Treatment for Dormant Malaria Shows Promise.


The first new drug in half a century to target malaria parasites in one of their best hideouts is showing encouraging results. The researchers developing the drug, called tafenoquine, said today that data from a recently completed phase II trial were promising enough that they will soon start a phase III trial—the last step before asking drug regulators for approval.

Tafenoquine kills the malaria parasite when it is lurking in liver cells, in a form called the hypnozoite, or “sleeping parasite.” Hypnozoites don’t cause any symptoms and are impossible to detect with blood tests. But when triggered by signals that aren’t fully understood, they can reactivate to cause a new bout of malaria—which can then be picked up by mosquitoes and passed on to new victims. Five species of Plasmodium can cause malaria in humans. Two of them—Plasmodium vivax, which is widespread, and the relatively rare P. ovale—can form hypnozoites. This ability to hide is one of the things that makes P. vivax so difficult to eliminate from a region.

Now, the only treatment that can cure vivax malaria—hiding parasites and all—is a 14-day course of a drug called primaquine, which was developed in the 1940s. It works fairly well, but it is difficult for people who don’t feel ill to complete the whole 2 weeks. “The compliance with the current regimen is really a problem,” says JP Kleim, director of clinical development for the pharmaceutical company GlaxoSmithKline (GSK). “The acute malaria is gone after a few days [of treatment],” so patients’ motivation to continue taking drugs is low. That’s why GSK decided to develop tafenoquine, together with the Medicines for Malaria Venture, a Geneva-based nonprofit. The partners launched a trial in 2011 to test whether a single dose of tafenoquine could work as well as the 2-week course of primaquine.

Vivax malaria, shown here in the blood stream, can hide out—undetectable—in liver cells.

The data, presented today at the American Society of Tropical Medicine and Hygiene Annual Meeting in Washington, D.C., suggest that a single dose works very well. The trial involved 329 patients in Brazil, India, Thailand, and Peru. In patients who received either a 300 mg or 600 mg dose of the drug, 90% had no relapses after 4 months. The partners will now go forward with a phase III trial, testing the safety and efficacy of the 300 mg dose in 600 patients, says Marcus Lacerda of the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado in Manaus, Brazil, who helped coordinate the study and presented the results at the meeting today.

A single-dose drug would be a huge advantage in the fight against vivax malaria, says Ric Price of the Menzies School of Health Research in Darwin, Australia, and the University of Oxford in the United Kingdom. “One of the biggest challenges we face is how can we adequately and reliably treat the hypnozoite stage.”

Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib.


This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib.

methods:

Patients received oral dovitinib, 500mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)–CT scans performed at baseline and after 4 weeks of treatment.

results:

Between September 2011 and April 2012, 30 patients were enroled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3–12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5–3.7 months) and median overall survival was 9.7 months (95% CI, 6.0–13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification.

conclusion:

Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.

Source: BJC

 

 

German Adjuvant Intergroup Node-Positive Study: A Phase III Trial to Compare Oral Ibandronate Versus Observation in Patients With High-Risk Early Breast Cancer.


Abstract

PURPOSE:

Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use.

PATIENTS AND METHODS:

The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed.

RESULTS:

Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093).

CONCLUSION:

Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Source: Pubmed