SCH 66336 is a potent specific inhibitor of farnesyl protein transferase. It has the potential advantage over cytotoxic cancer agents in that it may selectively inhibit abnormal cell proliferation while resulting in minimal toxicity to normal cells. Preclincial experiments in cultured cells and human xenograft models have revealed activity in a broad spectrum of tumors including lung, breast, colon, pancreas, and prostate cancer. Preclinical toxicologic studies identified myelosuppression and mild hepatomegaly in rodent and simian models. It is our hypothesis that SCH 66336 is a potent and effective antitumor agent. We are undertaking a phase I trial of SCH 66336 in patients with solid tumors refractory to standard therapy or for whom there is no standard treatment. The objectives of the trial are: 1) to characterize the safety, tolerability, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of SCH 66336 when administered orally twice daily for 7 out of 21 days in patients with advanced cancer who have no known bone marrow involvement by cancer, 2) to characterize the single- and multiple-dose pharmacokinetics of SCH 66336 following oral administration, 3) to evaluate in a preliminary manner the anti-tumor activity of SCH 66336, 4) to evaluate in a preliminary manner bFGF, VFGF, laminfarnesylation, and Ras farnesylation, as markers of farnesyl transferase inhibition. The eligibility criteria are malignancy for which no conventional therapies are available to offer reasonable hope of cure or significant palliation; age > 18 years; life expectancy > 12 weeks; adequate bone marrow, renal, and hepatic function; no leukemia, CNS metastases, myeloma or bone marrow involvement with tumor as assessed by the investigator; < 2 prior chemotherapy regimens for metastatic disease; and prior radiotherapy to > 30% of the bone marrow. Patients meeting the eligibility criteria will receive SCH 66336 administered orally twice daily for 7 consecutive days repeated every 21 days. The starting dose will be 25 mg every 12 hours and will be escalated using a modified continual reassessment method (CRM) after one patient has been treated at each dose level without significant toxicity. Dose-limiting toxicity is defined as that dose in which >2/3 or >2/6 patients experienced > grade 3 nonhematologic, serum creatinine twice the upper limit of normal or greater than twice baseline, or > grade 3 hematologic toxicities (> grade 4 anemia) according to NCI CTC. The maximally tolerated dose is one dose level below that dose which causes dose-limiting toxicity. As markers of farnesyl transferase inhibition, bFGF, VFGF, lamin farnesylation and RAS farnesylation will be related to the clinical effects and the pharmacokinetic parameters. The protocol opened for accrual in December 1997. The dose-escalation scheme has been; 25 mg, 50 mg, 100 mg, 200 mg, 400 mg given orally twice a day for seven days out of every 21 days. Ten patients have been treated through these five dose levels. The 400 mg dose level has been found to have unacceptable toxicities in 2 patients. An additional cohort of patients are being treated at 200 mg, which appears to be well-tolerated. The protocol has been amended to allow dose levels between 200 mg and 400 mg to be studied to better define the recommended phase II dose. Protein prenylation is a common event in eukaryoitic cells. Several mammalian proteins including the nuclear lamins, are known to be farnesylated. In ancillary transitional studies, fanesylation of lamin in buccal mucosa cells of patients is being assessed as a surrogate marker of SCH66336 activity. An immunoblotting assay has been developed. We have demonstrated the inhibition of prelamin farnesylation in buccal mucosa cells of patients treated at 400 mg. We are currently working on samples from patients treated at 200 mg.

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Mayo Clinic, Rochester
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Yu, Alan S L; Shen, Chengli; Landsittel, Douglas P et al. (2018) Baseline total kidney volume and the rate of kidney growth are associated with chronic kidney disease progression in Autosomal Dominant Polycystic Kidney Disease. Kidney Int 93:691-699
Kamimura, Daisuke; Suzuki, Takeki; Wang, Wanmei et al. (2018) Higher plasma leptin levels are associated with reduced left ventricular mass and left ventricular diastolic stiffness in black women: insights from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Hypertens Res 41:629-638
Nowak, Kristen L; You, Zhiying; Gitomer, Berenice et al. (2018) Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 29:571-578
Tirumanisetty, P; Prichard, D; Fletcher, J G et al. (2018) Normal values for assessment of anal sphincter morphology, anorectal motion, and pelvic organ prolapse with MRI in healthy women. Neurogastroenterol Motil 30:e13314
McKenzie, Katelyn A; El Ters, Mirelle; Torres, Vicente E et al. (2018) Relationship between caffeine intake and autosomal dominant polycystic kidney disease progression: a retrospective analysis using the CRISP cohort. BMC Nephrol 19:378
Dad, Taimur; Abebe, Kaleab Z; Bae, K Ty et al. (2018) Longitudinal Assessment of Left Ventricular Mass in Autosomal Dominant Polycystic Kidney Disease. Kidney Int Rep 3:619-624
Brosnahan, Godela M; Abebe, Kaleab Z; Rahbari-Oskoui, Frederic F et al. (2017) Effect of Statin Therapy on the Progression of Autosomal Dominant Polycystic Kidney Disease. A Secondary Analysis of the HALT PKD Trials. Curr Hypertens Rev 13:109-120
Kamimura, Daisuke; Suzuki, Takeki; Furniss, Anna L et al. (2017) Elevated serum osteoprotegerin is associated with increased left ventricular mass index and myocardial stiffness. J Cardiovasc Med (Hagerstown) 18:954-961
Chung, Jin Ook; Koutsari, Christina; Blachnio-Zabielska, Agnieszka U et al. (2017) Intramyocellular Ceramides: Subcellular Concentrations and Fractional De Novo Synthesis in Postabsorptive Humans. Diabetes 66:2082-2091
West, Nancy A; Lirette, Seth T; Cannon, Victoria A et al. (2017) Adiposity, Change in Adiposity, and Cognitive Decline in Mid- and Late Life. J Am Geriatr Soc 65:1282-1288

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