Current Clinical Trials of R115777 (Zarnestra)

R115777 (Zarnestra) is an orally availablemethylquinolone derivative from Johnson & Johnson Pharmaceutical Researchand Development L.L.C. that is a potent and selective nonpeptidomimeticfarnesyltransferase inhibitor (FTI).[1] FTIs represent a new class of agentsthat were originally developed to inhibit tumors by interfering withposttranslational processing of oncogenic Ras protein. The anticancer activityof FTIs might stem from their ability to effect various proteins other than Rasthat can also mediate signal transduction, apoptosis, angiogenesis, andgrowth.[2]

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to current clinical trials of R115777 (Zarnestra).

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at www.cancer.gov/cancer_information/pdq/, or contact the Cancer Information Service offices (1-800-4-CANCER).

In vitro experiments, using isolated human farnesyl protein transferase,demonstrated that R115777 competitively inhibited farnesylation of substrateswith IC₅₀ values of 0.86 nM (lamin B) to 7.9 nM (K-ras). Themajority of the FTI-sensitive cell lines had a wild-type ras gene.[3]R115777 has been shown to inhibit in vitro the metabolism of specific CYP3A4,CYP2D6, and CYP2C8/9/10 isoenzymes, possibly indicating a potential interactionwith comedicated drugs that are primarily metabolized by cytochrome P450.[1]

Antitumor Effects

R115777 was tested using human xenograft mouse models with twice daily oraldosing for 15 to 32 days. Xenograft model data revealed that this compoundinhibited growth of tumors derived from T24 (mutant H-ras), LoVo (mutantK-ras) and CAPAN-2 (mutant K-ras) at doses of 25 to 100 mg/kg.[4]Upon examination of the tumors treated with this FTI compound, theantiangiogenesis, apoptotic, and antiproliferative effects of treatment wereevident.[5]

In preclinical models, combinations of R115777 and several cytotoxic agents(eg, paclitaxel, cisplatin) produced an additive cytotoxic and cell-cycleeffect.[6]

Pharmacokinetic data from phase I studies revealed that R115777 is bestconsumed after a meal because bioavailability increases following foodingestion. Results demonstrated that under fasting conditions thebioavailability was less than that of the oral solution, although after a mealit equaled that of the oral solution.[1]

R115777 was the first farnesyltransferase inhibitor to enter clinical trials.The National Cancer Institute (NCI) is currently sponsoring phase I and IItrials of R115777 in several different tumor types with additional studies to beactivated. From phase I dose-escalation studies, the recommended phase II doseof R115777 for several tumor types (breast, pancreas, and glioma) has beendetermined 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 producedclinical responses in 10 of 34 evaluable patients (29%), including two completeremissions.[10] R115777 was shown to inhibit farnesyltransferase activity at the300 and 600 mg twice daily dose levels (in vitro inhibition of substrates laminA and HDJ-2).[10] Approximately 10% to 15% of patients with refractorymalignancies have achieved disease stabilization or an objective response insingle-agent R115777 trials.[11]

A company-sponsored phase II study was initiated to confirm the results ofthe UMCC phase I trial in patients with relapsed and refractory acutemyelogenous leukemia (AML). The regimen entailed a dose of 600 mg twice dailyfor 21 days every 28 days. To date, 151 patients have been enrolled in thetrial, with 42 evaluable AML patients. a reduction in bone marrow leukemicblasts to less than 5% was seen in seven relapsed patients.[12]

R115777 in combination with other standard cytotoxic chemotherapy agents iscurrently under clinical investigation. Phase II NCI-sponsored and phase II andIII company-sponsored clinical trials are ongoing.

Preliminary data from another phase II company-sponsored trial investigatingthe efficacy and tolerability of two dosing regimens of R115777 in patients withadvanced breast cancer, was presented at the 38th annual meeting of the AmericanSociety of Clinical Oncology (ASCO). Two cohorts of patients were sequentiallyrecruited. The first cohort received continuous dosing at 400 or 300 mg twicedaily, while the second cohort received 300 mg twice daily for 21 days every 28days (intermittent dosing). Trial results concluded that the two regimens showedsimilar clinical efficacy, but the intermittent-dosing regimen was associatedwith a significantly improved tolerability profile over the continuous-dosingregimen.[8]

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 alsopresented at the 2002 ASCO meeting. The 688 previously untreated patients withlocally advanced or metastatic pancreatic cancer were randomized to one of twotreatment arms. Patients randomized to the R115777-plus-gemcitabine arm received200 mg of oral R115777 twice daily and gemcitabine at 1,000 mg/m2 IV weeklyfor 7 weeks every 8 weeks, then weekly for 3 weeks every 4 weeks. Compared withsingle-agent gemcitabine, no statistically significant differences in overallsurvival were observed. The median overall survival for gemcitabine plus R115777was 193 days, compared to 182 days for the control group,[13]

Additional phase III colorectal data presented at the ASCO meeting comparedR115777 and placebo in 368 previously treated metastatic colorectal patients.The primary end point was overall survival. The median survival was 5.7 monthsin patients receiving R115777, compared to 6.1 months for those receivingplacebo. R115777 in combination with chemotherapy could still be investigated inearlier stages of colorectal cancer.[14]

The most common patient hematologic toxicities include anemia, leukopenia,neutropenia, granulocytopenia, and thrombocytopenia. Nonhematologic toxicitiesinclude skin rash, motor and sensory neuropathy, nausea, vomiting, fatigue, anddizziness.

