New Drug For Blood-Borne Cancer Moves Into Multi-Center Testing

This investigational drug, named PS-341 and made by Millennium Pharmaceuticals, is a proteasome inhibitor that interferes with the function of an important cellular protein complex, and provokes cells to program their own destruction.

In laboratory cell culture and animal studies at UNC and elsewhere, inhibitors such as PS-341 killed cancer cells much more readily than normal cells. These findings led to a Phase I clinical trial now nearing completion at UNC aimed at finding the best dose of PS-341 to use for patients.

"Most Phase I studies are able to find a tolerated dose of a drug, but it's less common to see significant clinical responses," said Robert Z. Orlowski, MD, PhD, assistant professor of medicine at the UNC-CH School of Medicine in the division of hematology-oncology. Orlowski, the principal investigator, noted that Drs. Thomas Stinchcombe, Beverly Mitchell, and Thomas Shea also played key roles in this effort.

"The results from this study are exciting because PS-341 was able to benefit several patients who were not helped by standard chemotherapy," Orlowski said. PS-341 seemed particularly active in two diseases: multiple myeloma and non-Hodgkin's lymphoma. One patient with myeloma had a complete response, with a normal bone marrow test and complete disappearance of a myeloma protein from their blood that is used to document how much disease is present.

"We also had five myeloma patients obtain a partial response, which means reduction either in the number of myeloma cells in the bone marrow or reduction of the protein level from the myeloma in the blood, or both," Orlowski explained. "Multiple myeloma is a difficult disease to treat because we don't have any chemotherapy that is really curative," he added. "We use various drugs and usually keep the disease at bay for some time, but as with many cancers myeloma has a tendency to become resistant to the available chemotherapy and patients often run out of options."

Only one myeloma patient who received a full treatment with PS-341 showed no response, though two other patients who received higher doses of PS-341 were taken off the study because they developed side effects.

"I think these results are very encouraging. All of these patients had already received everything that could be given to patients with myeloma, and some had bone marrow transplants as well. The fact that we had one complete response and several partial responses in this Phase I clinical trial is evidence that PS-341 has very good treatment activity in this disease," Orlowski said.

In addition to the patients with myeloma, treatment responses occurred in two people with non-Hodgkin's lymphoma. "Both had a partial response; one went on to a marrow transplant, while the other was able to return to work full-time as a carpenter after four cycles of therapy," Orlowski said.

Therapy is delivered intravenously, via a small syringe. Orlowski said it is very well tolerated, causing little or no nausea or vomiting, and no hair loss as would be expected with other chemotherapy drugs. Treatment was given twice a week for four weeks, followed by a two-week break.

Based in large part on the Phase I results, a Phase II study for myeloma patients has opened at UNC Lineberger and other cancer centers. These include the Memorial Sloan-Kettering Cancer Center in New York; Dana Farber Cancer Center, Boston; M.D. Anderson Comprehensive Cancer Center, Houston; and the Mayo Clinic, Rochester, Minn.

"The first clinical evidence of PS-341 activity in patients with hematological or blood-borne cancers came from UNC," Orlowski noted. "The Phase II trial is a very viable option for patients with multiple myeloma, and we have the drug available for patients. If this trial is as successful as the Phase I study, our next step would be to combine PS-341 with other drugs that work against myeloma, and also to treat people earlier in the disease." Financial support for the Phase I study came from the Leukemia and Lymphoma Society.

For information about these studies call Rita Bhagat or Mary Myers at the Oncology Protocol Office, UNC Lineberger Comprehensive Cancer Center, 919-966-4432.