Sc Tiw Research Articles

Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + BL-8040 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).

712 Background: The MORPHEUS platform comprises multiple Ph Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Due to the immune-mediated effects of BL-8040, a high-affinity antagonist for CXCR4, it was tested with atezo (anti-PD-L1) in pts with advanced/metastatic (m) PDAC and GC. Methods: In 2 separate randomized trials, pts with mPDAC or advanced/mGC who progressed on 1L chemo received either atezo + BL-8040 (BL-8040 1.25 mg/kg SC D1-5, then BL-8040 1.25 mg/kg SC TIW + atezo 1200 mg IV Q3W) or control tx (M-PDAC: mFOLFOX-6 or gemcitabine + nab-paclitaxel; M-GC: paclitaxel + ramucirumab). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: Efficacy from evaluable pts followed for ≥18 wks in M-PDAC and ≥8 wks in M-GC is summarized in the table; 24-wk M-GC data will be presented. There were 15 safety-evaluable pts in each M-PDAC arm, as well as 13 in the atezo + BL-8040 and 12 in the control arm of M-GC. Gr 3-5 AEs were seen in 47% of pts on atezo + BL-8040 and 67% on control in M-PDAC, and 77% on atezo + BL-8040 and 67% on control in M-GC. Tx-related SAEs in M-PDAC occurred in 7% of pts on atezo + BL-8040 and 20% on control, and in M-GC, in 8% of pts on control. No Gr 5 AEs occurred in atezo + BL-8040 arms. Tx-related AEs led to 7% and 8% of pts discontinuing tx in the M-PDAC and M-GC control arms, respectively, and 15% discontinuing BL-8040 in M-GC due to Gr 3 injection-related reactions. Biomarker and PK data will be presented. Conclusions: Atezo + BL-8040 had limited efficacy for PDAC or GC. Tx-related AEs with atezo + BL-8040 were consistent with each agent’s known safety profile. Clinical trial information: NCT03281369; NCT03193190 . [Table: see text]

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing\u2013remitting multiple sclerosis at year 1

BackgroundIn the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing–remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1.MethodsExploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed.ResultsPatients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006).ConclusionClinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.

Ease of use of two autoinjectors in patients with multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: results of the randomized, crossover REDEFINE study

ABSTRACTBackground: For interferon beta-1a subcutaneously three times weekly (IFN β-1a SC tiw), administration options include manually injected prefilled syringes; a preassembled, single-use autoinjector; and a reusable autoinjector. This study evaluated patient-perceived ease of use of two injection devices.Research design and methods: REDEFINE, a Phase IV, multicenter crossover study, randomized patients with multiple sclerosis and ≥5 weeks’ IFN β-1a 44 μg SC tiw use to 4 weeks using a single-use autoinjector, then 4 weeks using a reusable autoinjector, or vice versa. The primary endpoint was the proportion rating each ‘easy’ or ‘very easy’, with/without regard to previous device experience.Results: Of 97 randomized patients, 29 had most recent experience with manual injection; 23 with single-use autoinjector; and 45 with reusable autoinjector. 68.4% found using the single-use autoinjector very easy or easy, versus 77.9% for the reusable device (difference −9.5%; p = 0.200). 40.0% versus 29.5% found the respective devices very easy (difference 10.5%; p = 0.203).Conclusions: Most patients found both autoinjectors easy or very easy to use. Having two viable options may help accommodate patient preferences. Ease of administration and patient satisfaction relates to adherence; satisfied patients may more likely be adherent.Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02019550).

Early MRI results and odds of attaining ‘no evidence of disease activity’ status in MS patients treated with interferon β-1a in the EVIDENCE study

Introduction‘No evidence of disease activity’ (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. MethodsThis post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd+) lesions on NEDA and CAF were also investigated. ResultsMore patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24weeks were included (35.0% vs. 21.6%, respectively; p<0.001) versus the 24-week scan alone (59.5% vs. 41.2%; p<0.001). Absence of baseline Gd+ lesions predicted NEDA through Week 72 in the IFN β-1a IM qw group (p=0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw (p=0.024). ConclusionsIFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd+ lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status.

