Breakthrough pancreatic cancer treatment phase III trial opens in Israel

Hope is that successful trials will allow Rafael Pharmaceuticals will receive expedited FDA approval by late 2020.

By
July 18, 2019 21:56
4 minute read.
Cancer cells [illustrative]

Cancer cells [illustrative]. (photo credit: PIXABAY)

Rafael Pharmaceuticals launched a phase-3 clinical trial on Thursday for pancreatic cancer at eight sites throughout Israel. The primary investigator is Dr. Talia Golan, head of Sheba Medical Center’s Pancreatic Cancer Center.

“It’s exciting to see the growth of cancer metabolism research in the region, following the strides that [CPI-613] has been making in the United States,” Golan said.

CPI-613 is the name of the drug that is being used in the trial.

The trial kicked off at eight hospitals throughout the country, including Hillel Yaffe Medical Center, Yitzhak Shamir Medical Center, Soroka Medical Center, Sheba Medical Center, Rambam Health Care Campus, Laniado Hospital, Tel Aviv Sourasky Medical Center and Shaare Zedek Medical Center.

Starving cancer cells to death – a decades-old concept that has been repeatedly dismissed – is starting to turn a corner and make strides in cancer treatment. The concept of targeting cancer metabolism – called cell metabolic therapy – is that 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. 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,” he explained.

He said that hitting two complexes simultaneously has many advantages. One is that the carbon source the tumor is primarily dependent on does not matter; another is that evolved resistance for both complexes simultaneously is very unlikely to happen.

Pardee said CPI-613’s key differentiators are that it is highly selective on the uptake and target level in cancer cells, which leads to less toxicity to healthy cells. This allows for patients to receive extended treatment courses and for the drug to be used in combination with other drugs.

CPI-613 is being administered in this clinical trial with a chemotherapy combination of fluorouracil, leucovorin, irinotecan and oxaliplatin, called FOLFIRINOX.

THE TRIAL is a randomized pivotal phase-3 trial. Some 250 people will receive chemotherapy plus a full dose of CPI-613, while another 250 people will receive just the chemo. His hope is that by the end of September 2020, the results will prove the efficacy of the treatment and the company will be able to apply and receive expedited approval by the FDA. If not, he said that the earliest the drug would be on the market from this trial would be October 2021.

The 613 in CPI-613 stands for the 613 mitzvot (commandments) of the Torah, according to Sanjeev Luther, Rafael’s president and CEO. Luther is in Israel from July 16 to 19.

“To save a life is to save a universe,” he said, citing the Talmudic concept.

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.

“With pancreatic cancer being the fourth leading cause of cancer death in Israel, we wanted to expand the trial to a region in need,” said Howard Jonas, chairman of Rafael.

Luther said that the company has already done “compassionate work” in Israel – using CPI-613 to treat patients who are seriously ill with pancreatic cancer and where no other treatments have worked or are available.

According to Dr. Philip A. Philip, professor of medicine and oncology at the Barbara Ann Karmanos Cancer Institute at Wayne State University, pancreatic cancer is also a major concern in the US; it is estimated that by 2030, the disease will be the second leading cause of cancer death. Philip is in Israel for the launch of the phase-3 trial. He explained that one of the reasons pancreatic cancer is so deadly is that there are still no early detection tests, which means that the majority of patients discover they have it when it already at an advanced stage.

“Every day, more than 1,200 people around the world receive a pancreatic cancer diagnosis, and our trial brings hope as the only phase-3 trial in metastatic pancreatic cancer,” said Luther. He noted that the expansion of the trial into Israel is the “first step in bringing our commitment to developing treatments for patients with significant unmet medical needs to a global level.”

Luther is using his time in the country to meet with medical providers at the start of the trial. On Thursday, representatives from the eight hospitals, clinical trial nurses and pharmacists came together for a half day of training.

Rafael is conducting two phase-3 clinical trials – for pancreatic cancer and for acute myeloid leukemia – as well as a phase-2 trial in Burkitt’s lymphoma for CPI-613.


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