Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer.

OBJECTIVE: This study investigated the safety and tolerability of lifastuzumab vedotin (DNIB0600A) (LIFA), an antibody-drug conjugate, in patients with recurrent platinum-sensitive ovarian cancer (PSOC). METHODS: In this open-label, multicenter phase 1b study, LIFA was administered intravenously once every 3 weeks (Q3W) with starting dose 1.2 mg/kg in a 3 + 3 dose-escalation scheme. All patients received carboplatin at dose AUC 6 mg/mL·min (AUC6) Q3W for up to 6 cycles. Dose expansion cohorts were enrolled ± bevacizumab 15 mg/kg Q3W. RESULTS: Patients received LIFA at 1.2, 1.8, and 2.4 mg (n = 4, 5, and 20, respectively) with carboplatin. The maximum tolerated dose was not reached. The recommended phase 2 dose (RP2D) was LIFA 2.4 mg/kg + carboplatin AUC6 (cycles 1-6), with or without bevacizumab 15 mg/kg. Twelve patients received RP2D with bevacizumab. All patients experienced ≥1 adverse event (AE). The most common treatment-related AEs were neutropenia, peripheral neuropathy, thrombocytopenia, nausea, fatigue, anemia, diarrhea, vomiting, hypomagnesaemia, aspartate aminotransferase increased, alanine aminotransferase increased, and alopecia. Thirty-four (83%) patients experienced grade ≥ 3 AEs, the most frequent of which were neutropenia and thrombocytopenia. Nine (22%) patients experienced serious AEs. Pulmonary toxicities (34%), considered a potential risk of LIFA, included one patient who discontinued study treatment due to grade 2 pneumonitis. The median duration of progression-free survival was 10.71 months (95% CI: 8.54, 13.86) with confirmed complete/partial responses in 24 (59%) patients. Pharmacokinetics of mono-therapy LIFA was similar in combination therapy. CONCLUSION: LIFA in combination with carboplatin ± bevacizumab demonstrated acceptable safety and encouraging activity in PSOC patients.

Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.

PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49 years.

BACKGROUND: Three important studies have supported licensure of live, attenuated, cold-adapted influenza vaccine (CAIV-T [FluMist; MedImmune Vaccines]): (1) a pediatric efficacy trial involving children 15-71 months of age, (2) a large safety study of medically attended events occurring among children 1-17 years of age, and (3) an effectiveness trial involving healthy working adults 18-64 years of age. METHODS: During the United States Food and Drug Administration (FDA) review for the approval of CAIV-T for use in healthy persons, additional subgroup analyses were conducted to evaluate the safety, efficacy, and effectiveness of the vaccine, by use of various age subsets not prespecified by the original protocols. CAIV-T is currently approved by the FDA for use in healthy persons 5-49 years of age. In this article, we present data from some of the aforementioned subanalyses. RESULTS: The efficacy of CAIV-T in children >or=5 years of age (age range of the children in year 1 of the study, 60-71 months; age range of the children in year 2 of the study, 60-83 months) was similar to that reported for the entire cohort in year 1 (90.6%; 95% confidence interval [CI], 70.3%-97.1%). In year 2 of the study, efficacy was 86.9% (95% CI, 70.8%-94.1%), despite the presence of antigenically drifted influenza type A/Sydney/5/97 (H3N2), which caused most illnesses that occurred in year 2. Safety outcomes for children 5-17 years of age revealed no significant difference between vaccine recipients and placebo recipients, with regard to acute respiratory events, acute gastrointestinal events, systemic bacterial infection, or rare events possibly related to influenza. Effectiveness among adults 18-49 years of age was similar to that reported for the entire cohort--for example, for occurrence of severe febrile illness, there was a 19.5% reduction (P=.02) in adults. CONCLUSIONS: The present reanalysis summarizes data on the indicated uses for CAIV-T in the indicated population aged 5-49 years.

Measuring antibody responses to a live attenuated influenza vaccine in children.

BACKGROUND: Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children. METHODS: Sera were collected from 50 children 1-8 years of age before vaccination and 4-6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays. RESULTS: Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fisher's exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99). CONCLUSIONS: The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.

Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents.

