Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non-Small Cell Lung Carcinoma.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate. Here, we present safety and efficacy data from a phase I/Ib study of Teliso-V monotherapy evaluated in once every 2 weeks/once every 3 weeks schedules in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: During dose escalation, patients received Teliso-V monotherapy intravenously once every 3 weeks (0.15-3.3 mg/kg) or once every 2 weeks (1.6-2.2 mg/kg). The dose-expansion phase enrolled patients with NSCLC and c-Met H-score ≥150 (c-Met+) or MET amplification/exon 14 skipping mutations. Safety, pharmacokinetics, and efficacy were assessed. Herein, the analysis of patients receiving ≥1.6 mg/kg once every 2 weeks or ≥2.4 mg/kg once every 3 weeks Teliso-V is reported. RESULTS: Fifty-two patients with NSCLC were enrolled and received ≥1.6 mg/kg Teliso-V once every 2 weeks (n = 28) or ≥2.4 mg/kg Teliso-V once every 3 weeks (n = 24). The most common adverse events were fatigue (54%), peripheral neuropathy (42%), and nausea (38%). No dose-limiting toxicities were observed for Teliso-V once every 2 weeks and once every 3 weeks up to 2.2 and 2.7 mg/kg, respectively. The recommended phase II dose was established at 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks on the basis of overall safety and pharmacokinetics. Forty of 52 patients were c-Met+ (33 nonsquamous, 6 squamous, 1 mixed histology) and were included in the efficacy-evaluable population. Of those, 9 (23%) had objective responses with median duration of response of 8.7 months; median progression-free survival was 5.2 months. CONCLUSIONS: Teliso-V monotherapy was tolerated and showed antitumor activity in c-Met+ NSCLC. On the basis of overall safety, pharmacokinetics, and efficacy outcomes, 1.9 mg/kg Teliso-V once every 2 weeks and 2.7 mg/kg once every 3 weeks schedules were selected for further clinical development.

Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer.

The humanized KS-interleukin-2, tucotuzumab (huKS-IL2; EMD 273066), is an EpCAM-specific immunocytokine with reported immunologic activity in combination with cyclophosphamide. This Phase 2, randomized, open-label study compared tucotuzumab/cyclophosphamide, administered as maintenance, with best supportive care (BSC) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to first-line platinum-based chemotherapy with/without prophylactic cranial irradiation (PCI). Patients received cyclophosphamide (300 mg/m, Day 1 of every 3-week cycle), followed by tucotuzumab (1.5 mg/m, Days 2-4) until disease progression. The primary endpoint was 6-month progression-free survival (PFS); the secondary objectives included overall survival (OS), treatment response, and safety. The 6-month PFS rate was lower in the tucotuzumab/cyclophosphamide group (n=64) than in the BSC group (n=44): 6.4 versus 12.2% [hazard ratio (HR): 0.98; 80% confidence interval (CI): 0.74-1.31]. HRs for PFS, time to progression, and OS indicated a similar risk of disease progression and death in both groups and best overall responses were generally comparable. For patients with previous PCI (n=26), there was a nonsignificant trend toward prolonged median PFS (1.7 vs. 1.5 months; HR: 0.60; 80% CI: 0.33-1.11) and OS (21.5 vs. 14.3 months; HR: 0.58; 80% CI: 0.31-1.05) in the tucotuzumab/cyclophosphamide group. Adverse events were more frequent with tucotuzumab/cyclophosphamide (92.2%) than with BSC (47.7%). Tucotuzumab/cyclophosphamide was well tolerated in ED-SCLC patients, but did not show PFS or OS benefits compared with BSC. The observed trend toward prolonged PFS and OS in the subgroup of patients receiving previous PCI may support further confirmation in a larger population.

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.

A phase I clinical trial of darinaparsin in patients with refractory solid tumors.

PURPOSE: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used. RESULTS: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. CONCLUSIONS: The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks.