448PD - A phase I study of the combination of RO4929097 (RO) and cediranib (CD) in patients with advanced solid tumors (PJC-004/NCI 8503)

Date 30 September 2012
Event ESMO Congress 2012
Session Developmental therapeutics
Topics Clinical Research
Basic Scientific Principles
Presenter Solmaz Sahebjam
Authors S. Sahebjam1, P. Bedard2, V. Castonguay1, H. Chen3, S..P. Ivy3, A.M. Oza1, E.X. Chen1, H.W. Hirte4, L. Siu1, S.J. Hotte4
  • 1Drug Development Program, Medical Oncology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 2Dept Of Medical Oncology, Princess Margaret Hospital, CA-M5G 2M9 - Toronto/CA
  • 3Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda/US
  • 4Medical Oncology, Juravinski Cancer Centre, Hamilton/CA




The NOTCH signaling pathway has been implicated in the tumorigenesis and resistance to anti-VEGF therapy, providing a rationale for the combination of RO, a gamma secretase inhibitor of NOTCH signaling, and Cd, a VEGFR-tyrosine multi-kinase inhibitor.


The primary objectives of this study were to assess safety, tolerability, and recommended phase II dose (RP2D) of combination therapy in patients (pts) with advanced solid tumors. Secondary objectives were to determine preliminary anti-tumor efficacy, as per RECIST v1.1 criteria, as well as pharmacokinetic (PK) and pharmacodynamic (PD) studies. A standard 3 + 3 design was used. Cycle 1 is 42 days (D), where RO is given orally once daily D1-3, 8-10, 15-17, 22-24, 29-31, 36-38 and Cd is given orally once daily D22-42. Cycles 2 + are 21 days, with RO given D1-3, 8-10, 15-17 and Cd given D1-21. Dose-limiting toxicity (DLT) was evaluated during cycle 1 (42 days).


Twenty pts (median age of 54 [18-87]; ECOG 0-1) have been treated at 3 dose levels (DL): 7 pts at DL1 (RO = 10 mg; Cd =20 mg), 7 pts at DL2 (RO = 20 mg; Cd = 20 mg), and 6 pts at DL3 (RO = 20 mg; Cd = 30 mg). Primary tumors included: colorectal carcinoma (6), uterine sarcoma (4), renal cell carcinoma (3), and others (7). Pts received a median number of 3 cycles (range 1-20). The most common adverse events (AEs) of all grades possibly related to study drugs included (#pts): diarrhea (12), hypertension (HTN) (11), fatigue (11), and nausea (9). Grade 3+ AEs possibly related to study drugs included HTN, ALT and AST elevation, diarrhea, and hypophosphatemia. Two DLTs were observed: grade 4 HTN in DL1 which resolved after dose reduction and grade 4 AST elevation in DL2 which improved after discontinuing treatment. Of the 19 patients evaluable for response, the best response was stable disease (SD) in 12 pts and progressive disease in 7. Prolonged SD of ≥6 cycles was observed in 4 pts, including 1 pt with low grade endometrial stromal sarcoma on DL1 who remains on study after 20 cycles.


RO in combination with Cd is generally well tolerated at the DLs tested. The RP2D was defined as 20mg RO and 30mg Cd. PK data for RO and Cd, as well as PD data for circulating angiogenic factors will be presented.


All authors have declared no conflicts of interest.