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Choueiri T.K.,Dana-Farber Cancer Institute | Vaishampayan U.,Barbara Ann Karmanos Cancer Institute | Rosenberg J.E.,Dana-Farber Cancer Institute | Logan T.F.,Indiana University | And 19 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations. © 2012 by American Society of Clinical Oncology. Source

Coiffier B.,Hematology | Osmanov E.A.,Cancer Research Center | Hong X.,Fudan University | Scheliga A.,Instituto Nacional Of Cancer | And 15 more authors.
The Lancet Oncology | Year: 2011

Background: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m2, administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Findings: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc. © 2011 Elsevier Ltd. Source

Duchnowska R.,Military Institute of Medicine | Biernat M.,Medical University of Gdansk | Szostakiewicz B.,Medical University of Gdansk | Sperinde J.,Monogram Biosciences | And 16 more authors.
Oncologist | Year: 2012

Background. Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) inHER-2+ advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy forHER-2+ metastatic breast cancer. HER-2/ neu gene copy number was quantified as the HER-2/ centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab- containing therapy. Results. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p =.013, 28, and 25, respectively). In the subset of patients that was centrally determined by FISH to beHER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p =.005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p =.4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p =.024). Conclusions. These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse inHER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group. © AlphaMed Press. Source

Chumsri S.,Mayo Medical School | Weidler J.,Monogram Biosciences | Weidler J.,Oncology Research and Development | Ali S.,Foundation Medicine | And 9 more authors.
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2015

In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation. © JNCCN-Journal of the National Comprehensive Cancer Network. Source

Xu C.-F.,Glaxosmithkline | Reck B.H.,nc | Goodman V.L.,Oncology Research and Development | Xue Z.,nc | And 7 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. Methods: Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. Results: Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p <0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r2 = 0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6) × ULN for rs2858996 GG (n = 148), GT (n = 82), and TT (n = 1 2) genotypes, respectively. All 12 TT patients had a maximum ALT >ULN, and 8 (67%) had ALT ≥3 × ULN. The odds ratio (95% CI) for ALT ≥3 × ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT ≥3 × ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. Conclusions: The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

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