Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

Recombinant human interferon-beta in the treatment of condylomata acuminata.

The number of clinic consultations for condylomata acuminata (genital warts) has increased substantially during the last 30 years. Most infections produce benign lesions but a few types may be associated with cervical and penile cancers. Interferons (IFN) have shown antiviral properties to these infections and IFN-beta in particular has demonstrated a specific cytopathic effect in humans. A total of 124 patients with condylomata acuminata, the majority of whom had failed previous therapy, were treated intralesionally with either recombinant human interferon-beta la (r-hIFN-beta-1a) or placebo. Up to 6 lesions were treated in each patient, and injections were made 3 times per week for a total of 9 injections. The patients were then followed up for 3 months. Efficacy assessments at all time points (day 19, week 6 and month 3) showed a clear advantage for the r-hIFN-beta-1a interferon-beta treatment. Patients receiving r-hIFN-beta-1a showed a greater proportion of treatment success in terms of the complete or partial reduction (at least 50%) of the total area of the treated lesions. The treatment was also well tolerated. Headache, flu-like symptoms and asthenia were more common in patients receiving r-hIFN-beta-1a, but these adverse events were generally mild in severity and rarely led to patient withdrawal. It was concluded that r-hIFN-beta-1a has good efficacy in condylomata acuminata, and therefore presents a useful therapeutic alternative in this hard-to-treat condition.

Incidence of antibodies to interferon-beta in patients treated with recombinant human interferon-beta 1a from mammalian cells.

Patients receiving recombinant human interferon-beta 1a (IFN-beta 1a) produced in Chinese hamster ovary (CHO) cells were tested for the formation of neutralizing antibodies (NABs) to IFN-beta. Samples were tested in an enzyme-linked immunosorbent assay (ELISA), and if positive were then tested for neutralization of antiviral activity in an IFN-beta bioassay. A total of 793 patients with viral diseases, premalignant and malignant diseases, and multiple sclerosis received IFN-beta 1a in clinical studies. Long-term studies included 56 patients with cancer treated for 6 or 12 months and 334 patients with multiple sclerosis (MS) at the end of one year of treatment. All of the NAB-positive patients were found in the latter. Positivity in a single specimen was found in 14.4% of the MS patients. The incidence of sustained neutralizing antibody titres (i.e. positive in two tests at least 6 months apart) was 6.9% in this group. Comparison with results from other studies suggests that CHO-derived IFN-beta 1a induces less neutralizing antibody than IFN-beta 1b produced in E. coli.

Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers.

The pharmacokinetics and pharmacodynamics of recombinant human interferon-beta (rHuIFN-beta 1a) were assessed following administration to 12 healthy male volunteers. Each subject received, in a double-blind, balanced, random-order, crossover sequence, single doses of 6 MIU of rHuIFN-beta 1a (Rebif) i.v., i.m., and s.c. or matching placebo on four occasions separated by washout periods of 1 week. Blood samples were collected at preset times for the measurement of serum IFN-beta levels and of intracellular 2'-5'-oligoadenylate synthetase levels. Blood pressure, sitting heart rate, respiratory rate, oral body temperature, and tolerance were monitored regularly. All administrations of rHuIFN-beta 1a were well tolerated, although about half of the subjects had a flu-like syndrome, as expected. After i.v. bolus injection, the pharmacokinetics of rHuIFN-beta 1a were well described by a classic two-compartment model. Mean total clearance of rHuIFN-beta 1a was about 100 L.h-1. The distribution half-life was 5 min, and the terminal half-life was approximately 5 h. After i.m. or s.c. injection, serum IFN-beta profiles were rather flat, and about one sixth of the administered dose was available systemically. Extent and duration of clinical and biologic effects were independent of the route of administration and of the IFN-beta serum levels. Biologic pharmacodynamic effects persisted even when IFN-beta serum levels had returned to baseline and were still significantly elevated 3 days after a single dose. Because of the independence of the extent and duration of clinical and biologic pharmacodynamic effects from the route of administration and from the IFN-beta serum levels, the s.c route of administration is preferred in indications in which primarily an immunomodulatory action is sought. Predominantly antiviral and antiproliferative activity is enhanced by the i.v. route to provide adequate drug levels at the site of pathology, although its application is limited on practical grounds.

Randomised double-blind trial of recombinant interferon-beta for condyloma acuminatum.

