Abstract C17: A phase I study of the combination of RO4929097 (RO) and cediranib (Cd) in patients with advanced solid tumors (PJC-004/NCI 8503).
Authors: Castonguay Vincent , Bedard Philippe L. , Chen Helen X. , Ivy Percy , Oza Amit M. , Chen Eric X. , Hirte Hal W. , McGarrity Angela , Laughlin Anne , Lovell Sonya , Wang Lisa , Siu Lillian L. , Hotte Sebastien 
Published: June 2012

Abstract
Background: The NOTCH signaling pathway has been implicated in the tumorigenesis of several human cancers. Pre-clinical models have shown that deficiency of components of the NOTCH pathway results in abnormal vascular remodelling. Upregulation of NOTCH signaling has been implicated in resistance to anti-VEGF therapy, providing a rationale for the combination of RO, a gamma secretase inhibitor that disrupts NOTCH signaling, and Cd, a VEGFR-tyrosine kinase inhibitor. The primary objective of this study is to determine safety, tolerability and the recommended phase II dose (RP2D) of the combination of RO and Cd. Secondary objectives are preliminary anti-tumor efficacy, as per RECIST v1.1 measurements, as well as pharmacokinetic and pharmacodynamic studies.
Methods: Adults with histologically confirmed solid malignancies for whom no effective conventional treatment is available are eligible. A standard 3+3 dose-escalation design is 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. Cycle 2 and onwards are 21 days, with RO given D1–3, 8–10, 15–17 and Cd given continuously D1–21. The dose-limiting toxicity (DLT) evaluation period is 42 days (cycle 1).
Results: As of August 15 2011, 11 patients (pts) have been treated at two dose-levels (DL). 7 pts were treated at DL1 (RO = 10 mg; Cd =20 mg,) and 4 were treated at DL2 (RO = 20 mg; Cd = 20 mg). Pts had received a median of 3 prior lines of treatment prior to enrolment and received a median of 3 cycles on study. The most common drug related adverse events were: diarrhea (n = 9), hypertension (n = 6), nausea (n = 5), headache (n = 4), fatigue (n = 4), liver enzyme elevation (n = 3), hypophosphatemia (n = 3), anemia (n =3) and hypothyroidism (n =3). There were 2 DLTs observed: grade 3 hypertension occurred in a pt with metastatic melanoma treated at DL1 and grade 4 aspartate aminotransferase (AST) elevation in a pt with metastatic uterine leiomyosarcoma treated at DL2. Best response was stable disease in 7 pts, progressive disease in 3 and 1 pt was inevaluable. A prolonged response of over 6 cycles was observed in 3 pts (1 pt with cholangiocarcinoma withdrew consent after completing cycle 6, 1 pt with endometrial stromal sarcoma is still on study and stable after 8 cycles, 1 pt with colon cancer progressed after completing 7 cycles). Reasons for discontinuation were progressive disease in 6 pts, toxicity in 1 pt and withdrawal of consent in 1 pt. 3 pts are still on study.
Conclusion: The combination of RO and Cd appears feasible; dose escalation is ongoing to establish the RP2D. Pharmacokinetic and pharmacodynamic studies to evaluate soluble markers of angiogenesis will be conducted. The combination of RO and Cd shows encouraging early signs of activity, with 3 of 11 patients achieving stable disease for at least 6 cycles.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C17.