SAN FRANCISCOMany 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
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
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
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
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.