Interferon β-1a SC tiw Reduces Mild to Moderate and Moderate to Severe Relapses and Disease Activity over 1 Year in Patients with Relapsing MS: Post Hoc Analyses of PRISMS Data (P3.036)

Interferon β-1a SC tiw Reduces Mild to Moderate and Moderate to Severe Relapses and Disease Activity over 1 Year in Patients with Relapsing MS: Post Hoc Analyses of PRISMS Data (P3.036)

Postmarketing Safety Profile of Subcutaneous Interferon Beta-1a Given 3 Times Weekly: A Retrospective Administrative Claims Analysis.

Health insurance administrative claims databases represent a valuable source of information regarding the safety profile of marketed products as used in actual clinical practice in a broader range of patients than that assessed in clinical trials. Interferon beta-1a administered subcutaneously 3 times weekly (IFN β-1a SC tiw), which was approved in 2002 by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), has over a decade of postmarketing experience. To date, however, its postmarketing safety profile has not been described using a real-world evidence source such as administrative claims data. To describe the safety profile of IFN β-1a SC tiw as presented in its U.S. prescribing information (PI) for patients with MS initiating IFN β-1a SC tiw therapy using data from U.S. health care administrative claims databases. This study featured an observational and retrospective "new start" cohort design using data from the Truven MarketScan Commercial and Medicare Supplemental health care administrative claims databases. Patients were eligible for inclusion if they were aged ≥ 18 years; had ≥ 1 diagnosis for MS recorded between January 1, 2006, and December 31, 2012; had ≥ 2 prescriptions for IFN β-1a SC tiw; and had ≥ 90 days of continuous eligibility pre-index date and ≥ 180 days of continuous eligibility post-index date. Patients with a prescription for IFN β-1a SC tiw without a MS diagnosis were excluded. Patients were followed from first prescription for IFN β-1a SC tiw (index date) until date of therapy switch or discontinuation, end of insurance eligibility, or end of observation period. Adverse events (AEs) examined were those listed in the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections of the 2014 U.S. PI. Outcomes of interest were identified at the Medical Dictionary for Regulatory Activities (version 17.1) Preferred Term level and then coded to the corresponding ICD-9-CM criteria. Descriptive analyses of patient demographic, health status, health care utilization, and adherence status were performed, and incidence rates (IRs) per 100 person-years of labeled AEs with corresponding 95% CIs were calculated. The IR calculation was based on events that presented after therapy initiation and that were not present in the 90-day pre-index period. The top 6 AEs included influenza-like symptoms (IR = 15.65, 95% CI = 14.96-16.36); malaise (IR = 15.33, 95% CI = 14.65-16.04; fatigue (IR = 15.02, 95% CI = 14.35-15.72); abdominal pain (IR = 10.18, 95% CI = 9.67-10.70); chest pain (IR = 8.48, 95% CI = 8.03-8.95); and depression (IR = 7.75, 95% CI = 7.32-8.20). In contrast, the 6 lowest IRs were for maculo-papular rash (IR = 0.01, 95% CI = 0.00-0.04; injection-site necrosis (IR = 0.01, 95% CI = 0.00-0.03); erythema multiforme (IR = 0.01, 95% CI = 0.00-0.04); hypoesthesia (IR = 0.00, 95% CI = 0.00-0.02); Stevens-Johnson Syndrome (IR = 0.00, 95% CI = 0.00-0.02); and xerophthalmia (IR = 0.00, 95% CI = 0.00-0.02). Study results show strong convergence between the real-world safety profile of IFN β-1a SC tiw and its U.S. label. Our findings demonstrate the value of using real-world evidence obtained from administrative claims to complement clinical trial and postmarketing surveillance data in order to characterize the safety profile of established products, such as IFN β-1a SC tiw, in the postmarketing context.

