Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours.

Abstract

PURPOSE:

AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models.

METHODS:

This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts.

RESULTS:

Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease.

CONCLUSIONS:

The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.

• Authors: Takashi Seto, Taito Esaki, Fumihiko Hirai, Shuji Arita, Kaname Nosaki, Akitaka Makiyama, Takuro Kometani, Chinatsu Fujimoto, Motoharu Hamatake, Hiroaki Takeoka, Felix Agbo, Xiaojin Shi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 3 Pg. 619-27 (Sep 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23892959 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Thiophenes
• Deoxycytidine
• Urea
• Protein Kinases
• Checkpoint Kinase 2
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• Protein Serine-Threonine Kinases
• Gemcitabine

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Checkpoint Kinase 1
• Checkpoint Kinase 2
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Female
• Humans
• Japan
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Protein Kinases (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Thiophenes (administration & dosage)
• Urea (administration & dosage, analogs & derivatives)
• Gemcitabine