First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies.

PURPOSE: Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. METHODS: This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). RESULTS: In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. CONCLUSIONS: In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer.

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.