1-Year Efficacy and Tolerability Results for IFN Beta-1a SC tiw Treatment and Predictive Value of 6-Month MRI: Exploratory Analysis of PRISMS Data in Patients with RRMS (P7.242)

1-Year Efficacy and Tolerability Results for IFN Beta-1a SC tiw Treatment and Predictive Value of 6-Month MRI: Exploratory Analysis of PRISMS Data in Patients with RRMS (P7.242)

Early Onset and Predictive Value of MRI Measures among Patients Receiving Interferon Beta-1a SC tiw for RRMS: Post Hoc Analyses of PRISMS-2 Data (P7.254)

Early Onset and Predictive Value of MRI Measures among Patients Receiving Interferon Beta-1a SC tiw for RRMS: Post Hoc Analyses of PRISMS-2 Data (P7.254)

Three times weekly glatiramer acetate in relapsing–remitting multiple sclerosis

To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 3× weekly (tiw) compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS). This randomized, double-blind study was conducted in 142 sites in 17 countries. Patients with RRMS with at least 1 documented relapse in the 12 months before screening, or at least 2 documented relapses in the 24 months before screening, and an Expanded Disability Status Scale score ≤ 5.5, were randomized 2:1 to receive either subcutaneous (sc) GA 40mg tiw (1ml) or placebo for 12 months. Of 1,524 patients screened, 1,404 were randomized to receive GA 40mg sc tiw (n = 943) or placebo (n = 461). Ninety-three percent and 91% of patients in the placebo and GA groups, respectively, completed the 12-month study. GA 40mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with placebo (mean annualized relapse rate = 0.331 vs 0.505; p < 0.0001). Patients who received GA 40mg tiw experienced highly significant reduction (p < 0.0001) in the cumulative number of gadolinium-enhancing T1 (44.8%) and new or newly enlarging T2 lesions (34.7%) at months 6 and 12. GA 40mg tiw was safe and well tolerated. The most common adverse events in the GA group were injection site reactions (35.5% with GA vs 5.0% with placebo). GA 40mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the convenience of fewer sc injections per week.

Changes in magnetic resonance imaging disease measures over 3 years in mildly disabled patients with relapsing-remitting multiple sclerosis receiving interferon β-1a in the COGnitive Impairment in MUltiple Sclerosis (COGIMUS) study

BackgroundConventional magnetic resonance imaging (MRI) has improved the diagnosis and monitoring of multiple sclerosis (MS). In clinical trials, MRI has been found to detect treatment effects with greater sensitivity than clinical measures; however, clinical and MRI outcomes tend to correlate poorly.MethodsIn this observational study, patients (n = 550; 18-50 years; relapsing-remitting MS [Expanded Disability Status Scale score ≤4.0]) receiving interferon (IFN) β-1a therapy (44 or 22 µg subcutaneously [sc] three times weekly [tiw]) underwent standardized MRI, neuropsychological and quality-of-life (QoL) assessments over 3 years. In this post hoc analysis, MRI outcomes and correlations between MRI parameters and clinical and functional outcomes were analysed.ResultsMRI data over 3 years were available for 164 patients. T2 lesion and T1 gadolinium-enhancing (Gd+) lesion volumes, but not black hole (BH) volumes, decreased significantly from baseline to Year 3 (P < 0.0001). Percentage decreases (baseline to Year 3) were greater with the 44 μg dose than with the 22 μg dose for T2 lesion volume (-10.2% vs -4.5%, P = 0.025) and T1 BH volumes (-7.8% vs +10.3%, P = 0.002). A decrease in T2 lesion volume over 3 years predicted stable QoL over the same time period. Treatment with IFN β-1a, 44 μg sc tiw, predicted an absence of cognitive impairment at Year 3.ConclusionSubcutaneous IFN β-1a significantly decreased MRI measures of disease, with a significant benefit shown for the 44 µg over the 22 µg dose; higher-dose treatment also predicted better cognitive outcomes over 3 years.