The list below includes approved, active, in review, or temporarily closedR115777 protocols, sponsored by the Division of Cancer Treatment and Diagnosisof the NCI.

Breast

Title: A Phase I/II Study of R115777 (Zarnestra) Plus Doxorubicin andCyclophosphamide 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 FarnesyltransferaseInhibitor, R115777 With Docetaxel and Capecitabine for Patients WithStage 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, aNonpeptidomimetic Farnesyltransferase Inhibitor, and Trastuzumab in PatientsWith Advanced Breast Cancer
Protocol Number: 5330
Participating Institution: University of Texas Health Science Center
Contact: Garry Schwartz, MD, (210) 916-1057

Central Nervous System

Title: Phase I Trial With Radiation Therapy in Patients With NewlyDiagnosed Glioblastoma Multiforme
Protocol Number: NABTC-02-02
Participating Institution: North American Brain Tumor Consortium
Contact: Timothy F. Cloughesy, MD, (310) 825-5321

Title: Phase II Study of R115777 in Patients With Recurrent orProgressive Malignant Glioma
Protocol Number: NABTC-9901
Participating Institutions: Dana Farber Cancer Center, M. D. AndersonCancer Center, Memorial Sloan-Kettering Cancer Center, National Institutes ofHealth, North American Brain Tumor Consortium, University of California at LosAngeles, University of California San Francisco, University of Michigan MedicalCenter, University of Pittsburgh, University of Texas Health Science Center,University of Texas Southwestern Medical Center, University of Wisconsin
Contact: Timothy Cloughesy, MD, (310) 825-5321; for a complete listing ofstudy contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Gastrointestinal

Title: Phase II Randomized Study of Gemcitabine, Paclitaxel, andRadiotherapy With or Without R115777 in Patients With Locally AdvancedPancreatic Cancer
Protocol Number: RTOG-PA-0020
Participating Institution: Radiation Therapy Oncology Group
Contact: Tyvin Rich, MD, (804) 924-5191; for a complete listing of studycontacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Genitourinary

Title: A Phase II Study of R115777 (Zarnestra) in Patients With SuperficialTransitional Cell Carcinoma of the Bladder
Protocol Number: 5612
Participating Institution: Princess Margaret Hospital
Contact: Joseph L. Chin, MD, (519) 685-8451

Lung

Title: Phase I Study of Paclitaxel and Carboplatin Followed By R115777Concurrently With Radiotherapy Followed By Maintenance Therapy With R115777 inPatients With Stage IIIA or IIIB Non-Small Cell Lung Cancer
Protocol Number: NCI-5150, UPCC-NCI-5150
Participating Institution: University of Pennsylvania Cancer Center
Contact: Stephen Hahn, MD, (215) 662-7296
Latest Information:http://www.cancer.gov/clinical_trials/

Phase I Solid Tumors

Title: Phase I Study of R115777 in Patients With Advanced MalignantSolid Tumors
Protocol Number: NCI-4751
Participating Institutions: University of California at Davis, Veteran’sAdministration Medical Center
Contact: Primo Lara, MD, (916) 734-3772
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I Study of R115777 and Topotecan in Patients WithAdvanced Solid Tumors
Protocol Number: NCI-T99-0110, NYU-9932
Participating Institutions: Albert Einstein College of Medicine, New YorkUniversity Medical Center
Contact: Howard Hochster, MD, (212) 263-8210
Latest Information:http://www.cancer.gov/clinical_trials/

Hematologic Malignancies

Title: Phase I Randomized Study of R115777 in Patients With AdvancedHematologic Malignancies
Protocol Number: NCI-42, UCCRC-10294
Participating Institution: University of Chicago
Contact: Todd Zimmerman, MD, (773) 702-4159
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I Study of R115777 in Patients With MyelodysplasticSyndrome
Protocol Number: MDA-DM-01582, MDA-DM-99169, NCI-5625, NCI-T99-0101
Participating Institution: M. D. Anderson Cancer Center
Contact: Razelle Kurzrock, MD, (713) 794-1226
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I/II Study of R115777 in Patients With MyeloproliferativeDisorders
Protocol Number: NCI-38, SUMC-NCI-38
Participating Institutions: Stanford University, University of California SanFrancisco Medical Center
Contact: Peter Greenberg, MD, (650) 725-8355
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of R115777 in Patients With Previously UntreatedPoor-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, or ChronicMyelomonocytic Leukemia
Protocol Number: MSGCC-0116, MSGCC-U5400, NCI-1754
Participating Institutions: University of Maryland Cancer Center, StanfordUniversity, University of Rochester
Contact: Judith Karp, MD, (410) 328-7394
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Evaluation of FTI R115777 in the Treatment of AdvancedMultiple Myeloma
Protocol Number: 2030
Participating Institutions: Mayo Clinic, Moffitt Cancer Center, University ofWisconsin, Washington University
Contact: Melissa Alsina, MD, (813) 903-6886

