A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer

Abstract

Background A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. Methods In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1–3 along with cisplatin on day 1 and etoposide on days 1–3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. Results Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1–3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. Conclusions AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Pharmacologic inhibition of lactate production prevents myofibroblast differentiation

“…This is significant because genetic inhibition of gene expression presents significant challenges in a clinical setting. LDH is a promising therapeutic target for a variety of malignancies (22,25,27,30,33), and systemic inhibition of LDH is clinically feasible and can be well tolerated. Additional anti-LDH pharmacotherapies are in development along with strategies to more precisely target specific organs and cell types.…”

“…Many of the properties of gossypol appear to be dose and cell type specific. Gossypol also effectively inhibits cell differentiation in several types of malignancy (19,34,35) and is being investigated as a potential cancer therapy (25,27,30). Because of these properties, we wanted to determine whether gossypol would also be effective at inhibiting TGF-␤-induced myofibroblast differentiation and may therefore represent a possible treatment for pulmonary fibrosis.…”

The re-emergence of natural products for drug discovery in the genomics era

“…Gossypol and its derivatives inhibit the growth of cancer-cell lines and show anticancer activity in animal models 252 . Although earlier trials with racemic gossypol were not successful, a single enantiomer of gossypol (called AT-101) is now in clinical trials in patients with different forms of cancer 253 . Newer analogues of gossypol are also being tested in cancer 254 , but it remains to be seen whether or not they will be successful.…”

AT-101 inhibits hedgehog pathway activity and cancer growth

“…It is currently being investigated in phase I/ II clinical trial as an antagonist of Bcl-2 family proteins [2,10,28,32,35]. However, the clinical trial results showed that AT-101 administration did not extend overall survival or improved the progression-free survival [2,35].…”

“…Preclinical studies have shown that AT-101 exhibits broad activity against various types of cancers, such as breast, prostate, lung, lymphoma, and head and neck cancers [20,23,25,38,44]. Clinically, phase I/II trials evaluating safety and efficacy of AT-101 as a single agent or in combination with other anticancer drugs are ongoing in refractory small cell lung cancer, metastatic castration-resistant prostate cancer, to name a few [2,10,28,32,35].…”