Efficacy and safety of subcutaneous interferon beta-1a in relapsing–remitting multiple sclerosis: Further outcomes from the IMPROVE study

Background The IMPROVE study demonstrated that the fetal bovine serum (FBS)- and human serum albumin (HSA)-free formulation of subcutaneous (sc) interferon (IFN) beta-1a had beneficial effects on the numbers of combined unique active magnetic resonance imaging (MRI) lesions in relapsing–remitting multiple sclerosis (RRMS). Here we report additional MRI endpoints (including post hoc analyses), and clinical efficacy, safety, and immunogenicity outcomes. Methods Patients with active RRMS were randomized (2:1) to IFN beta-1a, 44 mcg sc three times weekly (tiw) (n = 120), or placebo (n = 60), for 16 weeks (double-blind phase). All patients then received IFN beta-1a, 44 mcg sc tiw, for 24 weeks (rater-blind phase). Patients underwent MRI brain scans every 4 weeks. Results Compared with placebo, there was a 68% reduction in the mean cumulative number of new gadolinium-enhancing lesions with IFN beta-1a as early as week 4 ( p < 0.001), and a 53% reduction in the mean cumulative number of new T2 lesions as early as week 8 ( p = 0.025; post hoc analyses). During the 16-week double-blind phase, the relapse rate was 0.14 (95% confidence interval [CI] 0.09–0.23) with IFN beta-1a and 0.33 (95% CI 0.22–0.52) with placebo ( p = 0.010). Safety outcomes were consistent with those expected with IFN-beta treatment. Conclusions The FBS/HSA-free formulation of sc IFN beta-1a has a beneficial impact on MRI and efficacy outcomes as early as 4 weeks after treatment initiation in patients with RRMS and has a safety profile consistent with previous trials of sc IFN beta-1a.

Impact of exposure to interferon beta-1a on outcomes in patients with relapsing–remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study

To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing-remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2-4 years. Long-term follow-up visits occurred 7-8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to evaluate further the effects of treatment exposure on outcomes and to determine the benefits of interventions to improve adherence.

Phase I Dose Escalation Study of Sodium Stibogluconate (SSG), a Protein Tyrosine Phosphatase Inhibitor, Combined with Interferon Alpha for Patients with Solid Tumors

Sodium stibogluconate (SSG), a small molecule inhibitor of protein tyrosine phosphatases, combined with IFN-alpha-2b (IFN-α) inhibited solid tumor cell line growth in vitro. We conducted a phase I clinical trial with SSG plus IFN-α in advanced cancer patients to assess tolerance, maximum tolerated dose (MTD) and immune system effects. SSG was administered intravenously alone for five days of week 1, cycle 1 (21 days per cycle) and together with IFN-α 2b s (3 million units sc TIW) in week 2, and after a rest during week 3, on a 2-week on/1-week off cycle. SSG dose levels were 400, 600, 900, 1125, and 1350 mg/m(2). Twenty-four patients were studied. Common toxicities included asymptomatic elevated serum lipase, thrombocytopenia, fatigue, fever, chills and anemia. The dose-limiting toxicities (DLT) were hypokalemia, thrombocytopenia, fatigue, pancreatitis and skin rash. The MTD was 900 mg/m(2 )SSG and IFN-α, 3 million units TIW. At this dose, patients had a significantly lower number of regulatory T cells (T(R )Cells) (p = 0.012), myeloid dendritic cells (mDC) (p = 0.028); higher percentage of natural killer (NK) cells that synthesized perforin (p = 0.046) and of plasmacytoid dendritic cells (pDC) that secreted IFN-α (p = 0.018) in response to activation through toll-like receptor (TLR) 7 and TLR 8 by CL097, the highly water-soluble derivative of the imidazoquinoline compound R848. SSG in combination with IFN-α 2b was well tolerated and augmented cellular immune parameters.

The Addition of Rituximab and/or Alpha-Interferon to High Dose Chemotherapy and Autologous Stem Cell Transplantation for Patients with Relapsed Follicular Lymphoma Produces Durable Progression Free Survival and Molecular Remissions

