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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
P1.01-084 - A Phase 2 Study of TH-4000 in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI (ID 2209)
09:30 - 17:00 | Author(s): C. Aggarawal
While EGFR-TKI therapy is initially effective for patients with EGFR-mutant NSCLC, eventual resistance to EFGR-TKI therapy is expected. For patients with non‑T790M resistance to EGFR-TKIs, the optimal treatment is unclear. Sensitizing mutations in EGFR are often heterozygous with co-expression of both wild type (WT) and mutant EGFR. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that EGFR-mutant NSCLC with WT EGFR present is associated with a poorer response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of EGFR-TKI resistance. TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, mutant EGFR and HER2. Hypoxic tumor targeting using TH-4000 may allow a greater therapeutic index with greater intratumoral TKI levels and less dose-limiting systemic toxicity seen with current EGFR-TKIs. In xenograft models of EGFR-mutant NSCLC that co‑express WT EGFR, TH-4000 reverses resistance to current EGFR-TKIs, and is effective as a single‑agent. A Phase 1 study was conducted in patients with advanced solid tumors; the maximum tolerated dose (MTD) of TH-4000 administered as a 1-hour weekly intravenous (IV) infusion was established at 150 mg/m. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue.
A multicenter Phase 2 trial was initiated to evaluate the safety and activity of TH-4000 as a single‑agent in patients with EGFR‑mutant, T790M-negative Stage IV NSCLC progressing on an EGFR TKI. Hypoxia PET imaging with [18F]-HX4 and molecular analyses of tumor tissue and plasma are incorporated in the study design to identify potential predictors of response to treatment. The primary endpoint is response rate. Secondary endpoints include progression-free survival, duration of response, overall survival, pharmacokinetics and safety, as well as evaluation of imaging, serum, and tissue biomarkers that may be associated with tumor response. Up to 37 patients will be enrolled with recurrent EGFR-mutant Stage IV NSCLC which has progressed while on treatment with EGFR-TKI, absence of EGFR T790M mutation, measureable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients must also have adequate pre-therapy tumor tissue available to enable tumor biomarker assessment. TH-4000 (150 mg/m) is administered weekly by IV infusion over 60 minutes. The study design incorporates a Simon two-stage design (alpha = 0.10; beta = 0.10). Recruitment is ongoing.
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