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A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer.
- Source :
-
Investigational new drugs [Invest New Drugs] 2015 Feb; Vol. 33 (1), pp. 177-86. Date of Electronic Publication: 2014 Oct 18. - Publication Year :
- 2015
-
Abstract
- Purpose: Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates.<br />Experimental Design: Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every 3 weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs).<br />Results: Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events ≥ grade 2 were diarrhea (n = 33, 35 %) and hypertension (n = 10, 11 %). The recommended phase 2 dose was trastuzumab 6 mg/m(2) (loading = 8 mg/m(2)) and bevacizumab 15 mg/kg every 3 weeks, with lapatinib 1,250 mg daily (full FDA-approved dose of each drug). One patient (1 %) achieved a complete response (CR); eight (9 %), a partial response (PR) (includes breast (n = 7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n = 1); and 14 (15 %), stable disease (SD) ≥6 months (total SD ≥ 6 months/PR/CR =23 (25 %). All patients with PR/CR received prior trastuzumab +/- lapatinib. SD ≥ 6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N = 75 patients tested) but not with HER2 SNPs.<br />Conclusions: Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized adverse effects
Antineoplastic Combined Chemotherapy Protocols adverse effects
Bevacizumab
Female
Humans
Lapatinib
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms genetics
Neoplasms metabolism
Quinazolines administration & dosage
Quinazolines adverse effects
Receptor, ErbB-2 genetics
Receptor, ErbB-2 metabolism
Trastuzumab
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 33
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 25323060
- Full Text :
- https://doi.org/10.1007/s10637-014-0173-7