m2/day. DLTs occurred at DL2 (5mg/m2/day) in 2 pts: grade (G) 3 unilateral peripheral motor neuropathy (PMN), and G4 neutropenia ≥7 days (n=1 each); thus, DL2 was declared the maximum tolerated dose (MTD). DL1 was then expanded, and only 1 of 14 pts had DLT (G3 bowel obstruction); hence, DL1 (4mg/m2/day) was declared the recommended dose (RD). Most toxicities and abnormalities were G1 or G2. Severe drug-related toxicities were G3 and comprised bowel obstruction (15%), vomiting, tumor pain, and PMN (5% each). Severe laboratory abnormalities comprised G3/4 neutropenia (75%) and G3 thrombocytopenia (5%). No episodes of febrile neutropenia occurred.
Preliminary PK data were consistent with those from previous dosing schedules (clearance 60.0 L/h, half-life 4.7 h, and volume of distribution 169 L). No drug accumulation between dosing days was observed.
Partial response occurred in one pt with breast cancer; stable disease occurred in 3 patients with several tumor types, including ovarian cancer and NSCLC (n=1 each).
Conclusions:
The change in schedule overcame the main DLT of weekly PM060184 (PSN) and made it more manageable and safer, but did not allow for increasing total dose as expected. The new schedule was also active in solid tumors. Updated results will be presented.