Infinity Pharmaceuticals, Inc. announced the initiation of a randomized, double-blind phase II clinical trial to evaluate the safety and efficacy of IPI-926 compared to placebo in patients with metastatic or locally advanced, inoperable chondrosarcoma. The trial is expected to enroll over 100 patients worldwide. Chondrosarcoma is a rare, life-threatening bone cancer. There are no approved systemic treatments for this disease and, when surgery is no longer possible, chondrosarcoma is uniformly fatal.
IPI-926 is a novel, oral molecule that inhibits Smoothened, a key component of the Hedgehog pathway. In chondrosarcoma, activation of the Hedgehog pathway is believed to be involved in tumor initiation, growth, survival and metastases. Inhibiting Smoothened with IPI-926 may represent a fundamentally new approach to treating chondrosarcoma by disrupting the Hedgehog pathway and inhibiting tumor growth.
“There is a strong preclinical rationale for treating chondrosarcoma by inhibiting the Hedgehog pathway with IPI-926, and we look forward to further exploring its potential in this rigorous phase II trial,” stated Julian Adams, PhD, president of research and development at Infinity. “Chondrosarcoma has been a challenging disease to treat because of its resistance to chemotherapy and radiation. With surgery as the primary treatment option, there is a significant unmet need for a therapy for patients with metastatic or inoperable chondrosarcomas.”
Infinity also announced that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation to IPI-926 for the treatment of chondrosarcoma. Orphan Drug Designation is a status granted by the FDA under the Orphan Drug Act for a product that treats a rare disease or condition and is designed to encourage companies to develop therapies to treat rare diseases or conditions.
The companies that receive Orphan Drug Designation for their products may receive funding for certain clinical trials, clinical trial design assistance, tax credits, a waiver of Prescription Drug User Fee Act (PDUFA) fees and marketing exclusivity for up to seven years following regulatory approval.
The phase II trial is designed to compare the safety and efficacy of IPI-926, administered orally once daily, to matching placebo in patients with metastatic or locally advanced, inoperable chondrosarcoma. The primary endpoint of the trial is progression free survival. Secondary endpoints include time to progression, overall survival, overall response rate and response duration. Patients in the placebo treatment arm who experience disease progression will have the option to crossover and receive IPI-926 in an open-label arm of the trial.
Through collaboration with Drs. Jay Wunder and Ben Allman at University of Toronto, preclinical data have been generated to suggest that the Hedgehog pathway is activated in chondrosarcoma tumour cells and that inhibition of the pathway may delay tumour progression. The rationale for development of IPI-926 in chondrosarcoma will be discussed by Margaret Read, Ph.D., senior director, product development at Infinity, during a symposium session at the upcoming American Association for Cancer Research (AACR) 102nd Annual Meeting 2011. Dr Read's presentation, entitled “Direct targeting of tumor cells with Smoothened inhibitor IPI-926,” will take place during “The Hedgehog Signalling Pathway: Biology and Therapeutics” symposium on Sunday, April 3, 2011, from 1:00 p.m. — 3:00 p.m. ET.
Chondrosarcoma is a rare, life-threatening bone cancer. In the US, chondrosarcoma accounts for approximately one-third of the 2,000 cases of primary bone cancer diagnosed each year. The most common locations for chondrosarcoma tumours are the bones of the extremities and the pelvis.
Chondrosarcoma predominantly affects middle-aged and older adults, usually occurring in patients over 40 years old, with the incidence gradually increasing up to age 75. Symptoms associated depends upon the size and location of the tumour and often include pain that increases in severity over time, localized swelling and decreased range of motion in joints near the affected bone.
As chondrosarcomas are largely resistant to chemotherapy and radiotherapy, the standard therapeutic strategy is surgery. For patients with metastatic disease or with locally advanced tumours who are not candidates for surgery, no treatment has been shown to be effective and there is no established standard of care.
Malignant activation of the Hedgehog pathway occurs in a broad range of cancers through three distinct mechanisms: signalling to the tumour microenvironment, signalling to tumour progenitor cells, and signalling directly to tumour cells. IPI-926 is a small molecule that inhibits Smoothened (Smo), a key component of the Hedgehog pathway. Smo inhibition represents a significant anti-cancer opportunity for addressing a number of difficult-to-treat cancers by disrupting malignant activation of the pathway.
IPI-926 is currently being evaluated in the phase II portion of an ongoing trial in combination with gemcitabine (also known as Gemzar) in previously untreated patients with metastatic pancreatic cancer and in a phase II trial as a single agent in patients with chondrosarcoma. In a phase I trial of IPI-926 in advanced solid tumours, including a cohort of patients with basal cell carcinoma, IPI-926 has been generally well-tolerated and demonstrated evidence of clinical activity. These clinical trials build upon a robust set of supporting data that provide a strong rationale for evaluating the potential of IPI-926 for treatment across a broad range of cancers.
Infinity is an innovative drug discovery and development company seeking to discover, develop, and deliver to patients best-in-class medicines for difficult-to-treat diseases.