Reference Detail

Ref Type

Journal Article

PMID

(26268924)

Authors

Cercek A, Wheler J, Murray PE, Zhou S, Saltz L

Title

Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	33	5	2015 Oct	1086-92	Invest New Drugs

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
APTO-253	APTO-253	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
APTO-253		LOR-253\|LT-253		APTO-253 is a small molecule that induces expression of KLF4 and CDKN1A, resulting in decreased tumor cell proliferation, cell-cycle arrest, and apoptosis, and has been shown to induce DNA damage (PMID: 26268924, PMID: 29626127, PMID: 29626126).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References