Second line treatment with Ramucirumab inhibiting angiogenesis is effective as monotherapy and combined with PTX. Reg, a multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases is effective as monotherapy. Since survival remains poor new treatment strategies are needed. Therefore, we conducted a phase I dose escalation trial to determine the recommended dose for phase 2 testing (RP2D) of Reg with PTX.
Adult patients (pts) with metastatic EGAC who failed at least one prior treatment line, including a fluoropyrimidine and a platinum compound, received PTX 80 mg/m2 i.v. on day 1, 8 and 15 of a 28 day cycle, with Reg on day 1-21 in one of 3 dose levels (DL-1: 80, DL-2: 120, DL-3: 160 mg QD) in a standard 3 + 3 design. Tumor response was assessed every 2 cycles (RECIST v1.1). Pts were treated until progressive disease (PD) or unacceptable adverse events.
We enrolled 14 pts (median age 63), 8 with esophageal and 6 with gastric cancer. Pts had received 1 (n = 7) or 2 (n = 7) prior lines of palliative chemotherapy and 13 pts were evaluable for dose limiting toxicity (DLT). No DLT occurred at DL-1, 1 DLT occurred at DL-2 (grade 3 hand-foot-syndrome), and 3 DLT’s occurred in 2 pts at DL-3 (grade 3 mucositis, diarrhea and GGT elevation). RP2D of Reg was established at 120 mg. Other grade 3/4 toxicities were hypertension (29%), mucositis (21%) and non-febrile neutropenia (14%). Grade 1/2 toxicities included neuropathy (64%), hoarseness (57%), infections (50%), nausea/vomiting (43%), toxicodermia (43%), mucositis (36%), diarrhea (29%) and epistaxis (29%). Median follow up is 8.3 months with 2 pts still on treatment. Median number of cycles is 4. Reasons for stopping were PD (n = 9) or toxicity (n = 3). Best responses were PR (n = 1), SD (n = 12) and PD (n = 1). Median PFS is 4.2 and median OS 8.5 months.
RP2D of Reg combined with PTX is 120 mg QD. This combination is well tolerated and shows promising effects on survival in heavily pretreated patients. An expansion cohort to further study efficacy as well as the effect of Reg on PTX uptake and expression of downstream Reg targets in metastases is being accrued.
Clinical trial identification
EudraCT: 2014-005433-31 December 10th 2014
Legal entity responsible for the study
Academic Medical Center Amsterdam
S. Schokker: Travel expenses paid by Roche R.A.A. Mathot: Consultant for Zeria LTD, unrestricted research funding from Shire, MSD and Roche, travel/accomodation funding from Shire M.F. Bijlsma: Unrestricted research funding from Celgene, travel/accommodation funding from Biouniversa M.G.H. Van Oijen: Unrestricted research grants from Amgen, Bayer, Lilly, Merck Serono, and Roche. C.J.A. Punt: Consultant for Nordic Pharma and Servier H.W.M. van Laarhoven: Consultant for Celgene, Lilly, and Nordic, unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, and Roche All other authors have declared no conflicts of interest.