Baseline characteristics from two ongoing phase III trials for the prevention and treatment of muscle wasting in NSCLC.

e19100 Background: Although muscle wasting and cancer cachexia occur in > 80% of patients with advanced cancer, few well-powered scientifically-based trials have been conducted. Using enobosarm, a novel SARM, we have now enlisted 650 patients (pts) with advanced NSCLC in two phase III trials. Recent studies indicate major advantages for supportive care in NSCLC at chemotherapy initiation (Temel, NEJM 2010).This presentation examines the feasibility of pt enlistment at chemo initiation, the major characteristics of these pts and trial design for the prevention and treatment of muscle wasting. Methods: Both double-blind, placebo-controlled, international trials evaluate the effect of enobosarm in NSCLC. ˜300 pts with stage III or IV NSCLC were randomized in each trial at initiation of first-line chemo to receive additionally enobosarm or placebo for 5 months. Pts were males and postmenopausal females ≥30 years, ECOG ≤1. First line chemo: a platinum + taxane (Power 1) or platinum + non-taxane (Power 2). Co-primary endpoints at Day 84 are physical function assessed by stair climb power (SCP) and lean body mass (LBM) by DXA. Baseline characteristics are available on 634 pts (98%), as in the Table. Results: See Table. Conclusions: These results indicate that it is feasible to enlist pts receiving first-line chemo in trials designed to prevent or treat muscle wasting and cachexia; their presenting characteristics are typical for NSCLC. Median weight loss at baseline was 5% even though weight loss was not required for study inclusion. LBM and SCP were lower than typically observed in healthy individuals indicating significant functional decline before starting chemo for NSCLC. These phase III trials will determine the effect of enobosarm on preventing and treating muscle wasting in NSCLC. Clinical trial information: NCT01355484 and NCT01355497. [Table: see text]

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Pharmacotherapy Options for Multiple Sclerosis: Focus on Natalizumab

Clinical Medicine Insights Therapeutics ◽

10.4137/cmt.s2043 ◽

2010 ◽

Vol 2 ◽

pp. CMT.S2043 ◽

Cited By ~ 1

Author(s):

Martin Stangel ◽

Bernd C. Kieseier

Keyword(s):

Multiple Sclerosis ◽

Monoclonal Antibody ◽

Safety Management ◽

Jc Virus ◽

Unmet Need ◽

Neurological Impairment ◽

Phase Iii ◽

First Line ◽

Two Phase ◽

Phase Iii Trials

Multiple sclerosis (MS) is considered an autoimmune disease causing demyelination in the central nervous system (CNS) that subsequently leads to axonal damage and neurological impairment. Currently available first line therapies are based on immunomodulation with beta-interferons or glatirameracetate. However, these treatments are only partially effective, thus, more powerful therapies represent an unmet need in MS. Natalizumab is a monoclonal antibody targeting the α4β1 integrin that has been shown to be crucial in the process of transmigration of immunocompetent cells across the blood-brain-barrier (BBB) into the CNS. Two phase III trials have demonstrated clinical and paraclinical efficacy of natalizumab and recent data suggest that many patients that have failed on a first-line disease modifying drug (DMD) benefit from a treatment with natalizumab. Unfortunately, since the licensing of natalizumab in 2006 there have been 75 cases of progressive multifocal leukoencephalopathy (PML) reported. This rare, but potentially fatal infection of the brain by JC-virus restricts the use of natalizumab. Currently there are attempts to define algorithms based on the identification of risk factors for the development of PML to achieve a better safety management for MS patients treated with this monoclonal antibody.

