Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors.
BACKGROUND
This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors.


METHODS
APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed.


RESULTS
Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months.


CONCLUSIONS
APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.
Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA. cerceka@mkscc.org.
Andrea
A
Cercek
MD Anderson Cancer Center, Houston, TX, USA.
Jennifer
J
Wheler
Aptose Biosciences, San Diego, CA, USA.
Peter E
PE
Murray
Aptose Biosciences, San Diego, CA, USA.
Shawn
S
Zhou
Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.
Leonard
L
Saltz
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010618:Phenanthrolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
C000608520:APTO-253; D000970:Antineoplastic Agents; D007093:Imidazoles; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D010618:Phenanthrolines
APTO-253; KLF4; Phase 1 trial; Solid tumors