Cornerstone Pharmaceuticals

A First in Class AEMD to Combat Cancer

Authors: R.C. Shepard1, K. Lee2, R. Shorr2, B. Rodriguez2, C. Maturo2, K. Gelmon3, K. Hoffman4, K. O’Donnell2; 1Raleigh/US, 2Cranbury/US, 3Vancouver/CA, 4Eastchester, Ny/US

CPI-613, an analogue of lipoic acid, is a member of a novel class of anticancer agents. These novel agents are directed to changes in the metabolic events specifically of cancer cells that control Adenosine Triphosphate (ATP) production and the generation of signal transduction molecules that regulate cell death, or growth and differentiation. While the concept of targeting cancer bioenergetics is not new, to do so with drugs that are safe has been challenging and elusive. Warburg demonstrated that tumor cells rapidly use glucose to generate ATP and lactate by cytosolic metabolism, largely independent of oxygen levels. Since then, tumor metabolism and more specifically cellular bioenergetics has been the subject of intense investigation. Clinically, the high rate of glucose uptake characteristic of many cancer types has been exploited by fluorodeoxyglucose (FDG) PET scanning. CPI-613 and related agents cause a large, rapid inhibition of mitochondrial energy metabolism selectively in tumor cells, followed by tumor cell death. Multiple components of mitochondrial energy metabolism are apparently inhibited by CPI-613, including the inactivation of the pyruvate dehydrogenase complex, the latter by hyper-phosphorylation of its regulated E1! subunit. These agents efficiently induce cell death in cultured cell lines derived from a diverse array of solid tumors by apoptosis or cancer cell specific necrosis. Tumor cell death is insensitive to many tumor cell line-specific genetic differences affecting oncogenes, cell death pathways and resistance pathways that engender dramatic differences in responses to other chemotherapeutic agents. We are now working on completing three phase 1 trials with CPI-613 for refractory cancers.

In our ongoing Phase I 002 trial, patients with solid tumors for whom there is no available therapy were treated with CPI-613 as a single agent, given IV twice weekly on a 3-weeks-on-1-week-off treatment cycle. The dose of CPI-613 followed a dose-escalation scheme with a 1-3-6 approach regarding the number of study subjects at each cohort. Additional treatment cycles were given if the subjects exhibited Stable Disease or better and in the absence of significant adverse events (AEs). To date, 18 subjects have been treated, and the dose range for CPI- 613 has been 21-588 mg/m2 in 7 cohorts. Eight subjects received one cycle of treatment at a dose range of 21- 588 mg/m2, six subjects received 2 cycles of treatment at a dose range of 84-588 mg/m2, and three subjects received 3 cycles of treatment at a dose range of 42-168 mg/m2. AEs that were considered to be possible-to definitively related to CPI-613 were of mild-to-moderate in nature, and they were: local reactions at the site of administration of CPI-613 (such as burning sensation, ache, numbness, vein irritation and phlebitis), fatigue, headache, constipation, nausea, leucopenia, facial flushing, erythema of lower extremities, and hypoglycemia. In the phase 1 portion of our ongoing Phase I/II004 trial, patients with solid tumors who were intended to be treated with Gemcitabine as a single agent were treated with Gemcitabine at 1000 mg/m2 administered once weekly plus CPI-613 at various doses administered twice weekly, both given IV on a 3-weeks-on-1-week-off treatment cycle. The dose of CPI-613 followed a dose-escalation scheme with a 3-6 approach regarding the number of study subjects at each cohort. Additional treatment cycles were given if the subjects exhibited Stable Disease or better, in the absence of significant AEs. Subjects could participate in more than one cohort, if they met eligibility criteria. To date, 11 subjects have been treated, and the dose range for CPI-613 has been 21-150 mg/m2 in 5 cohorts. Eight subjects received 1 cycle of treatment at a dose range of 21-150 mg/m2, two subjects received 3 cycles of treatment at a dose range of 21-150 mg/m2, and one subject received 5 cycles of treatment at a dose range of 21-70 mg/m2. AEs that were considered to be possibly related to CPI-613 include nausea, constipation, diarrhea, vomiting, bloating, swelling wrists, headache, elevated AST/ALT, and burning sensation in the throat. None of the AEs were of serious nature. Standardized Uptake Values (SUV) from PET were reduced or stabilized in the majority of the subjects after 1 cycle of treatment in both the 002 and 004 trials.

We have also started a single agent Phase 1 trial with CPI-613 for refractory hematological malignancies. Updated results of all trials will be presented at the ESMO Congress as well as any results if available on the phase 2 portion of the 004 trial which involves gemcitabine +/- CPI-613 for the first line treatment of locally advanced or metastatic pancreatic cancer.