Pancreatic cancer study hits benchmark, despite virus

Overall survival rate increased from 11.1 months to 19.9 in some trials

Rafael Pharmaceuticals has reached 85% of the 500-patient enrollment needed for the pivotal phase-3 clinical trial of its metastatic pancreatic cancer treatment despite the coronavirus crisis, the company told The Jerusalem Post. In addition, it has launched a COVID-19 task force to ensure that appropriate medical centers hosting the trials are implementing safety measures so that testing could continue.

Many of the participating patients are from Israel, according to Sanjeev Luther, Rafael’s president and CEO. He explained that the trial is evaluating the efficacy and safety of the company’s lead compound CPI-613 in combination with modified FOLFIRINOX as a first-line therapy.

The 613 in CPI-613 stands for the 613 mitzvot (commandments) of the Torah, he said. The company’s chairman is Jewish philanthropist Howard Jonas, who chose the name Rafael because “God heals,” Luther said.

Pancreatic cancer is currently the third leading cause of cancer death in the US (the seventh worldwide) and is expected to become the second leading cause after 2020, according to multiple studies.

In Israel, instances of pancreatic cancer have spiked in the last five years. As per the National Cancer Registry, 888 patients were diagnosed with the cancer in 2013. The number of incidents reached 1,024 in 2018 and is expected to be 1,086 by 2020.

Moreover, its prognosis is grim, with the five-year survival rate being only 6% to 8%, according to a report by the New England Journal of Medicine.

In July 2019, Rafael launched its phase-3 clinical trial for its pancreatic cancer treatment at seven sites throughout Israel, led by primary investigator Dr. Talia Golan, head of Sheba Medical Center’s Pancreatic Cancer Center. It is a global randomized pivotal phase-3 trial. Some 250 people will receive modified chemotherapy plus CPI-613, while another 250 people will receive just the chemo.

Luther said that the company is expected to get it’s interim data by the end of the year. He told the Post that with the rapid enrollment, the study is on schedule.

Literature provided by the company showed that since 1997, the median overall survival following standard front-line therapies for metastatic pancreatic cancer has increased from 6.8 months using gemcitabine to 11.1 months using FOLFIRINOX.

CPI-613 exhibited synergy with FOLFIRINOX in pre-clinical and clinical studies. A phase 1 clinical study of CPI-613 in combination with modified FOLFIRINOX exhibited excellent safety and efficacy profiles in patients with first-line metastatic pancreatic cancer, showing a median overall survival of 19.9 months and a median progression-free survival of 9.9 months.

Now, Rafael is investigating CPI-613 in the phase3 trial, with the immediate objective of improving the quality of life of patients with pancreatic cancer.

ISRAELI HOSPITALS participating in the trial include Hillel Yaffe Medical Center, Yitzhak Shamir Medical Center, Sheba Medical Center, Rambam Health Care Campus, Laniado Hospital, Tel Aviv Sourasky Medical Center and Shaare Zedek Medical Center.

To ensure that the trial was not delayed during the COVID-19 pandemic, Luther told the Post that “we have established a COVID-19 task force to closely monitor our clinical trials and make changes as needed.”

The task force reviewed all clinical trials and collected data relevant to the patients’ study treatments and schedules.

The concept: Tumors could be treated by disrupting their source of energy, hindering cancer cells from growing and spreading.

Specifically, CPI-613 is a small molecule lipoate analogue, explained Rafael’s chief medical officer Tim Pardee in a previous interview. This molecule mimics the catalytic intermediate of two key tricarboxylic acid (TCA) cycle enzymes: Pyruvate dehydrogenase and alpha-Ketoglutaric dehydrogenase. CPI-613 activates the regulatory elements around each of these complexes.

The TCA cycle is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA – derived from carbohydrates, fats and proteins – into adenosine triphosphate and carbon dioxide.

“What it does is feed misinformation to these regulatory elements, making them feel that there is too much carbon flow through both of these complexes, causing them to be inhibited,” Pardee said. “It simultaneously inhibits both complexes, so tumor cells that are primarily driven by glucose cannot utilize glucose in the TCA cycle. Tumor cells that are primarily driven by glutamine usage cannot use glutamine-derived carbons in the TCA cycle. And, importantly, tumors cannot switch from one source to the other in the presence of CPI-613.”

As the trial gets closer to completion, Rafael is starting to test its concept for extending and enhancing the lives of patients with gastro-intestinal (GI) cancers, since CPI-613 exhibited synergy with FOLFIRINOX – the standard of care for several GI cancers from colorectal and esophageal to biliary.

“We are trying to solve the pancreatic cancer puzzle,” Luther said. “The trials will speak for themselves.”

Rafael hopes to have the treatment from this trial approved and on the market by late 2021.