Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting

Razelle Kurzrock, Hagop M. Kantarjian, Jorge E. Cortes, Neil Singhania, Deborah A. Thomas, Edward F. Wilson, John J. Wright, Emil J. Freireich, Moshe Talpaz, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-α (TNF-α) levels by day 7 showed a trend toward correlation with response (P = .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.

Original languageEnglish (US)
Pages (from-to)4527-4534
Number of pages8
JournalBlood
Volume102
Issue number13
DOIs
StatePublished - Dec 15 2003

Fingerprint

tipifarnib
Farnesyltranstransferase
Myelodysplastic Syndromes
Toxicity
Mouth
STAT3 Transcription Factor
Phosphorylation
Platelets
Appointments and Schedules
Prenylation
Blood
Tumor Necrosis Factor-alpha
Mutation
Modulation
Fatigue of materials
Maximum Tolerated Dose
Platelet Count
Fatigue
Enzymes
Blood Cells

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kurzrock, R., Kantarjian, H. M., Cortes, J. E., Singhania, N., Thomas, D. A., Wilson, E. F., ... Sebti, S. M. (2003). Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting. Blood, 102(13), 4527-4534. https://doi.org/10.1182/blood-2002-11-3359

Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome : Clinical and biologic activities in the phase 1 setting. / Kurzrock, Razelle; Kantarjian, Hagop M.; Cortes, Jorge E.; Singhania, Neil; Thomas, Deborah A.; Wilson, Edward F.; Wright, John J.; Freireich, Emil J.; Talpaz, Moshe; Sebti, Saïd M.

In: Blood, Vol. 102, No. 13, 15.12.2003, p. 4527-4534.

Research output: Contribution to journalArticle

Kurzrock, R, Kantarjian, HM, Cortes, JE, Singhania, N, Thomas, DA, Wilson, EF, Wright, JJ, Freireich, EJ, Talpaz, M & Sebti, SM 2003, 'Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting', Blood, vol. 102, no. 13, pp. 4527-4534. https://doi.org/10.1182/blood-2002-11-3359
Kurzrock, Razelle ; Kantarjian, Hagop M. ; Cortes, Jorge E. ; Singhania, Neil ; Thomas, Deborah A. ; Wilson, Edward F. ; Wright, John J. ; Freireich, Emil J. ; Talpaz, Moshe ; Sebti, Saïd M. / Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome : Clinical and biologic activities in the phase 1 setting. In: Blood. 2003 ; Vol. 102, No. 13. pp. 4527-4534.
@article{056132c9220f4b62bc1c4bb72483c6ef,
title = "Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting",
abstract = "R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19{\%}) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30{\%}) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-α (TNF-α) levels by day 7 showed a trend toward correlation with response (P = .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.",
author = "Razelle Kurzrock and Kantarjian, {Hagop M.} and Cortes, {Jorge E.} and Neil Singhania and Thomas, {Deborah A.} and Wilson, {Edward F.} and Wright, {John J.} and Freireich, {Emil J.} and Moshe Talpaz and Sebti, {Sa{\"i}d M.}",
year = "2003",
month = "12",
day = "15",
doi = "10.1182/blood-2002-11-3359",
language = "English (US)",
volume = "102",
pages = "4527--4534",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "13",

}

TY - JOUR

T1 - Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome

T2 - Clinical and biologic activities in the phase 1 setting

AU - Kurzrock, Razelle

AU - Kantarjian, Hagop M.

AU - Cortes, Jorge E.

AU - Singhania, Neil

AU - Thomas, Deborah A.

AU - Wilson, Edward F.

AU - Wright, John J.

AU - Freireich, Emil J.

AU - Talpaz, Moshe

AU - Sebti, Saïd M.

PY - 2003/12/15

Y1 - 2003/12/15

N2 - R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-α (TNF-α) levels by day 7 showed a trend toward correlation with response (P = .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.

AB - R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras, 3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor-α (TNF-α) levels by day 7 showed a trend toward correlation with response (P = .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS.

UR - http://www.scopus.com/inward/record.url?scp=10744227474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744227474&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-11-3359

DO - 10.1182/blood-2002-11-3359

M3 - Article

C2 - 12947010

AN - SCOPUS:10744227474

VL - 102

SP - 4527

EP - 4534

JO - Blood

JF - Blood

SN - 0006-4971

IS - 13

ER -