Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

Vemurafenib prolongs survival in patients with BRAFV600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAFV600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers.

Cell-free DNA concentration and integrity as a screening tool for cancer.

AIM OF THE STUDY: This study aims to evaluate cell-free DNA (CFDNA) concentration and integrity in patients with malignant and nonmalignant diseases and in controls to investigate their value as a screening test for cancer, and to correlate them with clinicopathological parameters of cancer patients. MATERIALS AND METHODS: The study included three groups; group I: 120 cancer patients, group II: 120 patients with benign diseases and group III: 120 normal healthy volunteers as control. One plasma sample was collected from each subject. CFDNA was purified from the plasma then its concentration was measured and integrity was assessed by PCR amplification of 100, 200, 400, and 800 bp bands. RESULTS: There was a highly significant difference in CFDNA levels between cancer group and each of benign and control groups. AUC of ROC curve for cancer group versus normal and benign groups were 0.962 and 0.895, which indicated the efficiency of CFDNA as a marker of cancer. As for integrity, normal and benign subjects showed only two bands at 100 and 200 bp, while all cancer patients demonstrated the 400 bp band and 78% of them had the 800 bp whose presence correlated with vascular invasion. CONCLUSION: The combined use of CFDNA concentration and integrity is a candidate for a universal screening test of cancer. Upon setting suitable boundaries for the test it might be applied to identify cancer patients, particularly among subjects with predisposing factors. Being less expensive, CFDNA concentration could be applied for mass screening and for patients with values overlapping those of normal and benign subjects, the use of the more expensive, yet more specific, integrity test is suggested.

Randomized study of concurrent carboplatin, paclitaxel, and radiotherapy with or without prior induction chemotherapy in patients with locally advanced non-small cell lung cancer.

BACKGROUND: Multiple concepts of combined modality therapy for locally advanced inoperable non-small cell lung cancer have been investigated. These include induction chemotherapy, concomitant chemo-radiotherapy, and radiation only. To date, combined modality therapy specially the use of concomitant chemo-radiotherapy has led to promising results and was shown to be superior to radiotherapy alone in phase II studies. However the optimum chemo-therapeutic regimen to be used as well as the benefit of induction chemotherapy before concomitant chemo-radiotherapy are yet to be determined. Based on these observations, we investigated the use of paclitaxel and carboplatin concomitantly with radiotherapy and the benefit of prior two cycles induction chemotherapy. MATERIALS AND METHODS: In this trial 60 patients with locally advanced inoperable non small cell lung cancer, good performance status and minimal weight loss have been randomized into 3 groups each of 20 patients. Group A received induction 2 cycles paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 and 28th followed by concomitant paclitaxel (45 mg/m2) and carboplatin (AUC 2) weekly with radiotherapy. Group B received concomitant carboplatin, paclitaxel (same doses as in group A) and radiotherapy with no prior induction chemotherapy. Group C received only radiotherapy to a total dose of 60 Gy in conventional fractionation. RESULTS: A total of 60 patients were enrolled in this study between 1998 and 2000. Pretreatment characteristics, including age, gender, performance status, histological features and stage were comparable in each group. The incidence of oesophagitis was significantly higher in group A and B than in group C (p=0.023). Hematological toxicities was also significantly higher in group A & B than in group C (p=0.003). The response rate was significantly higher in group A and B than in group C (75%, 79%, and 40% respectively) (p=0.020). The time to in-field progression was significantly higher in group B as compared to group A (48% vs. 32% failure in 2 years respectively) (p=0.000). The median 2 year survival was significantly higher in group A and B than in group C (p=0.039) but no statistical difference was seen between group A and B. CONCLUSION: Combined chemo-radiotherapy resulted in better response and survival as compared to conventional radiotherapy in the treatment of locally advanced nonsmall cell lung cancer. Early initiation of radiation with concomitant chemotherapy resulted in prolonged time to infield progression. On the other hand, two cycles of induction chemotherapy did not show any significant difference regarding the response or survival. Weekly paclitaxel and carboplatin plus radiotherapy is a well tolerated regimen for outpatients with encouraging results.