Title: A Phase II Trial of R115777 in Myelofibrosis With Myeloid Metaplasia(MMM)
Protocol Number: 5576
Participating Institution: Mayo Clinic
Contact: Ayalew Tefferi, MD, (507) 284-2511

Title: A Phase II Study of the Farnesyltransferase Inhibitor Zarnestra(R115777, NSC 702818, IND 58,359) in Complete Remission Following Inductionand/or Consolidation Chemotherapy in Adults With Poor-Risk Acute MyelogenousLeukemia (AML) and High-Risk Myelodysplasia (MDS)
Protocol Number: 5689
Participating Institution: University of Maryland Cancer Center
Contact: Judith Karp, MD, (410) 328-7394

Pediatric

Title: Phase I Study of R115777 in Pediatric Patients With RefractoryLeukemia
Protocol Number: COG-ADVL0116, NCI-01-C-0196, NCI-1930
Participating Institutions: Children’s Hospital and Regional MedicalCenter, Children’s Oncology Group Phase 1 Consortium, Columbia-PresbyterianMedical Center, Johns Hopkins University, National Cancer Institute PediatricOncology Branch, Packard Children’s Hospital-Stanford, Saint-Justine,University of California at San Francisco, University of Texas SouthwesternMedical Center
Contact: Brigitte Widemann, MD, (301) 496-7387; for a complete listing ofstudy contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of R115777, Isotretinoin, Cytarabine, andFludarabine Followed By Allogeneic Bone Marrow or Umbilical Cord BloodTransplantation in Children With Newly Diagnosed Juvenile MyelomonocyticLeukemia
Protocol Number: COG-AAML0122
Participating Institution: Children’s Oncology Group
Contact: Robert Castleberry, MD, (205) 939-9285; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

References:

1. Janssen Pharmaceutical Corporation: Clinical brochure R115777.

2. Karp JE: Farnesyl protein transferase inhibitors as targeted therapies forhematologic malignancies. Semin Hematol 38 (3 suppl 7): 16-23, 2001.

3. End DW, Smets G, Todd AV, et al: Characterization of the antitumor effectsof the selective farnesyl protein transferase inhibitor R115777 in vivo and invitro. Cancer Res 61(1): 131-137, 2001.

4. Smets G, Xhonneux B, Cornelissen F et al: R115777, a selective farnesylprotein transferase inhibitor (FTI), induces antiangiogenic, apoptotic andantiproliferative activity in CAPAN-2 and LoVo tumor xenografts (abstract). ProcAm Assoc Clin Res 39:318, 1998.

5. Smets G, Eyck NV, Devine A, et al: R115777, a selective farnesyl proteintransferase inhibitor (FTI), induces predominantly apoptotic activity in C32melanoma tumor xenografts (abstract). Proc Am Assoc Clin Res 40:522, 1999.

6. Skrzat SG, Bowden CR, End DW: Interaction of the farnesyl proteintransferase inhibitor (FTI) R115777 with cytotoxic chemotherapeutics in vitroand in vivo (abstract). Proc Am Assoc Clin Res 40:523, 1999.

7. Cohen SJ, Ho L, Ranganathan S, et al: Phase II and pharmacokinetic trialof the farnesyltransferase inhibitor R115777 as initial therapy in patients withmetastatic pancreatic adenocarcinoma (abstract). Proc Am Soc Clin Oncol 21:545,2002.

8. Johnston SRD, Hickish T, Houston S, et al: Efficacy and tolerability ofthe two dosing regimens of R115777 (Zarnestra), a farnesyl protein transferaseinhibitor, in patients with advanced breast cancer (abstract). Proc Am Soc ClinOncol 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 ClinOncol 21:317, 2002.

10. Karp JE, Lancet JE, Kaufman SH, et al: Clinical and biologic activity ofthe farnesyltransferase inhibitor R115777 in adults with refractory and relapsedacute leukemias: A phase I clinical-laboratory correlative trial. Blood97(11): 3361-3369, 2001.

11. Karp JE, Kaufmann SH, Adjei AA, et al: Current status of clinical trialsof 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 IIstudy of R115777 (Zarnestra) in patients with relapsed or refractory acutemyelogenous leukemia (abstract). Proc Am Soc Clin Oncol 21:1056, 2002.

13. Van Cutsem E, Karasek P, Oettle H, et al: Phase III trial comparinggemcitabine + 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-blindplacebo-controlled trial of the farnesyltransferase inhibitor R115777 (Zarnestra)in advanced refractory colorectal cancer (abstract). Proc Am Soc Clin Oncol21:502, 2002.