NC-6004 is a polymeric micelle exhibiting sustained release of cisplatin (CDDP) and selective distribution to tumors, resulting in a lower plasma Cmax and higher AUC. Preclinical data exhibited less neuro- and nephrotoxicity with greater anti-tumor activity versus CDDP. A previous trial evaluated NC-6004 and G defining a RP2D of 90 mg/m2. Escalating doses of NC-6004/G were evaluated in this trial using a Bayesian NCRM.
Pts with refractory solid tumors were enrolled at 4 US sites. NC-6004 at 60 - 180 mg/m2 IV was given over 1 hr on day 1 with G at 1250 mg/m2 IV over 30 mins on day 1 and day 8 every 3 wks. Escalation of NC-6004 began with a single pt run-in, escalating by 15 mg/m2 until a DLT occurred at 180 mg/m2. Cohorts of 4 pts were then enrolled at each dose predicted by the NCRM model with real time updates. The MTD was defined as the dose with the greatest posterior probability of target toxicity
Among 22 pts (10 M, 12 F) enrolled, common Grade 3/4 hematologic AEs were leukopenia (67%), thrombocytopenia (55%), neutropenia (55%), lymphopenia (45%) and anemia (23%). All AEs/DLTs were manageable and resolved. Results are presented below (19/22 evaluable for response). Activity was observed in heavily pretreated pts (mean = 2.5 prior lines of therapy): tumor shrinkage in 9/19 (47%), unconfirmed PRs in 3/19 (16%) in H&N and NSCLC pts (1 who failed prior anti-PD1) and SD in 12/19 (63%). The MTD was 135 mg/m2. Of the 8 pts treated at the MTD, the average number of cycles received was 7 (2-17) and none experienced neuro-, oto- or nephrotoxicity. 50% of pts received a prior platinum. Of these, SD was observed in 9 (82%).
|Dose (mg/m2)||Best tumor shrinkage (%)||DLTs|
The nanoparticle formulation allowed greater CDDP equivalent doses. No clinically significant neuro-, oto- or nephrotoxicity was observed. The NCRM design allowed exploration of the pharmacologic zone of interest and projected a higher MTD versus a 3 + 3. This data demonstrates promising activity and tolerability of NC-6004/G in heavily pretreated pts.
Clinical trial identification
Legal entity responsible for the study
V. Subbiah: Research funding from NanoCarrier, no other relevant COI. A. Combest: Employed by PPD, no other COI. J. Griley-Olsen: Advisory consulting role for Sanofi, research funding received from GSK, Ziopharm, Kyowa Hakko Kirin, Bayer, Morphotek, Novartis, Peregrine, NanoCarrier, Genentech, Seattle Genetics, MedIummune. N. Sharma: Stock in IDRA, ICPI, Synta, Opexa, Ariad, Peregrine. Research funding from BMS, GSK, ICRM, Mirati, Novartis, IMGN, Halozyme, NanoCarrier, Astellas. I. Bobe, A. Masada: Employed by NanoCarrier. J. Balkissoon, A. Camp, D. Reitsma: Employed by PPD. L. Bazhenova: Stock in Epic Sciences. Consulting/advisory role for Heat Biologics, AstraZeneca, Pfizer, Genoptix. On speakers bureau for Genentech and Novartis. All other authors have declared no conflicts of interest.