AbstractAbstract 1357 Introduction:High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is historically effective treatment for patients with relapsed follicular lymphoma (FL) but relapse is common possibly due to contaminated stem cell grafts or inadequate eradication of primary disease. The addition of immunotherapy to HDT/ASCT may augment “in vivo” graft purging and achieve more effective eradication of minimal residual disease (MRD) post ASCT. This may lead to improved PFS and OS. Methods:We conducted 3 sequential prospective phase 2 trials of HDT/ASCT combined with immunotherapy in patients with relapsed FL from 1997–2010. Protocol 1 (n=13) used a-interferon 3 MU/m2 SC TIW for 2 years post ASCT. Protocol 2 (n=23) used a single infusion of rituximab (R) 375 mg/m2 for ‘in vivo’ purging 3–5 days pre-stem cell collection and 2 sets of 4 weekly R at 2 and 6 months post ASCT respectively. Protocol 3 (n=32) used 3 infusions of R 375 mg/m2 pre stem cell collection, followed by a-interferon 3 MU/m2 SC TIW × 2 years + R 375mg/m2 × 6 weekly infusions post ASCT. Eligibility included adult patients age 18–65 with stage III or IV follicular lymphoma grades 1–3a in first or second relapse. Salvage chemotherapy was either CHOP or DHAP depending on prior anthracycline exposure. High dose therapy was cyclophosphamide, carmustine, and etoposide (CBV). Minimal residual disease (MRD) assessment of t(14; 18) by quantitative PCR was serially performed in blood, PBSC and marrow. Studies were REB approved and all patients gave informed consent. Results:Sixty-eight patients from the 3 trials are included. Median age at study enrolment was 47 (30-71) and patients were a median of 31 mo (9-197) from diagnosis. 54% were male. Median FLIPI score was 2. Median # of prior chemotherapies was 1. Median number of cycles of salvage chemotherapy was 4 (2 - 10). 63 patients proceeded to ASCT. 5 patients were not transplanted either do to disease progression (2), or failed stem cell mobilization (3). Baseline characteristics of the patients enrolled in the three trials were similar, with the exception of rituximab(R) exposure in 22% of the patients in Protocol 3. 4 (6%) patients were lost to follow up.Median time to death or last follow was 84.5 mo (7-166). 32 patients (47%) relapsed and 20 (29%) have died. Median follow up times for each trial were 116, 99 and 57 mo. Actuarial median OS for Protocol 1 was 136 mo from enrolment and has not yet been reached for Protocols 2 and 3. Actuarial median PFS for Protocols 1 and 3 are 49 and 78 mo respectively and has not yet been reached for Protocol 2.MRD assessment by PCR was collected on 48 patients. Compared with study 1, the increased use of R pre SC collection improved in vivo purging by 2 logs. In Protocols 1 and 2, most still had detectable disease in the graft to a sensitivity of 1 cell/100,000. In Protocol 3, 56% had MRD negative apheresis products. 91% of 46 evaluable patients achieved molecular remission post stem cell transplant.Thirteen patients (19%) developed secondary malignancies post ASCT with a median time to malignancy of 88.5 mo (39-144). 1 patient developed 2 distinct malignancies. Secondary malignancies present were: MDS (4), AML (1), ALL (1), basal cell carcinoma (2), squamous cell carcinoma (3), thyroid cancer (1), non small cell lung cancer (1) and adenocarcinoma of unknown origin (1). Five (7%) patients transformed to DLBCL, with a median time to transformation post ASCT of 43.5 mo (17-142).The majority of patients who received rituximab immunotherapy pre and post ASCT developed persistent hypogammaglobulinemia. 17 patients (26%) developed interstitial pneumonitis or >2 respiratory complications post rituximab. 4 patients (6%) require monthly IVIG to treat recurrent respiratory infections. 10 patients (15%) developed herpes zoster <90 days post ASCT.15% and 30% of patients in Protocols 1 and 3 did not complete the 2 years of alpha-IFN post ASCT secondary to one or more of depression, fatigue or cytopenias. Conclusion:HDT + ASCT combined with R +/− a-IFN produces durable PFS and molecular remissions but is associated with prolonged hypogammaglobulinemia and higher rates of interstitial pneumonitis. Three infusions of R pre SC collection achieve higher rates of molecular remission. Compliance with 2 years of a-IFN added to R post ASCT is poor and may not add clinical benefits to R alone. The additional role of HDT/ASCT in the era of R-chemotherapy for FL needs to be explored. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase II evaluation of tremelimumab (Treme) combined with high-dose interferon alpha-2b (HDI) for metastatic melanoma.

