R115777 Shows Promise Against Breast, Colorectal, and Other Solid Tumors

SAN FRANCISCO—Many signaling cascade proteins, such as Ras, that lead to cancerous changes require an isoprenyl moiety attached by farnesyl transferase for activity. Farnesyl transferase inhibitors (FTI) are under study as a possible way to derail cancer progression. Three early studies of one such compound, R115777, show that it has promise against breast, colorectal, and other solid tumors. Janssen Research Foundation of Titusville, New Jersey, sponsored all three studies.

Combined with Capecitabine

A phase I pharmacokinetic and biological study tested R115777 and capecitabine (Xeloda) in patients with advanced solid malignancies. Scott N. Holden, MD, assistant professor of medicine at the University of Colorado Cancer Center in Denver, told ONI that this combination is expected to move into phase II trials soon.

The principal toxicity of R115777 is myelosuppression. Capecitabine, an oral prodrug of fluorouracil (5-FU), has been shown to be active against breast and colorectal cancer and has principal toxicities of diarrhea and hand-foot syndrome. The rationale for combining the two included nonoverlapping toxicity, overexpression of thymidine phosphorylase (which converts capecitabine to 5-FU) in tumors that may be sensitive to the inhibition of Ras activity, and the feasibility of an all-oral regimen.

During the "run-in" period, patients receive a single R115777 dose, followed 2 days later by a single dose of capecitabine. The treatment phase includes oral R115777 (escalated from 100 to 500 mg bid) plus capecitabine (escalated from 2,000 to 2,500 mg/m²/d) for 14 days, repeating every 3 weeks.

Patients in the phase I study included six with colorectal cancer, four with breast cancer, three with head/neck cancer, two with melanoma, two with renal cell carcinoma, and ten with other cancer types. Thus far 27 patients have been treated with 88 courses of therapy.

Dr. Holden reported that objective clinical responses were seen in four patients. The first was a 48-year-old woman with metastatic colorectal cancer. This patient’s carcinoembryonic antigen (CEA) level decreased from 1,362 to 336 after 6 cycles of treatment. This was associated with a greater than 50% reduction in abdominal in situ disease.

The second response occurred in a 45-year-old man with locally recurrent head/neck cancer. Dr. Holden told Oncology News International that although this patient experienced complete resolution of a 2-cm oropharyngeal mass after two cycles of treatment, he took himself off study. "Following surgery, radiation, and treatment with platinum, and 5-FU, this patient had a 2-cm lesion as the only site of disease and was judged to be in clinical complete remission," Dr. Holden reported. "This lesion was a small area of scar tissue and was not biopsied, so the patient is classified only as a partial response, although this was maintained for four cycles. The patient left the study for personal reasons unrelated to either treatment or disease progression."

The other two responses were in a 53-year-old woman with biliary squamous cell carcinoma, who had a greater than 50% decrease in tumor bulk that persisted for two cycles, and a 75-year-old-woman with breast cancer metastatic to the chest wall, neck nodes, and brain. Dr. Holden said that this patient had a greater than 50% decrease in tumor bulk at all sites after two cycles of treatment and that this improvement has persisted through seven cycles of chemotherapy.

In addition, 10 of 27 patients had stable disease that persisted for more than four cycles. Some of these responses were clinically significant, such as that in a 34-year-old woman whose melanoma had progressed through radiation and chemotherapy, but has remained stable through 20 cycles of R115777/capecitabine.

Dr. Holden said that the combination appears tolerable up to R115777 doses of 300 mg bid and capecitabine of 2,000 mg/m²/d. Dose-limiting toxicities at higher capecitabine doses were hand-foot syndrome and diarrhea. Escalation of R115777 is ongoing, with capecitabine held at 2,000 mg/m²/d.

In Tandem with Docetaxel

Martine J. Piccart-Gebhart, MD, of the Jules Bordet Institute, Brussels, Belgium reported data from a phase I trial of R115777 plus docetaxel (Taxotere) in patients with solid tumors. The researchers concluded that R115777 can be combined with docetaxel with acceptable toxicity.

Febrile neutropenia and prolonged grade 4 neutropenia were the dose-limiting toxicities, and the majority of patients with febrile neutropenia were managed with oral antibiotics. The study also showed that intermittent dosing of R115777 was better tolerated than continuous dosing.

To date, 24 patients have been enrolled on the study. Tumor types include breast (15), non-small-cell lung cancer (NSCLC, 4), unknown primary tumor (3), and other (2). Nineteen patients had prior chemotherapy but none had prior docetaxel. Patients who developed febrile neutropenia received subsequent cycles with prophylactic antibiotics, ciprofloxacin (Cipro) plus amoxicillin/clavulanate potassium (Augmentin).

The median number of cycles of combination therapy was 3 (range 1-9). No dose-limiting toxicities were observed in 6 patients (20+ cycles) given R115777 alone as maintenance therapy after withdrawal of docetaxel. Nonhematologic toxicities, which were mainly grade 2, included asthenia (67% of patients), diarrhea (46%), myalgia (42%), mucositis (33%), and neurotoxicity (13%).

Responses included one complete response (breast cancer), four partial responses (two breast cancer, one each NSCLC and unknown primary), and six stable disease (including a decline in tumor markers of 50%). Pharmacokinetic data show no influence of R115777 on docetaxel clearance.

Dr. Piccart-Gebhart said that accrual is ongoing for two groups: docetaxel 85 mg/m² plus R115777 200 mg bid ´ 14 days (breast), and docetaxel 60 mg/m² plus R115777 300 mg bid ´ 14 days (other solid tumors, mainly NSCLC).

With Gemcitabine and Cisplatin

A three-drug regimen of R115777, gemcitabine (Gemzar), and cisplatin (Platinol) was tested in patients with advanced solid tumors. Results of the phase I trial were reported by Alex A. Adjei, MD, PhD, of the Division of Medical Oncology at the Mayo Clinic in Rochester, Minnesota.

"FT-catalyzed transfer of the farnesyl moiety from farnesyl pyrophosphate to a cystein residue is the first step in converting cytoplasmic precursors of small proteins involved in cell signaling (including Ras and Rho) to mature membrane-bound forms," he explained. "Ras proteins are molecular switches linking receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic and nuclear events. Thirty percent of human cancers have oncogenic mutations in Ras. Farnesylation of Ras is crucial for oncogenicity, so we think that FT inhibition is a promising strategy for developing new cancer treatments."

The investigators previously demonstrated cytotoxic synergy between the FTIs and cisplatin and additive effects between the FTIs and gemcitabine. "Based on these studies, we undertook a phase I trial to define the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and clinical activity of the combination of R115777 (po BID d1-14), gemcitabine (d1, d8), and cisplatin (d1), on a 21-day cycle in patients with advanced cancers," Dr. Adjei said.

Dr. Adjei reported data from 22 patients who have received 66 cycles of treatment through five dose levels. Significant toxicities in all cycles of treatment were graded according to the National Cancer Institute Common Toxicity Criteria. These included neutropenia (7 grade 3, 3 grade 4), thrombocytopenia (11 grade 3, 1 grade 4), rash (2 grade 3), nausea (5 grade 2, 1 grade 3), and fatigue (1 grade 2). All three patients at level five had dose-limiting toxicities of neutropenia, including febrile neutropenia and neutropenia with infection. Doses at this level were R115777 400 mg bid, gemcitabine 1,000 mg/m², and cisplatin 75 mg/m².

Six objective responses, including one complete response and five partial responses occurred in 15 evaluable patients.