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
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
In preclinical models, combinations of R115777 and several cytotoxic agents
(eg, paclitaxel, cisplatin) produced an additive cytotoxic and cell-cycle
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
Phase III Trials
Data from a phase III company-sponsored trial comparing 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
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 and
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 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 in Patients
With Advanced Breast Cancer
Protocol Number: 5330
Participating Institution: University of Texas Health Science Center
Contact: Garry Schwartz, MD, (210) 916-1057
1. Janssen Pharmaceutical Corporation: Clinical brochure R115777.
2. Karp JE: Farnesyl protein transferase inhibitors as targeted therapies for
hematologic malignancies. Semin Hematol 38 (3 suppl 7): 16-23, 2001.
3. End DW, Smets G, Todd AV, et al: Characterization of the antitumor effects
of the selective farnesyl protein transferase inhibitor R115777 in vivo and in
vitro. Cancer Res 61(1): 131-137, 2001.
4. Smets G, Xhonneux B, Cornelissen F et al: R115777, a selective farnesyl
protein transferase inhibitor (FTI), induces antiangiogenic, apoptotic and
antiproliferative activity in CAPAN-2 and LoVo tumor xenografts (abstract). Proc
Am Assoc Clin Res 39:318, 1998.
5. Smets G, Eyck NV, Devine A, et al: R115777, a selective farnesyl protein
transferase inhibitor (FTI), induces predominantly apoptotic activity in C32
melanoma tumor xenografts (abstract). Proc Am Assoc Clin Res 40:522, 1999.
6. Skrzat SG, Bowden CR, End DW: Interaction of the farnesyl protein
transferase inhibitor (FTI) R115777 with cytotoxic chemotherapeutics in vitro
and in vivo (abstract). Proc Am Assoc Clin Res 40:523, 1999.
7. Cohen SJ, Ho L, Ranganathan S, et al: Phase II and pharmacokinetic trial
of the farnesyltransferase inhibitor R115777 as initial therapy in patients with
metastatic pancreatic adenocarcinoma (abstract). Proc Am Soc Clin Oncol 21:545,
8. Johnston SRD, Hickish T, Houston S, et al: Efficacy and tolerability of
the two dosing regimens of R115777 (Zarnestra), a farnesyl protein transferase
inhibitor, in patients with advanced breast cancer (abstract). Proc Am Soc Clin
Oncol l 21:138, 2002.
9. Cloughesy TF, Kuhn J, Wen P, et al: Phase II trial of R115777 (Zarnestra)
in patients with recurrent glioma taking enzyme inducing antiepileptic drugs (EIAED):
A North American Brain Consortium (NABTC) report (abstract). Proc Am Soc Clin
Oncol 21:317, 2002.
10. Karp JE, Lancet JE, Kaufman SH, et al: Clinical and biologic activity of
the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed
acute leukemias: A phase I clinical-laboratory correlative trial. Blood
97(11): 3361-3369, 2001.
11. Karp JE, Kaufmann SH, Adjei AA, et al: Current status of clinical trials
of farnesyltransferase inhibitors. Curr Opin Oncol 13(6):470-476, 2001.
12. Harousseau J-L, Stone R, Thomas X, et al: Interim results from a phase II
study of R115777 (Zarnestra) in patients with relapsed or refractory acute
myelogenous leukemia (abstract). Proc Am Soc Clin Oncol 21:1056, 2002.
13. Van Cutsem E, Karasek P, Oettle H, et al: Phase III trial comparing
gemcitabine + R115777 versus gemcitabine + placebo in advanced pancreatic cancer
(PC) (abstract). Proc Am Soc Clin Oncol 21:517, 2002.
14. de Gramont A, Scheithauer W, Smakal M, et al: Randomized double-blind
placebo-controlled trial of the farnesyltransferase inhibitor R115777 (Zarnestra)
in advanced refractory colorectal cancer (abstract). Proc Am Soc Clin Oncol