8524 Background: Anti-CTLA4 antibodies and HDI have significant immunomodulatory and antitumor activity in advanced melanoma. We hypothesized that the combination might abrogate immunologic tolerance and induce more significant and durable clinical responses. Methods: Treme was given at 15 mg/kg IV/course q12 wks. HDI was given concurrently including IV induction at 20 MU/m2 IV, 5 d/wk × 4 wks followed by maintenance at 10 MU/m2 SC TIW, for 8 wks/course. From course 2 onward, HDI maintenance was given SC. Dose delays were allowed for Treme, and if HDI was tolerable with dose modification pts continued HDI even if Treme was discontinued. Results: Thirty-six pts (23 M, 13 F), age 28-76 were enrolled. All had AJCC stage IV (9 M1a, 6 M1b, 21 M1c) and most had previously received therapy (0-5 regimens). Two pts had prior treated brain metastases. Seventy courses of Treme have been administered to date (average 2/pt; 5 pts continue on therapy). Grade 3/4 toxicities include neutropenia (6 pts; 17%), diarrhea/colitis (5; 14%), liver enzyme elevation (4; 11%), rash (4; 11%), fatigue (12; 33%), anxiety/depression (5; 14%). Autoimmune toxicities due to Treme were successfully managed with steroids. Response data are available for 33 pts. Two pts included in survival analysis and one responder who developed a second malignancy are not evaluable. Best OR rate (33 evaluable pts) is 30% (3 CR and 7 PR lasting 3, 9, 2+, 3+, 5+, 7+, 10+, 14+, 24+, 27+ months), including M1a (4), M1b (2), and M1c (4; one ocular). Twelve pts (36%) had SD (3 ongoing at 1+ to 7+ month and 9 progressed after 1.5 to 21 months). Disease control rate is 0.67, 95% CI (0.51, 0.83). Six mos PFS rate is 53%, 95% CI (0.34, 0.68) and median PFS is 6.4 mos, 95% CI (3.2, 16.3). One year OS rate is 57.8%, 95% CI (0.370, 0.739) and median OS is 15.9 mos, 95% CI (9.34, −). Baseline CRP ≤ 2.5ULN (p = 0.049) and the induction of autoimmunity (autoantibodies or AE) (p = 0.0059) are significantly associated with therapeutic benefit. Conclusions: HDI and Treme can be administered with acceptable toxicity, and exhibit promising durable antitumor efficacy. Baseline CRP is a predictive biomarker of response. Autoimmunity induced by therapy is significantly correlated with therapeutic benefit. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer

Tumor Necrosis Factor-α and Insulin-Like Growth Factor-1 Levels in Patients with Relapsing–Remitting Multiple Sclerosis Receiving Interferon-β1a

To examine the effect of high-dose interferon (IFN)-beta1a [44 microg administered subcutaneously (sc) 3 times weekly (tiw)] on tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-1 (IGF-1) levels in patients with relapsing-remitting multiple sclerosis (RRMS), and any correlation with clinical and magnetic resonance imaging (MRI) data. Previously treatment-naive patients with RRMS and an Expanded Disability Status Scale score < or = 3.5 were enrolled. At baseline, monthly for the first 5 months, and then after 12 months of treatment with 44 microg sc tiw of IFN-beta1a, all patients underwent clinical examination, assessment of serum TNF-alpha and IGF-1 levels and baseline, 5th, and 12th months to MRI scanning. Mean TNF-alpha values decreased significantly from months 0 to 12 of the study (P = 0.003), but mean IGF-1 values showed a nonsignificant reduction (P = 0.265). Serum levels of TNF-alpha and IGF-1 were sometimes correlated throughout the study, but no significant interactions were observed between serum TNF-alpha or IGF-1 and clinical or MRI findings. A borderline significant trend toward higher basal TNF-alpha levels was found in patients who developed new T1 lesions at 12 months compared with those who did not (P = 0.057). Interferon-beta1a therapy may reduce serum TNF-alpha levels in patients with RRMS, without a clear correlation with disease activity.