OBJECTIVE: To determine the safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV) in children and adolescents. STUDY DESIGN: A randomized, double blind, placebo-controlled safety trial in healthy children age 12 months to 17 years given CAIV (FluMist; MedImmune Vaccines, Inc.) or placebo (randomization, 2:1). Children <9 years of age received a second dose of CAIV or placebo 28 to 42 days after the first dose. Enrolled children were then followed for 42 days after each vaccination for all medically attended events. Prespecified outcomes included 4 prespecified diagnostic groups and 170 observed individual diagnostic categories. The relative risk and the 2-sided 90% confidence interval were calculated for each diagnostic group and individual category by clinical setting, dose and age. More than 1500 relative risk analyses were performed. RESULTS: A total of 9689 evaluable children were enrolled in the study. Of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events and rare events potentially associated with wild-type influenza), none was associated with vaccine. Of the biologically plausible individual diagnostic categories, 3, acute gastrointestinal events, acute respiratory events and abdominal pain, had different analyses that demonstrated increased and decreased relative risks, making their association with the vaccine unlikely. For reactive airway disease a significant increased relative risk was observed in children 18 to 35 months of age with a relative risk of 4.06 (90% confidence interval, 1.29 to 17.86) in this age group. The individual diagnostic categories of upper respiratory infection, musculoskeletal pain, otitis media with effusion and adenitis/adenopathy had at least one analysis that achieved a significant increased risk ratio. All of these events were infrequent. CONCLUSION: CAIV was generally safe in children and adolescents. The observation of an increased risk of asthma/reactive airway disease in children <36 months of age is of potential concern. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine.

Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma.

BACKGROUND: Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children. PURPOSE: To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma. METHODS: In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination. RESULTS: The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 > or =15% from baseline, reductions in peak flows > or =15%, > or =30% or > or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred. CONCLUSION: CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.

Live attenuated influenza vaccine induces cross-reactive antibody responses in children against an a/Fujian/411/2002-like H3N2 antigenic variant strain.

Serum antibody titers against the A/Panama/2007/99(H3N2) and A/Fujian/411/2002(H3N2)-like viruses were determined in children 6-35 months of age who received either 1 dose of the inactivated influenza vaccine or the live attenuated influenza vaccine containing the A/Panama strain. Results indicated that the live vaccine induced higher antibody responses than the inactivated vaccine against the A/Panama and A/Fujian-like viruses.

Safety and immunogenicity of concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella and varicella vaccines to infants 12 to 15 months of age.

OBJECTIVE: This study evaluated the safety, tolerability, and immunogenicity of live attenuated influenza vaccine administered concurrently with measles-mumps-rubella vaccine and varicella vaccine to healthy children 12 to 15 months of age. METHODS: Children were assigned randomly to receive (1) measles-mumps-rubella vaccine, varicella vaccine, and intranasal placebo on day 0, followed by 1 dose of live attenuated influenza vaccine on days 42 and 72; (2) measles-mumps-rubella, varicella, and live attenuated influenza vaccines on day 0, followed by a second dose of live attenuated influenza vaccine on day 42 and intranasally administered placebo on day 72; or (3) 1 dose of live attenuated influenza vaccine on days 0 and 42, followed by measles-mumps-rubella and varicella vaccines on day 72. Serum samples were collected before vaccination on days 0, 42, and 72. Reactogenicity events and adverse events were collected through day 41 after concurrent vaccinations and through day 10 after administration of live attenuated influenza vaccine or placebo alone. RESULTS: Among 1245 (99.5%) evaluable children, seroresponse rates and geometric mean titers for measles-mumps-rubella vaccine and varicella vaccine were similar with concurrent administration of live attenuated influenza vaccine or placebo (seroresponse rates of > or = 96% for measles-mumps-rubella vaccine and > or = 82% for varicella vaccine in both groups). Hemagglutinin-inhibiting antibody geometric mean titers and seroconversion rates to influenza strains in live attenuated influenza virus vaccine were similar after the vaccine was administered alone (seroconversion rates of 98%, 92%, and 44% for H3, B, and H1 strains, respectively) or with measles-mumps-rubella and varicella vaccines (seroconversion rates of 98%, 96%, and 43%). The incidences of reactogenicity events and adverse events were similar among treatment groups. CONCLUSIONS: Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated.

Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children.

Highest attack rates for influenza occur in children. Immunization of schoolchildren with inactivated influenza vaccine in Michigan and Japan was associated with decreased morbidity and mortality, respectively, in older community contacts. An open-labeled, non-randomized, community-based trial in children with the cold adapted influenza vaccine, trivalent (CAIV-T) was initiated to determine the coverage necessary to reduce spread of influenza in the community. Age-specific baseline rates of medically attended acute respiratory illness (MAARI) for Scott and White Health Plan (SWHP) members at intervention (Temple and Belton) and comparison communities (Waco, Bryan, and College Station) were obtained in 1997-1998. During three subsequent vaccination years, 4298, 5251 and 5150 children received one dose per season of CAIV-T. Vaccinees represented 20-25% of the age-eligible children. Age-specific MAARI rates were compared for SWHP members in the intervention and comparison sites during the influenza outbreaks. Baseline age-specific MAARI rates per 100 persons for the influenza season were comparable between the intervention and comparison communities. In the subsequent three influenza seasons, the age groups 35-44, 45-54, 55-65 and >64 years experienced reductions in MAARI rates in the intervention communities. In adults > or =35 years of age, significant reductions in MAARI of 0.08 (95% CI: 0.04, 0.13), 0.18 (95% CI: 0.14, 0.22) and 0.15 (95% CI: 0.12, 0.19), were observed in the influenza seasons for vaccination years 1, 2 and 3, respectively. No consistent reduction in MAARI rates was detected in the younger age groups. Vaccination of approximately 20-25% of children, 1.5-18 years of age in the intervention communities resulted in an indirect protection of 8-18% against MAARI in adults > or =35 years of age.

