Phase 1b/2 trial targets stroma barrier in metastatic pancreatic cancer
Pancreatic cancer has literally walled itself off for decades from efforts to find an effective drug therapy. A stromal shell, built largely of cancer-associated fibroblasts and inflammatory cells, shields most pancreas tumors from chemotherapy. The current standard of chemotherapeutic care, gemcitabine, extends survival by only a few months. From the time of diagnosis, usually at an advanced stage, about five percent of patients will live as long as five years.
Taking aim at the cancer’s armor, Brian Wolpin, MD, MPH (DFCI) just enrolled the first patient in a two-phase clinical trial to test the safety and overall survival resulting from pairing gemcitabine with a targeted inhibitor of the stroma-sustaining molecular signal from the cancer.
“Part of the reason modern medicine has been so unsuccessful at treating pancreatic cancer may be that the drugs are not getting through to the tumor,” Wolpin says. The trial will enroll patients with metastatic pancreatic cancer who have not had chemotherapy, which includes patients whose tumors recurred after surgical resection.
Objectives and importance of this trial
The phase 1b portion of the trial will define the best dose of the experimental agent, IPI-926, using an open label dose-escalation of IPI-926 in combination with gemcitabine in as many as 18 patients. Later this fall, the phase 2 portion will open for an additional 118 patients worldwide, opening at Dana-Farber Cancer Institute and Massachusetts General Hospital.
The inhibitor targets a key molecule in the hedgehog signaling pathway (Smoothened or Smo). During embryogenesis, the pathway directs the proper placement of organs and other tissues and then shuts down in most cell types. A growing body of evidence supports the hedgehog pathway as a target for treatment of several types of cancer.
Less than 10 years ago, a DF/HCC team and several other groups reported abnormal hedgehog signaling in laboratory studies of both pancreatic adenocarcinoma and the precancerous pancreas lesions, known as PanIN. Subsequent research implicated the hedgehog pathway in the maintenance of a rare subset of cells that propagate the tumor and resist chemotherapy.
Even more convincing, a mouse study published last year showed, inhibitors of the hedgehog pathway reduced pancreatic tumor growth when given with gemcitabine. The hedgehog inhibitor transiently reduced cancer-associated fibroblasts and disrupted the stromal barrier. In those mice treated with IPI-926, more chemotherapeutic drugs appeared to reach pancreas tumors and inhibit tumor growth, apparently by increasing angiogenesis in a tumor type that seems to thrive with few blood vessels.
In this trial, investigators want to learn if the inhibitor similarly will disrupt the stromal barrier around pancreas tumors in humans to allow the gemcitabine to better reach the tumor and more efficiently kill tumor cells. “This is the type of expedient progress—from the findings in the lab to testing in people—that you like to see in a disease that is notoriously hard to treat,” Wolpin says.
Beyond tumor response and patient survival, investigators have several secondary objectives to attempt to better understand how the drug works in humans. Using steady-state magnetic resonance imaging, the team will assess microvascular tumor changes in response to the inhibitor. They will also examine genomic predictors of cancer survival and tumor-based predictive markers of treatment response. In an exploratory objective, investigators will assess the health-related quality of life of patients enrolled on the study, with the overall goal of improving both quality and length of life for patients with metastatic pancreatic cancer.
A Phase 1b/2 Study Evaluating IPI-926 in Combination with Gemcitabine in Patients with Metastatic Pancreatic Cancer
Brian Wolpin, MD, MPH (DFCI)
For eligibility criteria, contact information, and sites, go to NCT01130142 on ClinicalTrials.gov.
— Carol Cruzan Morton