Subcutaneous interferon beta-1a has a positive effect on cognitive performance in mildly disabled patients with relapsing—remitting multiple sclerosis: 2-year results from the COGIMUS study

The effect of interferon (IFN) beta-1a (44 and 22 μg subcutaneously [sc] three times weekly [tiw]) on cognition in mildly disabled patients with relapsing-remitting multiple sclerosis (McDonald criteria; Expanded Disability Status Scale =4.0) was assessed by validated neuropsychological testing at baseline and at regular intervals for up to 2 years in this ongoing open-label, 3-year study. Year-2 data were available for 356 patients (22 μg, n = 175; 44μg, n = 181). The proportion of patients with impaired cognitive function was stable during the study: 21.4% at baseline and 21.6% at 2 years. At 2 years, the proportion of patients with =3 impaired cognitive tests was significantly lower in the 44 μg treatment group (17.0%) compared with the 22 μg group (26.5%; p = 0.034), although there was already a trend towards a higher proportion of patients with cognitive impairment in the 22 μg group at baseline. Factors associated with impairment in = three cognitive tests after 2 years were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.00-1.09), verbal intelligence quotient (OR: 0.95; 95% CI: 0.92-0.98), and having = three impaired cognitive tests at baseline (OR: 11.60; 95% CI: 5.94-22.64). These interim results show that IFN beta-1a sc tiw may have beneficial effects on cognitive function as early as 2 years after treatment initiation, but the final 3-year data of the study are required to confirm these results.

A novel needle for subcutaneous injection of interferon beta-1a: effect on pain in volunteers and satisfaction in patients with multiple sclerosis

BackgroundTo reduce injection pain and improve satisfaction, a thinner (29-gauge [29G]), sharper (5-bevel) needle than the 27G/3-bevel needle used previously to inject interferon (IFN) beta-1a, 44 or 22 mcg subcutaneously (sc) three times weekly (tiw), was developed for use in multiple sclerosis (MS).MethodsTwo clinical trials in healthy volunteers and five surveys of patients with MS were conducted to assess whether the 29G/5-bevel needle with a Thermo Plastic Elastomer (TPE) needle shield (a sleeve that houses the tip of the needle in a secure location) is an improvement over the 27G/3-bevel needle with a rubber shield for injection of IFN beta-1a, 44 or 22 mcg sc tiw. Parameters assessed were: pain and ease of insertion (healthy volunteer and nurse responses on subjective pain measurement scales); and patient satisfaction (surveys of patients with MS).ResultsIn healthy volunteers, the 29G/5-bevel needle with TPE shield was associated with the least perceived pain on the Visual Analog Scale (VAS) and Verbal VAS (VB-VAS); mean VAS pain scores decreased by 40% and skin penetration improved by 69% compared with the 27G/3-bevel needle with standard rubber shield (p < 0.01). Pooled results from surveys of patients with MS indicated that 63% of patients thought that injections were less painful with the 29G/5-bevel needle than the 27G/3-bevel needle. Results from individual surveys indicated that the 29G/5-bevel needle was an improvement over the 27G/3-bevel needle for ease of insertion, injection-site reactions, bruising, burning and stinging.ConclusionTogether these studies indicate that the 29G/5-bevel needle with the TPE shield is an improvement over the 27G/3-bevel needle with standard rubber shield in terms of pain, ease of insertion and patient satisfaction. These improvements are expected to result in improved compliance in patients with MS treated with IFN beta-1a, 44 or 22 mcg sc tiw.

Reduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple sclerosis: analysis of 48-week data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study

BackgroundThe EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study assessing the efficacy and tolerability of interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), and IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this analysis was to assess whether reductions in T2 burden of disease (BOD) were greater for patients receiving IFN beta-1a, 44 mcg sc tiw, than for those treated with IFN beta-1a, 30 mcg im qw, and to assess the impact of neutralizing antibodies (NAbs).MethodsA post-hoc analysis was performed on magnetic resonance imaging (MRI) data collected prospectively from the EVIDENCE study. The analysis included all patients with evaluable T2 MRI scans at the start of dosing and at week 48, and those who received at least one drug dose (n = 553). Lesions were identified by a radiologist blinded to treatment codes and the total volume of T2 lesions (BOD) was reported in mm3.ResultsBoth median percentage decreases and absolute reduction in BOD were greater in the IFN beta-1a, 44 mcg sc tiw, treatment group. The adjusted mean treatment difference in percentage change in BOD from baseline to week 48 showed a significant treatment benefit for patients treated with IFN beta-1a, 44 mcg sc tiw, over those treated with IFN beta-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002). The presence of NAbs reduced the effect of IFN beta-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN beta-1a, 30 mcg im qw.ConclusionPatients with RRMS treated with IFN beta-1a, 44 mcg sc tiw, had greater reduction in T2 BOD after 48 weeks than those treated with IFN beta-1a, 30 mcg im qw, which is consistent with other clinical and MRI outcome measures in the EVIDENCE study. In patients testing positive for NAbs (NAb+) to IFN beta-1a 44 mcg sc tiw, changes in BOD were smaller than in NAb negative (NAb-) patients, but similar to those receiving IFN beta-1a, 30 mcg im qw.