A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.

BACKGROUND: A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS: One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS: The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS: Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities.

This study was designed to compare the safety and immunogenicity of a trivalent live-attenuated, cold-adapted influenza vaccine (CAIV-T) blended and filled at two different manufacturing facilities (Medeva and Aviron-PA). The vaccines contained approximately 10(7) TCID(50) (median tissue culture infectious dose) of each of the three recommended 1997-1998 influenza vaccine components, A/Shenzhen/227/95 (H1N1) (A/Bayern/7/95 (H1N1)-like strain), A/Wuhan/359/95 (H3N2), and B/Ann Arbor/1/94 (B/Beijing/184/93-like strain). Two hundred and twenty-five healthy Australian children aged 12-42 months were enrolled and randomized in a 3:2 ratio to receive CAIV-T blended and filled either at Medeva or at Aviron-PA. Two doses of CAIV-T were given 4-6 weeks apart as an intranasal spray. Three blood specimens were collected (immediately before doses one and two, and 28 +/- 5 days following dose two) for measuring hemagglutination inhibition (HAI) antibody responses. Adverse events occurring within 10 days and serious adverse events occurring within 42 days were collected. Serum HAI antibody levels were measured against the three vaccine strains. Equivalent immunogenicity between the two vaccine groups was pre-specified as: (1) within 20% difference in seroconversion rates (HAI titers > or =4-fold rise); and (2) within 4-fold difference in the 90% confidence interval of geometric mean titer ratio. Among 10 pre-specified adverse events, only vomiting had significantly different incidence rates in the two vaccine groups following dose one (3% versus 13%, P = 0.01) but the difference disappeared following dose two (4% versus 4%). Differences in seroconversion rates following dose two between the two vaccine groups in pre-vaccination seronegative children were all <20% for the three vaccine strains (16% for H1N1, 0% for H3N2, and 0% for B). The results indicate that CAIV-T blended and filled in the two facilities had equivalent profiles of safety and immunogenicity.

Safety of the trivalent, cold-adapted influenza vaccine in preschool-aged children.

OBJECTIVE: To provide additional information on the safety of trivalent, cold-adapted influenza vaccine (CAIV-T) in children. METHODS: Children 15 to 71 months of age were enrolled in a multicenter, prospective, randomized, double-blind, and placebo-controlled trial to receive by nasal spray CAIV-T or placebo. In year 1 (1996-1997), 1314 were enrolled in the 2-dose cohort and 288 were enrolled in the 1-dose cohort. In year 2 (1997-1998), 1358 of the original participants received 1 dose of vaccine or placebo according to their original treatment group assignment. In year 3 (1998-1999) and year 4, the trial continued as an open-label safety trial of CAIV-T. A total of 642 and 549 children enrolled in years 3 and 4, respectively, received their third and fourth sequential annual doses of CAIV-T. Measured were 1) the occurrence of specific respiratory, gastrointestinal and systemic symptoms, unexpected symptoms (not specified in the diary card), and use of medications within the first 10 days after vaccination; 2) the occurrence of an acute illness and use of medication within 11 to 42 days after vaccination; and 3) the occurrence of serious adverse events within 42 days after vaccination. RESULTS: The adjusted odd ratios of specific respiratory and gastrointestinal symptoms during the 10 days after vaccination were determined in years 1 and 2. Runny nose or nasal congestion, vomiting, muscle aches, and fever were significantly associated with the first dose of CAIV-T. With the second dose, runny nose was the only symptom that was associated with CAIV-T. In year 2, CAIV-T did not cause excess in any of the specific respiratory and gastrointestinal symptoms. In years 3 and 4, specific respiratory and gastrointestinal symptoms were comparable to that observed in year 2. A CAIV-T-associated symptom was most likely to occur on day 2 with the first dose of vaccine. The occurrence of unexpected symptoms was primarily of the gastrointestinal system. Approximately 6% of CAIV-T and 3.6% of placebo recipients had a gastrointestinal symptom. CAIV-T seemed to be associated with a mild excess in abdominal pain and vomiting only with the first vaccine dose. A statistically significant increase in the use of analgesics/antipyretics was detected only with the first dose in CAIV-T vaccinees compared with placebo recipients (23.5% vs 16.6%). Between days 11 and 42, CAIV-T use was not associated with an excess of illness, otitis media, or use of medication. None of the 6 serious adverse events in CAIV-T recipients in years 1 to 4 was attributed to the vaccine. CONCLUSIONS: CAIV-T was safe in children. Mild respiratory, gastrointestinal, and systemic symptoms of short duration were observed in a minority of children and primarily with the first vaccine dose. Sequential annual doses of CAIV-T were well tolerated.