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In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of −7·1 (SD 7·0) mV (p<0·0001), and in the second, with a change of −3·7 (SD 7·3) mV (p=0·032). We recorded a response in total chloride transport (defined as a change in nasal PD of −5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0·0001) and in eight of the 21 patients in the second cycle (p<0·0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0·0003) and for nine of 21 in the second cycle (p=0·02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. PTC Therapeutics, Cystic Fibrosis Foundation Therapeutics.

The antimetabolite fluorouracil is widely used to treat metastatic colorectal cancer, the second-leading cause of death from cancer in North America. 1 The drug inhibits thymidylate synthase, an enzyme required for the synthesis of DNA. 2 It is commonly administered with leucovorin, a reduced folate (tetrahydrofolate) that increases the affinity of fluorouracil for thymidylate synthase. Among various schedules of administration, the efficacy of the Mayo Clinic bolus regimen, in which the two drugs are injected daily for five days every four weeks, has been validated in randomized trials 3 – 5 and is frequently used as first-line therapy for metastatic colorectal cancer. Irinotecan (Camptosar, . . .

A placebo-controlled study of idelalisib in patients with relapsed chronic lymphocytic leukemia who were receiving rituximab was stopped early because of significant improvement in rates of response, progression-free survival, and overall survival with idelalisib. Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among adults. Standard treatments include combinations of purine analogues, alkylating agents, and monoclonal antibodies. In younger patients without major coexisting illnesses, these regimens can provide high response rates of durable length but have substantial toxic effects. As a result, these treatments often have unacceptable side effects in older patients and those with coexisting illnesses. 1 Patients with relapsed CLL often have limited options because of the development of resistance to, or persisting toxic effects of, previous therapies. This is particularly true for elderly patients and those with coexisting illnesses. 2 For these patients, . . .

Idelalisib, which inhibits PI3K isoform delta, produced antitumor responses in nearly 60% of pretreated patients with indolent non-Hodgkin's lymphomas. Responses lasted a median of 11 months. Grade 3 or higher toxic effects were seen in 13 to 27% of patients. Indolent non-Hodgkin's lymphomas constitute approximately one third of all cases of non-Hodgkin's lymphoma and include follicular lymphoma, small lymphocytic lymphoma, marginal-zone lymphoma, and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia. 1 – 3 It was estimated that approximately 20,000 people in the United States were diagnosed with indolent non-Hodgkin's lymphoma in 2012 and that approximately 7000 died of this disease. 4 , 5 The mainstay of treatment for indolent non-Hodgkin's lymphoma is an anti-CD20 antibody (primarily rituximab) in combination with chemotherapy consisting of alkylating agents, anthracyclines, antimitotic agents, or purine analogues. Although the current treatments for indolent non-Hodgkin's lymphomas are initially effective in inducing . . .

Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

To the Editor: In the September 28 issue of the Journal, Saltz et al. 1 reported the superiority of the chemotherapy combination of irinotecan, fluorouracil, and leucovorin over irinotecan alone or fluorouracil and leucovorin in the initial treatment of metastatic colorectal cancer. The results of this large clinical trial indicated that the three-drug combination was tolerable and not associated with a significantly increased incidence of toxicity as compared with the other two forms of treatment. The incidence of treatment-related death was approximately 1 percent during the study. The Food and Drug Administration (FDA) has approved this regimen of irinotecan, fluorouracil, and . . .

Neutropenia and resultant infection are potentially life-threatening side effects of cancer chemotherapy. The use of dose-intensive chemotherapeutic regimens has made the management of myelosuppression increasingly important. Recombinant hematopoietic colony-stimulating factors, which stimulate the production of granulocytes, may be a way of reducing the infectious complications of myelotoxic cancer treatment. 1 – 3 The efficacy of colony-stimulating factors has been studied in several settings. Initially, attention was focused on preventing infection by starting treatment with the agents immediately after chemotherapy and continuing through the anticipated period of neutropenia. 4 – 6 These agents were then used therapeutically in patients with established neutropenia after chemotherapy, although . . .

PTC124: a no-nonsense drug Many inherited diseases result from premature termination during translation of a messenger RNA into protein; one such disease is muscular dystrophy. Welch et al . now report that a small molecule, PTC124, enables the translation machinery to bypass sites that cause premature termination, but still terminate normally at the end of the mRNA. In human and mouse cells, this drug restores normal translation of the gene that is mutated in muscular dystrophy, and it restores muscle function in the mdx mouse model for the human disease. This work offers the hope that similar drugs might be used to target nonsense mutations and restore protein function in a wide variety of diseases. PTC124 is now undergoing clinical trials in muscular dystrophy and cystic fibrosis patients. A small molecule, PTC124, enables the translation machinery for mRNA into proteins to bypass sites that cause premature termination, but still terminate normally at the end of the mRNA. In human and mouse cells, this drug restores normal translation of the gene that is mutated in muscular dystrophy, and restores muscle function in mdx mice that model the human disease. Nonsense mutations promote premature translational termination and cause anywhere from 5–70% of the individual cases of most inherited diseases 1 . Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease 2 , 3 . To address the need for a drug capable of suppressing premature termination, we identified PTC124—a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2–8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks. Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC. 20 patients (median age 61.5 years, range 40-75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m(2)/day. Of the eight patients enrolled at 60 mg/m(2), three patients experienced DLT (> or = grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m(2) dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC(0-24)) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated. Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m(2)/d.