A Phase II, Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma.

BACKGROUND: Overexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma. PATIENTS AND METHODS: Patients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination. RESULTS: The 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity. CONCLUSION: While sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).

A Phase II Study Alternating Erlotinib With Second-line mFOLFOX6 or FOLFIRI for Metastatic Colorectal Cancer.

BACKGROUND: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer. PATIENTS AND METHODS: A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate. RESULTS: The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%. CONCLUSION: In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity.

Severe bleeding in a woman heterozygous for the fibrinogen gammaR275C mutation.

The dysfibrinogen gammaR275C can be a clinically silent mutation, with only two out of 17 cases in the literature reporting a hemorrhagic presentation and four cases reporting a thrombotic presentation. We describe here a particularly severe presentation in 54-year-old female patient who required a hysterectomy at 47 years of age due to heavy menstrual bleeding. Coagulation studies revealed a prolonged prothrombin time and thrombin time, a normal fibrinogen antigen level, and a low fibrinogen activity level. Molecular analysis of the patient's DNA revealed a gamma chain gene mutation resulting in an amino acid substitution at residue 275 (gammaR275C). Protein sequencing of the fibrinogen gamma chain confirmed this mutation, which was named Fibrinogen Portland I. This case demonstrates that the gammaR275C mutation can lead to a severe hemorrhagic phenotype.

Treatment advice on the internet leads to a life-threatening adverse reaction: hypotension associated with Niacin overdose.

We describe a case of massive oral niacin overdose that resulted in severe persistent hypotension without the manifestation of cutaneous flushing. This case is the highest overdose of niacin reported in the literature to date and the first time severe persistent hypotension has been attributed to niacin. A 56-year-old male with a history of schizophrenia presented to the emergency department after orally ingesting 11,000 mg of niacin. The patient cited an Internet resource that recommended high-dose niacin for therapy of schizophrenia as the reason for his ingestion. He stopped his psychiatric medications several weeks prior to his niacin overdose. At presentation, the patient was alert and normothermic. His pulse was 68 beats per minute and his blood pressure was initially 92/41 mmHg. Hypotension with a blood pressure of 58/40 developed over the next few hours and persisted despite intravenous infusion of over 4 liters of normal saline. The physical exam was otherwise unremarkable, specifically without signs of an allergic reaction or cutaneous flushing. He required intravenous dopamine infusion for 12 hours to support a mean arterial blood pressure greater than 60 mmHg. Evaluation for other etiologies of hypotension was unrevealing. Serum niacin levels were 8.2 ug/ mL and 5.6 ug/mL at 48 and 96 hours post ingestion, respectively, giving an apparent T1/2 of 87 hours. Massive overdose of niacin appears to be capable of causing severe, persistent hypotension in the absence of cutaneous flushing. In this case, the ingestion of a dietary supplement based on Internet advice led to a severe adverse reaction.

Novel cytotoxic and biological agents for prostate cancer: where will the money be in 2005?

In 2004, docetaxel-based chemotherapy became the first treatment capable of extending life in androgen-independent prostate cancer. The era of therapeutic nihilism in this disease has thus been put to rest and a broad range of agents is being tested with the goal of improving on the successes of 2004. Lessons learned from other tumour types will need to be applied to prostate cancer in order to harness the bounty of available ideas. Target amplification or activating mutations and not merely the presence of a target are likely to be important to the success of targeted agents. Thus, the promise of the current crop of targeted agents is most likely to be realised when pursued in the context of well-credentialed targets and tested in highly translational clinical trials that are capable not only of assessing tumour response, but also of evaluating the status of the targeted pathway. The most promising agents in clinical development are reviewed.