ABSTRACT
PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.
Subject(s)
Aminopyridines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Morpholines/adverse effects , Trastuzumab/adverse effects , Adult , Aged , Aminopyridines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/analysis , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Capecitabine/administration & dosage , Capecitabine/adverse effects , Disease Progression , Drug Resistance, Neoplasm/drug effects , Female , Humans , Maximum Tolerated Dose , Middle Aged , Morpholines/administration & dosage , Receptor, ErbB-2/metabolism , Response Evaluation Criteria in Solid Tumors , Trastuzumab/administration & dosageABSTRACT
Preoperative chemoradiotherapy has demonstrated to improve resectability and local control in locally advanced rectal cancer (LARC). 5-fluorouracil (5FU) has traditionally been the drug of choice in combination with radiation therapy. Early studies of capecitabine (CAP) have shown its potential to replace 5FU. Between March 2002 and April 2005, 31 patients with newly diagnosed LARC (T2 N+ 2 cases, T3 N0-N+ 25 cases, T4 N0-N+ 4 cases) received the combined treatment. Surgery was planned 6-8 weeks after chemoradiation. Adjuvant chemotherapy with 5FU plus leucovorin for 6 courses was given in pN+ patients. All patients completed the planned treatment. Grade 3 acute toxicity was observed in 5 patients (16%). Nineteen patients (61%) had a downstaging. A complete pathological remission was observed in 3 cases (10%). Median follow-up is of 23 months (range; 6-36 months). The results of this experience confirm the data of the literature about the feasibility and efficacy of a neoadjuvant treatment with radiation and CAP in LARC.
