Pilot Study Using Molecular Profiling of Patients' Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers

Abstract

It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.

The SHIVA01 Trial: What Have we Learned?

“…Patients in SHIVA01 were allowed to cross over at disease progression in either arm. The propor tion of patients who had a PFS2toPFS1 ratio exceed ing 1.3 in the subgroup of patients who crossed over in SHIVA01 compared favorably with the results obtained from the von Hoff study and in MOSCATO (37 vs 27 and 33%) [13,16,18].…”

“…The results of the prospective randomized SHIVA01 did not confirm the hypotheses generated by nonran domized clinical studies, including the pilot study by von Hoff et al [13], the experience from the MD Ander son Cancer Center [14,15] and the MOSCATO trial [16]. All these three studies also belong to algorithmtesting studies in the sense they were not powered to assess the efficacy of a specific drug in a specific subgroup of patients.…”

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

“…Mood alterations observed in this phase I study of BKM120, therefore, highlight the need for close monitoring for psychiatric symptoms in patients treated with PI3K/Akt/mTOR inhibitors. Other PI3K inhibitors including GDC-0941, SAR245408, and the irreversible PI3K inhibitor PX-866 have also been shown to be well tolerated and have demonstrated signs of preliminary activity in patients with advanced solid tumors (Edelman et al 2010, Jimeno et al 2010, Von Hoff et al 2010. Common adverse events included nausea, diarrhea, vomiting, fatigue, decreased appetite, dysgeusia, and rash with GDC-0941 (Von Hoff et al 2010); skin rash with SAR245408 (Edelman et al 2010); and nausea, vomiting, and diarrhea with PX-866 (Jimeno et al 2010).…”

Evaluating the Utility of a ‘N-of-1' Precision Cancer Medicine Strategy: The Case for ‘Time-to-Subsequent-Disease Progression'

“…In this search for novel but objectively valid assessment strategies, it is relevant to note the efforts of several groups who have proposed an approach that would permit observation of the natural history of the malignant disease process in an individual patient to serve as the ‘study control' in a subsequent evaluation of the clinical utility of the molecular-based ‘targeted' therapeutic against that individual patient's cancer [2,3,4]. …”

“…In a landmark multi-center trial that helped usher in the modern precision cancer medicine era, investigators compared the PFS of patients treated with a ‘targeted' antineoplastic agent selected based on the presence of an observed molecular target in the cancer to the PFS that resulted from that individual patient's prior therapy [2]. A 30% increase (i.e., 1.3 times the previous measured time-to-disease progression) was considered a ‘positive outcome'.…”