BACKGROUND: MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). METHODS: Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. RESULTS: Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. CONCLUSION: Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.
BACKGROUND:MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). METHODS:Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. RESULTS: Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. CONCLUSION: Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Ramon Salazar; Donald Bissett; Chris Twelves; Lars Breimer; Mark DeMario; Sophia Campbell; Jay Zhi; Steve Ritland; Jim Cassidy Journal: Clin Cancer Res Date: 2004-07-01 Impact factor: 12.531
Authors: Jakob Dupont; Bryan Bienvenu; Carol Aghajanian; Sandra Pezzulli; Paul Sabbatini; Phothisath Vongphrachanh; Christine Chang; Christina Perkell; Kenneth Ng; Sharon Passe; Lars Breimer; Jianguo Zhi; Mark DeMario; David Spriggs; Steven L Soignet Journal: J Clin Oncol Date: 2004-08-15 Impact factor: 44.544
Authors: Jason E Faris; Jamie Arnott; Hui Zheng; David P Ryan; Thomas A Abrams; Lawrence S Blaszkowsky; Jeffrey W Clark; Peter C Enzinger; Aram F Hezel; Kimmie Ng; Brian M Wolpin; Eunice L Kwak Journal: Invest New Drugs Date: 2011-07-29 Impact factor: 3.850
Authors: Nolan A Wages; Thomas M Braun; Daniel P Normolle; Matthew J Schipper Journal: Int J Radiat Oncol Biol Phys Date: 2022-07-01 Impact factor: 8.013
Authors: Kari B Wisinski; Amye J Tevaarwerk; Mark E Burkard; Murtuza Rampurwala; Jens Eickhoff; Maria C Bell; Jill M Kolesar; Christopher Flynn; Glenn Liu Journal: Clin Cancer Res Date: 2016-03-29 Impact factor: 12.531
Authors: Jennifer A Harrington; Graham M Wheeler; Michael J Sweeting; Adrian P Mander; Duncan I Jodrell Journal: Nat Rev Clin Oncol Date: 2013-03-19 Impact factor: 66.675
Authors: Erik van Werkhoven; Samantha Hinsley; Eleni Frangou; Jane Holmes; Rosemarie de Haan; Maria Hawkins; Sarah Brown; Sharon B Love Journal: BMC Med Res Methodol Date: 2020-06-22 Impact factor: 4.615
Authors: Cathie Spino; Jordan S Jahnke; David T Selewski; Susan Massengill; Jonathan Troost; Debbie S Gipson Journal: Front Pediatr Date: 2016-03-23 Impact factor: 3.418