R115777 (Zarnestra) is an orally available methylquinolone derivative from Johnson & Johnson Pharmaceutical Research and Development L.L.C. that is a potent and selective nonpeptidomimetic farnesyltransferase inhibitor (FTI). FTIs represent a new class of agents that were originally developed to inhibit tumors by interfering with posttranslational processing of oncogenic Ras protein. The anticancer activity of FTIs might stem from their ability to effect various proteins other than Ras that can also mediate signal transduction, apoptosis, angiogenesis, and growth.
In vitro experiments, using isolated human farnesyl protein transferase, demonstrated that R115777 competitively inhibited farnesylation of substrates with IC50 values of 0.86 nM (lamin B) to 7.9 nM (K-ras). The majority of the FTI-sensitive cell lines had a wild-type ras gene. R115777 has been shown to inhibit in vitro the metabolism of specific CYP3A4, CYP2D6, and CYP2C8/9/10 isoenzymes, possibly indicating a potential interaction with comedicated drugs that are primarily metabolized by cytochrome P450.
R115777 was tested using human xenograft mouse models with twice daily oral dosing for 15 to 32 days. Xenograft model data revealed that this compound inhibited growth of tumors derived from T24 (mutant H-ras), LoVo (mutant K-ras) and CAPAN-2 (mutant K-ras) at doses of 25 to 100 mg/kg. Upon examination of the tumors treated with this FTI compound, the antiangiogenesis, apoptotic, and antiproliferative effects of treatment were evident.
In preclinical models, combinations of R115777 and several cytotoxic agents (eg, paclitaxel(Drug information on paclitaxel), cisplatin(Drug information on cisplatin)) produced an additive cytotoxic and cell-cycle effect.
Pharmacokinetic data from phase I studies revealed that R115777 is best consumed after a meal because bioavailability increases following food ingestion. Results demonstrated that under fasting conditions the bioavailability was less than that of the oral solution, although after a meal it equaled that of the oral solution.
R115777 was the first farnesyltransferase inhibitor to enter clinical trials. The National Cancer Institute (NCI) is currently sponsoring phase I and II trials of R115777 in several different tumor types with additional studies to be activated. From phase I dose-escalation studies, the recommended phase II dose of R115777 for several tumor types (breast, pancreas, and glioma) has been determined to be 300 mg twice daily on a schedule of 21 days every 28 days.[7-9]
Phase I and II Trials
In a phase I trial conducted by the University of Maryland Cancer Center (UMCC), R115777 in patients with refractory and relapsed acute leukemias produced clinical responses in 10 of 34 evaluable patients (29%), including two complete remissions. R115777 was shown to inhibit farnesyltransferase activity at the 300 and 600 mg twice daily dose levels (in vitro inhibition of substrates lamin A and HDJ-2). Approximately 10% to 15% of patients with refractory malignancies have achieved disease stabilization or an objective response in single-agent R115777 trials.
A company-sponsored phase II study was initiated to confirm the results of the UMCC phase I trial in patients with relapsed and refractory acute myelogenous leukemia (AML). The regimen entailed a dose of 600 mg twice daily for 21 days every 28 days. To date, 151 patients have been enrolled in the trial, with 42 evaluable AML patients. a reduction in bone marrow leukemic blasts to less than 5% was seen in seven relapsed patients.
R115777 in combination with other standard cytotoxic chemotherapy agents is currently under clinical investigation. Phase II NCI-sponsored and phase II and III company-sponsored clinical trials are ongoing.
Preliminary data from another phase II company-sponsored trial investigating the efficacy and tolerability of two dosing regimens of R115777 in patients with advanced breast cancer, was presented at the 38th annual meeting of the American Society of Clinical Oncology (ASCO). Two cohorts of patients were sequentially recruited. The first cohort received continuous dosing at 400 or 300 mg twice daily, while the second cohort received 300 mg twice daily for 21 days every 28 days (intermittent dosing). Trial results concluded that the two regimens showed similar clinical efficacy, but the intermittent-dosing regimen was associated with a significantly improved tolerability profile over the continuous-dosing regimen.
Phase III Trials
Data from a phase III company-sponsored trial comparing gemcitabine(Drug information on gemcitabine) (Gemzar) and R115777 vs gemcitabine and placebo in pancreatic cancer patients was also presented at the 2002 ASCO meeting. The 688 previously untreated patients with locally advanced or metastatic pancreatic cancer were randomized to one of two treatment arms. Patients randomized to the R115777-plus-gemcitabine arm received 200 mg of oral R115777 twice daily and gemcitabine at 1,000 mg/m2 IV weekly for 7 weeks every 8 weeks, then weekly for 3 weeks every 4 weeks. Compared with single-agent gemcitabine, no statistically significant differences in overall survival were observed. The median overall survival for gemcitabine plus R115777 was 193 days, compared to 182 days for the control group,
Additional phase III colorectal data presented at the ASCO meeting compared R115777 and placebo in 368 previously treated metastatic colorectal patients. The primary end point was overall survival. The median survival was 5.7 months in patients receiving R115777, compared to 6.1 months for those receiving placebo. R115777 in combination with chemotherapy could still be investigated in earlier stages of colorectal cancer.
The most common patient hematologic toxicities include anemia, leukopenia, neutropenia, granulocytopenia, and thrombocytopenia. Nonhematologic toxicities include skin rash, motor and sensory neuropathy, nausea, vomiting, fatigue, and dizziness.
The list below includes approved, active, in review, or temporarily closed R115777 protocols, sponsored by the Division of Cancer Treatment and Diagnosis of the NCI.
Title: A Phase I/II Study of R115777 (Zarnestra) Plus Doxorubicin(Drug information on doxorubicin) and Cyclophosphamide(Drug information on cyclophosphamide) in Patients with Locally Advanced and Metastatic Breast Cancer
Protocol Number: 5598
Participating Institution: Montefiore Medical Center
Contact: Joseph Sparano, MD, (212) 746-2844
Title: Phase IB/II Neoadjuvant Trial of the Farnesyltransferase
Inhibitor, R115777 With Docetaxel(Drug information on docetaxel) and Capecitabine for Patients With
Stage IIIA or IIIB Breast Cancer
Protocol Number: 5599
Participating Institution: Mayo Clinic
Contact: Bennett Yu, (313) 966-7198
Title: A Phase II Evaluation of the Efficacy and Safety of R115777, a
Nonpeptidomimetic Farnesyltransferase Inhibitor, and Trastuzumab(Drug information on trastuzumab) in Patients
With Advanced Breast Cancer
Protocol Number: 5330
Participating Institution: University of Texas Health Science Center
Contact: Garry Schwartz, MD, (210) 916-1057