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Amifampridine for the Management of Lambert-Eaton Myasthenic Syndrome: A New Take on an Old Drug

Annals of Pharmacotherapy ◽

10.1177/1060028019864574 ◽

2019 ◽

Vol 54 (1) ◽

pp. 56-63

Author(s):

Connie H. Yoon ◽

Jocelyn Owusu-Guha ◽

Adam Smith ◽

Pamela Buschur

Keyword(s):

English Language ◽

Human Subjects ◽

Data Extraction ◽

Phase Iii ◽

Pharmacokinetic Studies ◽

First Line ◽

Two Phase ◽

Phase Iii Trials ◽

Improved Stability ◽

Myasthenic Syndrome

Objective: The purpose of this article is to review the literature for both 3,4-diaminopyridine (3,4-DAP) and amifampridine for the treatment of Lambert-Eaton myasthenic syndrome (LEMS). Amifampridine (Firdapse) is the salt form of 3,4-DAP and was approved by the Food and Drug Administration for the treatment of LEMS. Data Sources: PubMed, TRIP database, and EMBASE searches were conducted without a back date (current to June 2019) utilizing the following search terms: amifampridine, 3,4-diaminopyridine, and Lambert-Eaton myasthenic syndrome. Completed trials were also reviewed at clinicaltrials.gov. Study Selection and Data Extraction: Criteria for article inclusion consisted of human subjects, age ≥18 years, phase II or III clinical trials, and English language for both drugs. Observational and pharmacokinetic studies for amifampridine were also included. Data Synthesis: Prior to the approval of amifampridine, 3,4-DAP was first-line for the management of LEMS symptoms. Two phase III trials have evaluated amifampridine to confirm efficacy, both showing superiority over placebo in the management of LEMS symptoms, with minimal adverse effects. A significant improvement in both quantitative myasthenia gravis scores and Subjective Global Impression scores was established at days 4 and 14. Relevance to Patient Care and Clinical Practice: With an improved stability profile and decreased dose variability, amifampridine will likely assume the role of first-line management of LEMS. Conclusions: Amifampridine has been shown to improve symptoms of LEMS and is generally well tolerated.

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Comparison of the Efficacy and Toxicity of Fludarabine (F) in First Line Therapy of Younger Versus Elderly Patients (Pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Meta-Analysis of Two Phase III Trials of the German CLL Study Group (GCLLSG).

Blood ◽

10.1182/blood.v106.11.717.717 ◽

2005 ◽

Vol 106 (11) ◽

pp. 717-717 ◽

Cited By ~ 3

Author(s):

Barbara F. Eichhorst ◽

Raymonde Busch ◽

Clemens M. Wendtner ◽

Michael Hallek ◽

Keyword(s):

Age Groups ◽

The Elderly ◽

Phase Iii ◽

First Line ◽

Two Phase ◽

First Line Therapy ◽

Line Therapy ◽

Phase Iii Trials ◽

Binet Stage ◽

Grade 3

Abstract Introduction: F based regimen have become the standard treatment in CLL at least in younger pts. However, in elderly pts chlorambucil is still frequently used since it is easy to administer and has less side effects. Here we compare the efficacy and toxicity of F administered to younger pts and elderly pts treated between 1999 and 2004 within two phase III trials of GCLLSG. Patients: 362 pts (median age 59 [range 37–65] years) were randomized to F (n=182) or F plus cyclophosphamide (n=180) within the CLL4 trial. 191 elderly pts (median age 71 [range 65–79] years) were treated with F (92 pts) or chlorambucil (99 pts) within the CLL5 protocol. Inclusion criteria were identical in both trials except for age limits. All pts were previously untreated and in advanced stage Binet C or Binet B with symptoms which require therapy or Binet A with severe B-symptoms. In both studies the F regimen consisted of 30 mg/m2/day (d) IV for 5 consecutive days, every 28 d for up to 6 cycles. Anti-infective prophylaxis and growth factors were not given routinely in both trials. Results: Most of patients in both age groups were in Binet stage B (54% of the younger pts and 52% of the elderly), 35% in each age group were in Binet stage C, 11% and 13% respectively in Binet stage A. No significant difference in the main clinical features was observed except for a higher incidence of concomitant disease in the elderly (61% versus 36%, p=0.001). A mean number of 5.2 F courses was administered in the CLL4 trial and 4.9 courses in the CLL5 trial. The mean administered cumulative dose of F per pt was lower in the elderly pts (1076 mg vs. 1194 mg, p= 0.05). Overall response rates were similar in both arms, with 82.9% in the younger group and 85.7% in the elderly. The complete remission rate was 6.7% in the younger patients and 10.4% in the elderly (p= 0.3). After a follow up time of 24 months (mo) the progression-free survival (PFS) was significantly shorter in the elderly group with 18.7 mo compared to 19.8 mo in the younger group after 22 mo observation time (p=0.03). The overall survival (OS) was significantly impaired in elderly pts as well (29 mo versus median not reached, p<0.001). Progressive disease was the main cause of death in both age groups. In each group 3 treatment related deaths occurred due to infection or hemolysis. The incidence of side effects was similar in both age groups. Severe, CTC grade 3 and 4, myelosuppression occurred in 39% of the younger and 41% of the elderly pts. No difference in the rate of leukocytopenia, thrombocytopenia or anemia was oberved as well. The incidence rate and severity of infections was similar in both groups (24% vs. 32% all and 8.7% vs. 6.9% CTC grade 3 and 4). The incidence of second neoplasia was significantly higher in the elderly pts (2.2% vs. 12.2%, p=0.001). In comparison the prevalence rate of neoplasia in the U.S. population peaks at 11% in the age group of 70–79 (SEER cancer statistic review: 1972–2002). Conclusion: F is a well tolerated treatment regimen in first line therapy of elderly pts with CLL. Response rates were similar in both age groups. PFS and OS were significantly shorter in the elderly population. The incidence of second neoplasia was significantly higher in the elderly pts, but is only slightly increased in comparison to the normal population.

