Tailoring therapy for metastatic malignant melanoma by sequencing the multitargeted TKI sunitinib malate (SU11248) prior to temozolomide
Authors: Marina Kleiman, Boris Gorelik, Yael Ronen, Yael Sagi, Zvia Agur
Journal: Clinical Cancer Research (2007)

B48  Introduction: Recently, a new PhaseI/II clinical trial has been announced, for evaluating a Temozolomide and Sunitinib (SU11248) combination as a first-line therapy for patients with metastatic malignant melanoma (NCT00304200; oral Temozolomide 7-day on/ 7-day off over a 28-day cycle and oral Sunitinib for 3 weeks, beginning on day 8 of each cycle). Such a schedule is corroborated by mathematical models of physiological, pathological and pharmacological processes in a patient9s body (denoted virtual cancer patient or OVP), suggesting that tumor growth is suppressed when vascularization and cellular tumor growth are decoupled. Based on this result we assumed that efficacy of the cytotoxic drug, Temozolomide, combined with the vascularization targeting drug, Sunitinib, will be improved when their administration is decoupled (denoted sequential therapy). We use the OVP for theoretically testing this assumption in melanoma patients.  Materials and Methods:OVP disease models were fine-tuned to retrieve the observed growth patterns of human melanoma. Pharmacokinetics (PK) and pharmacodynamics (PD) of Temozolomidewere modeled based on literature. Effects on human melanoma xenografts were scaled to human to model Sunitinib PK/PD. To evaluate drug efficacy in melanoma patient-population a Virtual Melanoma Patient-Population (VMPP) was created by using the OVP to generate a large set of virtual patients from experimental results of disease progression in humans. Combination schedules were virtually administered to the VMPP for simulating efficacy: (A) Temozolomide (5 days on 23 days off - the standard Temozolomide regimen) with Sunitinib (1-week on 1-week off); (B) Temozolomide (1-week on 1-week off) with Sunitinib (3-week on 1-week off - ongoing trial, NCT00304200). Combination A and B were tested for Sunitinib and Temozolomide starting on the same day (denoted parallel schedule; A1, B1), orin seven days delay (sequential schedule; A2a,A2b, B2a,B2b, respectively). Results were classified according to RECIST criteria. The VMPP was further employed for identifying factors that aid in an a priori response classification.  Results: Combination A: Simulations of both sequential schedules, A2a and A2b, resulted in higher overall response rates (43.4% and 42.1%, respectively) as compared to that of the parallel ones, A1, B1. These values were higher than those of parallel delivery, A1, and those of Temozolomide mono-therapy (34.2% and 35.6%, respectively). Combination B: Simulating the parallel schedule predicted an overall response of 21.0% whereas that of Temozolomide mono-therapy was only 13.1%. When Sunitinib treatment was initiated one week before Temozolomide (B2a), the overall response increased to 22.3%, whereas B2b suggested an overall response of 19.8% of the patients. The overall group of responders to combination B could be subdivided into patients responding well to either parallel or sequential therapy. Our analysis predicts that the initial vessel volume is significantly larger in the former sub-population.  Conclusions: Our study suggests that sequencing Sunitinib prior to Temolozomide is superior to currently accepted treatments, in terms of tumor shrinkage. We further suggest classifying patients by their vessel volume, and using the OVP for adjusting combination regimens to the specific patients.