OBJECTIVE: To evaluate the safety and efficacy of two intralesional doses of recombinant human interferon-beta (r-hIFN-beta: Rebif, Ares Serono), given 3 times a week for 3 weeks, in the treatment of condyloma acuminatum. DESIGN: A randomised, double-blind, within-patient, placebo-controlled study. SUBJECTS: 25 patients (24 males, 1 female) with a history of condyloma acuminatum. Twenty had failed previous treatment for condyloma acuminatum. In each patient, 3 distinct lesions were selected for treatment. Each selected lesion was randomly assigned to receive intralesionally one of the following: r-hIFN-beta 33,000 IU/day, r-hIFN-beta 1 x 10(6) IU/day, or matching placebo. SETTING: Institut Alfred Fournier, Paris, France. OUTCOME MEASURES: Response was evaluated colposcopically at the end of treatment (day 22) and 5 weeks later (month 2). Complete response (CR) was defined as disappearance of the treated lesion. Partial response (PR) was defined as at least a 50% reduction in size, but not disappearance of the treated lesion. RESULTS: The higher dose of 1 x 10(6) IU achieved significantly more complete and partial remissions than placebo, both by the end of treatment, and 5 weeks later. CONCLUSIONS: r-hIFN-beta appears to be safe and effective when administered intralesionally to patients with condyloma acuminatum. Most of the treated patients had failed previous treatments and were therefore a resistant population.

Recombinant human interferon beta in the treatment of relapsing-remitting and secondary progressive multiple sclerosis.

Two multicenter, randomized, double-blind, placebo-controlled phase III studies to evaluate the safety and efficacy of 6 and 12 MIU of recombinant human interferon beta (r-hIFN-beta) (Rebif) given subcutaneously three times per week, in patients with MS, are described. In one study, patients with relapsing-remitting multiple sclerosis are treated for 24 months; the primary efficacy end point is the number of exacerbations. In the other study patients with secondary progressive multiple sclerosis are treated for 36 months; the primary efficacy end point is time to sustained progression in disability as determined by the Expanded Disability Status Scale (EDSS). Both studies are conducted in centers in Europe, Australia and Canada.

Mechanisms of tumour cell escape encountered in treating lymphocytic leukaemia with anti-idiotypic antibody.

Four patients with chronic lymphocytic leukaemia were treated by one or more infusions of polyclonal antibody specific for the immunoglobulin idiotype expressed on their leukaemic cells. The antibody was in the form of IgG from sheep antiserum. Three of the 4 cases showed a significant fall in blood lymphocyte count. On one occasion most of the residual circulating lymphocytes were apparently dead. However on all occasions the cell counts rebounded to near pre-infusion levels within one week. Viable lymphocytes recovered from the blood after infusion always showed evidence of antigenic modulation: a diminished level of surface idiotype in a patched distribution, with an accompanying refractoriness to lysis by anti-idiotype plus complement. When cultured in vitro blood lymphocytes from three of the four patients revealed an appreciable export of idiotypic Ig. These 3 patients showed plasma levels of idiotypic Ig up to 400 micrograms ml-1, reduced by plasma exchange prior to infusion. The fourth patient had a level of less than 4 micrograms ml-1, and was the only one in whom free antibody could be found in the plasma after infusion. These cases demonstrate two major factors which thwart antibody attack on leukaemic cells--extracellular antigen and antigenic modulation--as well as problems relating to sparseness of surface antigen, recruitment of effectors, and exhaustion of effectors.

Preliminary experience in treating lymphocytic leukaemia with antibody to immunoglobulin idiotypes on the cell surfaces.

Tumour-specific antiserum was raised in sheep against idiotypic determinants on the surface immunoglobulin of neoplastic lymphocytes from a patient with chronic lymphocytic leukaemia (prolymphocytic variant). The complement-activating IgG1 subclass of the anti-idiotype was prepared from the serum in monodisperse form for infusion. Two treatments of 480 and 1200 mg caused the white-cell count to fall by one-third and one-half respectively. However, there was a rapid resurgence, so that by 8 days after each treatment the counts were restored to approximately 85% of their former levels. No change was noted in the size of spleen or lymph nodes. Each treatment probably destroyed 4-8 X 10(11) cells, some 10% of the total tumour load. The antibody was rapidly consumed, and there was evidence of heavy utilization of complement.