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|Canadian Cancer Trials Group IND.217 - A Phase I and Enrichment Study of Low-Dose Metronomic Topotecan and Pazopanib in Pediatric Patients with Recurrent or Refractory Solid Tumours Including CNS Tumours
AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.
Patients with advanced refractory solid tumours or non-Hodgkin?s lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients.
Thirty-four patients were enroled and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg/m2. Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients? skin biopsies post treatment.
AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg/m2. At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
Chen EX, Hotte S, Hirte H, Siu LL, Lyons J, Squires M, Lovell S, Turner S, McIntosh L, Seymour L. A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: Canadian Cancer Trials Group IND 177. Br J Cancer 111: 2262-7, 2014.
Canadian Cancer Trials Group IND.200 - A Randomized Phase II Study of Reolysin in Combination with FOLFOX6 and Bevacizumab or FOLFOX6 and Bevacizumab Alone in Patients with Metastatic Colorectal Cancer
A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway.
Patients and Methods
SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 out of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods.
Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were evaluable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score >5, 7/10 had SD, vs. 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced >grade 3 toxicity.
This study was stopped prematurely due to prolonged unavailability o s interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population.
Chu QSC, Nielsen TO, Alcindor T, Gupta A, Endo M, Goytain A, Xu H, Verma S, Tozer R, Knowling M, Bramwell VB, Powers J, Seymour LK, Eisenhauer EA. A Phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200 (ONLINE). Ann Oncol 2015.