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Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7113 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7113-7113 ◽

Cited By ~ 1

Author(s):

M. O’Brien ◽

P. Bonomi ◽

C. Langer ◽

K. O’Byrne ◽

B. Bandstra ◽

...

Keyword(s):

Weight Loss ◽

Regression Analysis ◽

Advanced Nsclc ◽

Cox Regression ◽

Phase Iii ◽

Two Phase ◽

Cox Regression Analysis ◽

Phase Iii Trials ◽

Baseline Factors ◽

Cox Analysis

7113 Background: Two phase III trials in chemo-naïve PS2 patients with advanced NSCLC compared paclitaxel poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naïve PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p < 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined by multivariate analysis are summarized in the table . Other baseline factors evaluated but not predictive of survival included gender, number of comorbidities, age, and history of tobacco use. Treatment differences between subgroups were not statistically significant; however, a strong trend towards improved survival was observed for women receiving PPX in STELLAR 4 compared to those in the control-arm (HR = 0.65; p = 0.069). In contrast, men had similar survival between treatment arms (HR = 1.08; p = 0.579). Conclusion: In this large PS2 patient population, weight loss, presence of extra-thoracic metastasis, low LCS scores, and high LDH were found to be important clinical determinants of survival. In addition, significant differences in survival based on geographic region in STELLAR 3 highlight the importance of stratification by region. [Table: see text] [Table: see text]

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Efficacy of anamorelin in cachectic patients with non-small cell lung cancer (NSCLC) and low BMI (< 20 kg/m2): Post-hoc analysis of two phase III studies.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.26_suppl.203 ◽

2016 ◽

Vol 34 (26_suppl) ◽

pp. 203-203 ◽

Cited By ~ 2

Author(s):

David Christopher Currow ◽

Jennifer S. Temel ◽

Amy Pickar Abernethy ◽

Ruben Giorgino ◽

John Friend ◽

...

Keyword(s):

