Infinity launches trial of IPI-504 vs. GIST

Early clinical trial will see if novel treatment addresses Gleevec resistance

Editor's note: In the November newsletter of the Life Raft Group, Science Coordinator Jerry Call wrote about the development of a new inhibitor that targets the protein that stablizes KIT, the driver of GIST. On Jan. 10, the maker of this new inhibitor announced it has started clinical trials for GIST treatment.

CAMBRIDGE, Mass. (PRNewswire) — Infinity Pharmaceuticals Inc. has announced another early clinical trial of IPI-504, the company’s heat shock protein 90 (Hsp90) inhibitor and lead investigational anti-cancer agent. The study will evaluate the safety, pharmacokinetic profile and potential effectiveness of IPI-504 in patients with gastrointestinal stromal tumors (GIST) whose cancer is resistant to Gleevec (imatinib mesylate).

This open-label, dose-escalation phase I clinical trial of IPI-504 is being conducted at Dana-Farber Cancer Institute in Boston, under the direction of Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology.

“We are very excited about this phase I clinical trial of IPI-504 in patients with refractory GIST as it pioneers a novel treatment paradigm for these patients with an unmet medical need,” said Demetri. “Previous treatments for GIST have been dramatically effective but over time we have seen the emergence of resistance to targeted therapy such as Gleevec, and this leads to progression of the cancer. IPI-504 has an important new mechanism of action with the potential to treat patients with resistant disease.

“Even more importantly,” Demetri noted, “GIST may serve as a bellwether of activity, since the mechanism of action of IPI-504 may also apply to patients with breast cancer resistant to Herceptin, lung cancer resistant to Tarceva, and multiple myeloma resistant to VELCADE.”

In preclinical work performed with Dr. Jonathan Fletcher’s lab at Brigham and Women’s Hospital in Boston, Infinity Pharmaceuticals has demonstrated that IPI-504 kills GIST cancer cells as effectively as Gleevec in vitro (in the test tube). Moreover, when cancer cells have mutations that make them resistant to Gleevec, IPI-504 kills these cells with even greater effectiveness. The more mutated the GIST cells become, the more sensitive they are to IPI-504.

These data were presented in November at the molecular targeting meeting held in Philadelphia by the National Cancer Institute, the American Association of Cancer Researchers, and the European Organization for Research and Treatment of Cancer.

“The initiation of this additional phase I trial of IPI-504 represents an important milestone for our lead product candidate and a significant validation of our strategy to discover and develop therapies that attack cancer cell survival mechanisms,” said Julian Adams, Ph.D., Infinity’s chief scientific officer. “We are delighted to be collaborating with Dr. Demetri and his outstanding team of scientists and caregivers at the Dana-Farber on this study.”

ABOUT IPI-504

IPI-504 is Infinity’s novel anti-cancer agent that potently and selectively inhibits Hsp90. IPI-504 has broad anti-tumor activity in animal models as a single agent as well as in combination with existing anti-cancer therapeutics.

Research shows that inhibition of Hsp90 forces cancer cells to “commit suicide” through a process of programmed cell death or apoptosis. In addition to Gleevec-resistant GIST, IPI-504 is currently undergoing evaluation as a monotherapy for relapsed or relapsed, refractory multiple myeloma in a multi-center, phase I, dose-escalation trial. Interim data from the first phase I trial of IPI-504 was presented at the annual meeting of the American Society of Hematology held Dec. 10-13 in Atlanta, Ga.

ABOUT GIST

The American Cancer Society reports that GIST is the most frequent form of gastrointestinal sarcoma, a life-threatening disease highly resistant to traditional chemotherapy or radiation treatment. The ACS estimates that between 4,500 and 6,000 Americans develop GIST each year.

In a majority of cases, specific mutations in cellular signaling enzymes called KIT or PDGFRA allow the survival signal of the mutated cancer cell to be switched “on” all the time. Both KIT and PDGFRA are signaling enzymes that belong to the class of tyrosine kinases and are responsible for sending growth and survival signals inside the cell.

The mutations in KIT or PDGFRA allow the GIST cells to grow uncontrollably and spread (metastasize). The initial identification of tyrosine kinase mutations in GIST has allowed for the development of targeted kinase inhibitors, such as Gleevec, as an effective treatment of the disease.

However, over time new kinase mutations evolve so that the targeted kinase inhibiting drugs are no longer effective at treating the disease.