Immunogenicity and tolerability of an investigational formulation of interferon-β1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis

RNF (Rebif New Formulation, Merck Serono International S.A., Geneva, Switzerland), a formulation of interferon-beta1a (IFN-beta1a) without human- or animal-derived components, is currently under investigation. It was developed with the aim of maximizing the treatment benefit for patients with multiple sclerosis (MS) by improving injection tolerability and reducing the development of neutralizing antibodies (NAbs). This paper reports the results of planned 24- and 48-week interim analyses comparing immunogenicity and tolerability data from an ongoing study of RNF with historical-control data for the currently approved formulation of IFN-beta1a from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. Patients in the 96-week, multicenter, singlearm, Phase IIIb RNF study received 44 microg/0.5 mL SC tiw; patients in the EVIDENCE study received an identical regimen of the currently approved formulation of IFN-beta1a. Criteria for inclusion in the RNF study were age between 18 and 60 years, an Expanded Disability Status Scale (EDSS) score <6.0, and a diagnosis of relapsing MS (McDonald criteria). Criteria for inclusion in the EVIDENCE study were age between 18 and 55 years, an EDSS score of 0 to 5.5, and a diagnosis of clinically definite relapsing-remitting MS (Poser criteria). Patients in both studies were treatment naive. Both studies used the same cytopathic-effect assay for NAbs to assess immunogenicity; patients who had NAb titers >or=20 neutralizing units (NU)/mL were considered NAb+. The primary end point was to compare the proportions of NAb+ patients in the RNF study and the historical data. Comparisons were descriptive and used exact 95% CIs. Safety analyses included 8 prespecified adverse events (AEs) of interest. Baseline demographic characteristics were well balanced between the RNF (N = 260) and EVIDENCE (N = 339) studies, except that patients in the RNF study were slightly younger (median age, 34.0 vs 39.0 years, respectively), and a few had secondary progressive MS (n = 6) or progressive relapsing MS (n = 1). At week 48, 87.3% of patients in the RNF study remained on treatment. The incidence of the prespecified AEs of interest in the RNF and EVIDENCE studies was as follows: flu-like symptoms (70.8% and 48.1%, respectively), injection-site reactions (29.6% and 83.8%), hepatic disorders (13.1% and 16.8%), cytopenia (9.6% and 11.8%), depression and suicidal ideation (5.8% and 19.8%), skin rashes (5.4% and 12.1%), hypersensitivity reactions (5.4% and 3.2%), and thyroid disorders (2.3% and 5.0%). Overall, the majority (96.9%) of AEs in the RNF study were mild (69.5%) or moderate (27.5%) in severity. The proportions of patients in the RNF and EVIDENCE studies with NAbs at both 24 and 48 weeks were 2.5% (95% CI, 0.9-5.5) and 14.3% (95% CI, 10.7-18.6), respectively; the proportions with NAbs at week 48 only were 13.9% (95% CI, 9.9-18.7) and 24.4% (95% CI, 19.9-29.4). The proportions of NAb+ patients with high NAb titers (>1000 NU/mL) at week 48 were 11.1% in the RNF study and 19.5% in the EVIDENCE study. The results of these interim analyses suggest that RNF had an improved overall tolerability and safety profile and a lower immunogenic potential compared with the approved IFN-beta1a formulation assessed in the EVIDENCE study. Two-year results from the RNF study are anticipated before the end of 2007.