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New class of anti-cancer drug effective against kidney cancer

Jan 25,2018

Cancer

mdlinx

Source: https://www.mdlinx.com/oncology/article/1389

PT2385, a new first-in-class drug, was well tolerated and effective as a treatment for clear cell renal cell carcinoma (ccRCC). The findings were published by researchers at the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center in Dallas in the Journal of Clinical Oncology.

PT2385 belongs to a new classification of drugs called hypoxia-inducible factors (HIF-2α). The study, led by Kevin Courtney, MD, PhD, was a phase 1 dose-escalation trial in patients who had locally advanced or metastatic ccRCC that had progressed during prior regimens. Prior regimens included a vascular endothelial growth factor (VEGF) inhibitor.

“PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC,” the authors wrote.

Hypoxic conditions contribute to the development of an aggressive phenotype and resistance to radiation therapy and chemotherapy. Hypoxia is also predictive of a poor outcome in many tumor types.

Adaptation to hypoxia is mediated by hypoxia-inducible factors including HIF-2α, which regulates genes promoting angiogenesis, increased tumor growth, or metastasis. In kidney cancer, HIF-2α is believed to be the most important driver for development and progression of ccRCC, suggesting that HIF-2α antagonists could have therapeutic potential.

The von Hippel-Lindau (VHL) tumor suppressor is inactivated in the majority of ccRCCs, leading to inappropriate stabilization of HIF-2α. Inhibition of the transcriptional activity of HIF-2α has the potential to inhibit several pathways that contribute to tumor growth in ccRCC.

The primary objective of the study was to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PT2385 in patients with advanced ccRCC. Other objectives included evaluating the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and the antitumor activity of PT2384.

In a standard 3 + 3 design, groups of three to six patients were treated with oral PT2385 twice daily. The starting dose of 100 mg twice daily was increased by 100% until the first drug-related toxicity (grade of 2 or greater). Thereafter, dose increases were ≤50% to a maximum of 1,800 mg.

Blood samples for PK and PD assessments were drawn 1 hour before and at various predetermined intervals after administration, and at every 12 weeks. At day fifteen, 800 mg of PT2385 was rapidly absorbed (median Tmax 2 hours); mean half-life was 17 hours. A 2.5-fold accumulation in area under the curve was observed from day 1 to day 15.

Adverse events (AEs) were noted, and severity was graded. Tumors were assessed by contrast or noncontrast CT or MRI at baseline, before week 7, and at every 9 weeks. The majority of AEs were grade 1 or 2. The most common all-grade AEs were anemia (45%), peripheral edema (39%), and fatigue (37%). No patients stopped treatment due to AEs and there were no deaths reported.

No patient reported a dose limiting toxicity (DLT) at any dose ≤1,800 mg twice daily; the MTD was not identified.

Of the 51 patients treated, 50 were evaluable for response. As best response, one patient had a complete response at 200 mg twice daily, six (12%) had a partial response (PR), 26 (52%) had stable disease (SD), and 17 (34%) had tumor progression. At data cutoff, eight patients were still in the study; 13 were in the study for one year or longer.

PT2385 is the first HIF-2α to be tested in humans and the first to show activity in patients with ccRCC. The investigators noted that the favorable tolerability and activity provide rationale for exploring PT2385 in combination with other active agents for ccRCC.