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ABSTRACT: Background: Anaplastic Thyroid Cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogeneis mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor which acts on raf-1 serine/threonine kinase. In preclinical mouse models sorafenib inhibits growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with anaplastic thyroid carcinoma who had failed up to two previous therapies. Methods: The primary endpoint of the trial was RECIST-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. Results: Two of 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months respectively. For the patients with stable disease the median duration was 4 months (range 3-11 months). The overall median PFS was 1.9 months with a median and 1-year survival of 3.9 months and 20% respectively. Toxicity was manageable and as previously described for sorafenib including hypertension and skin rash. Conclusion: Sorafenib has activity in ATC but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 Impact Factor
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ABSTRACT: Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy.
We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale.
Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily.
This combination is well-tolerated and has significant clinical activity.
Cancer Chemotherapy and Pharmacology 08/2012; 70(4):547-53. · 2.83 Impact Factor
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ABSTRACT: We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN).
Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m(2) and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B(12) supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF.
Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034).
The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
Journal of Clinical Oncology 02/2011; 29(9):1140-5. · 18.37 Impact Factor
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Charles J Nock,
Joanna M Brell,
Joseph A Bokar,
Matthew M Cooney,
Brenda Cooper,
Joseph Gibbons,
Smitha Krishnamurthi,
Sudhir Manda, Panayiotis Savvides,
Scot C Remick,
Percy Ivy,
Afshin Dowlati
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ABSTRACT: Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.
Investigational New Drugs 09/2009; 29(1):126-30. · 3.36 Impact Factor
