Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer.

BACKGROUND: Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer. MATERIALS AND METHODS: This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer. RESULTS: Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit. CONCLUSIONS: Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.

Phase I dose-escalation trial of afatinib, an irreversible ErbB family blocker, in combination with gemcitabine or docetaxel in patients with relapsed or refractory solid tumors.

Background Afatinib, an irreversible ErbB family blocker, has shown synergistic antitumor activity and manageable tolerability in combination with chemotherapy. This phase I study assessed oral afatinib plus intravenous gemcitabine or docetaxel in patients with relapsed/refractory solid tumors. Methods Patients received afatinib (30, 40, or 50 mg) plus gemcitabine (1000 or 1250 mg/m2) or docetaxel (60 or 75 mg/m2). Dose escalation proceeded via a 3 + 3 design until the maximum tolerated dose (MTD) was reached. Adverse events (AEs), pharmacokinetics and antitumor activity were also assessed. Results Dose-limiting toxicities during Cycle 1 were reported in 6/39 patients receiving afatinib/gemcitabine (most commonly diarrhea, thrombocytopenia and vomiting) and 16/54 patients receiving afatinib/docetaxel (most commonly febrile neutropenia and stomatitis). The MTDs were established as afatinib 40 mg/gemcitabine 1000 mg/m2 and afatinib 30 mg/docetaxel 60 mg/m2. The most common drug-related AEs were diarrhea, asthenia and rash with afatinib/gemcitabine, and diarrhea, asthenia and stomatitis with afatinib/docetaxel. No relevant pharmacokinetic interactions were observed for either combination. Both combinations demonstrated clinical activity and durable disease control at the MTDs. Compared with the MTD, higher response rates were achieved with afatinib 30 mg/docetaxel 75 mg/m2 (28% vs 6%); however, this regimen was associated with problematic febrile neutropenia, an expected AE with docetaxel, that is often managed with growth factor support. Conclusions Afatinib/gemcitabine and afatinib/docetaxel demonstrated manageable safety profiles, with evidence of clinical efficacy at the MTDs. For afatinib/docetaxel, a dose level of afatinib 30 mg/docetaxel 75 mg/m2 produced higher response rates. Trial registration: NCT01251653 ( ClinicalTrials.gov ).

A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole.

UNLABELLED: Phase II, open-label study assessing the efficacy and safety of the ErbB family blocker afatinib combined with letrozole in estrogen receptor-positive metastatic breast cancer (MBC) patients who had progressed on letrozole monotherapy. Adult females (N = 28) received oral afatinib (50 [n = 7], 40 [n = 13] or 30 [n = 8] mg/day) plus letrozole 2.5 mg/day in 28-day cycles until disease progression. Primary endpoint was the progression-free rate at or after 16 weeks of afatinib. At 16 weeks, four patients remained on afatinib without progression; two of these were HER2 negative. Fifteen (54 %) patients had a best response of stable disease according to Response Evaluation Criteria in Solid Tumors. Median progression-free survival was 60, 107 and 79 days with 50, 40 and 30 mg/day afatinib, respectively. Diarrhea, asthenia, rash, mucosal inflammation and nausea were the most frequent adverse events. In this small, exploratory study, afatinib combined with letrozole was able to induce disease stabilization in 54 % of hormone-refractory MBC patients previously progressing on letrozole. CLINICAL TRIAL REGISTRATION: NCT00708214.

Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel.

This open-label, phase II trial assessed the efficacy and safety of two doses of nintedanib, a triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor signaling, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on docetaxel-based regimens. Patients were randomized to nintedanib 150 mg (arm A, n=40) or 250 mg (arm B, n=41) twice daily for 6 months unless disease progression or adverse events (AEs) led to discontinuation. The primary endpoint was the prostate-specific antigen (PSA) response rate (confirmed PSA decline of ≥20% from baseline). Eighty-one patients were enrolled. The PSA response rate was 0% (0/32) in arm A versus 11.1% (4/36) in arm B (P=0.12); 5.6% of patients (2/36) in arm B showed a PSA reduction of at least 50%. In arm B, the rate of PSA increase was significantly decelerated on treatment versus before treatment (P=0.002). The median progression-free survival was 73.5 and 76.0 days for arm A and arm B, respectively (P=0.3). AEs included gastrointestinal disorders, asthenia, hypertension, and reversible elevated transaminases. The incidence of drug-related serious AEs (no drug-related deaths) was 20.0% (arm A) and 24.4% (arm B). The primary endpoint was not met. Nintedanib (250 mg) showed only modest activity with manageable AEs in patients with mCRPC post-docetaxel.