Weight Loss ◽

Fat Mass ◽

Symptom Burden ◽

Phase Iii ◽

Two Phase ◽

Double Blind ◽

Ghrelin Receptor ◽

Low Bmi ◽

Nsclc Patients ◽

Post Hoc

203 Background: Patients with advanced cancer frequently experience anorexia/cachexia, which can be characterized by weight loss or low BMI, and is associated with reduced function and quality of life. The randomized, phase III, double-blind ROMANA 1 [NCT01387269; N = 484] and ROMANA 2 [NCT01387282; N = 495]) trials in cachectic NSCLC patients demonstrated that the ghrelin receptor agonist anamorelin improved LBM, body weight, fat mass (FM), and symptom burden compared with placebo, and was well tolerated. The aim of this analysis was to assess the response to anamorelin specifically in patients with BMI below 20 kg/m2. Methods: Stage III/IV NSCLC patients with cachexia ( ≥ 5% weight loss during prior 6 months or BMI < 20 kg/m2) were randomly assigned (2:1) to daily oral 100 mg anamorelin or placebo for 12 weeks. A post-hoc pooled analysis of efficacy data from both trials was conducted in patients with BMI < 20 kg/m2 (N = 182) and with BMI ≥ 20 kg/m2(N = 647). Endpoints included changes in lean body mass (LBM), fat mass (FM), and changes in self-reported anorexia/cachexia symptoms/concerns and fatigue. Results: Compared with placebo, anamorelin significantly increased LBM both in patients with low BMI (treatment difference: 1.71 kg [95% CI 0.88 – 2.54]) and in those with normal/high BMI (1.47 kg [1.00 - 1.94]) (p < 0.001). Greater increases in FM were observed in the BMI < 20 kg/m2 (1.66 kg [0.86 – 2.46], p < 0.001) than in the BMI ≥ 20 kg/m2 subgroup (0.79 kg [0.30 - 1.28], p = 0.002). Significant improvements in anorexia/cachexia symptoms/concerns were observed in the BMI < 20 kg/m2 subgroup (5.27 [2.11 - 8.43], p = 0.001), while in the BMI ≥ 20 kg/m2 subgroup these were not significant (0.91 [(-0.56) - 2.37], p = 0.224). In patients with low BMI, anamorelin also improved fatigue (3.94 [0.56 – 7-32], p = 0.023), while this was not significant in patients with BMI ≥ 20 kg/m2 (-0.42) [(-2.07) – 1.23], p = 0.616). Conclusions: In patients with BMI < 20 kg/m2 anamorelin increased lean and fat mass as well as improved anorexia/cachexia symptoms/concerns. Additionally, improvements in fatigue were also noted in patients with BMI < 20 kg/m2. Clinical trial information: NCT01387282; NCT01387269.

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Subgroup analysis of ECOG2 patients from ROMANA 2: A phase III study of anamorelin in NSCLC patients with cachexia.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.31_suppl.6 ◽

2014 ◽

Vol 32 (31_suppl) ◽

pp. 6-6 ◽

Cited By ~ 2

Author(s):

Amy Pickar Abernethy ◽

David Christopher Currow ◽

Lyon L. Gleich ◽

Ying Yan ◽

John Friend ◽

...

Keyword(s):

Weight Loss ◽

Functional Assessment ◽

Handgrip Strength ◽

Performance Status ◽

Phase Iii ◽

Double Blind ◽

Ghrelin Receptor ◽

Phase Iii Trials ◽

Grade 3 ◽

Nsclc Patients

6 Background: Cancer anorexia-cachexia syndrome (CACS), often observed in NSCLC patients, is characterized by decreased body weight, mainly lean body mass (LBM), and is associated with worse morbidity and survival. Anamorelin HCl (ANAM), a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity, is in development as a treatment of NSCLC CACS. Methods: ROMANA 2 was one of two global, double-blind, Phase III trials assessing ANAM efficacy and safety in NSCLC. Patients with unresectable stage III/IV NSCLC, ECOG 0-2 and cachexia (≥5% weight loss within prior 6 months or BMI <20 kg/m2), were randomized (2:1) to 100 mg ANAM or placebo, given daily orally for 12 weeks. Co-primary endpoints were change from baseline over 12 weeks in LBM (measured by DXA) and in handgrip strength (HGS). Secondary endpoints included change in patient symptoms/concerns regarding anorexia-cachexia and fatigue (via Functional Assessment of Anorexia/Cachexia Treatment [FAACT] and Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F]). Safety assessments included lab values and adverse events (AEs). This pre-specified analysis focused on ECOG2 patients. Results: ROMANA 2 (N=495) enrolled 130 ECOG2 patients (N=41 placebo; N=89 ANAM). Subgroup demographics were balanced: median age= 64 yr, male (81.5%), metastatic (74.6%), and prior weight loss >10% (61.5%). In the overall trial, ANAM significantly increased LBM vs placebo (0.75 vs -0.96 kg; p<0.0001) and improved FAACT over 12 weeks (3.48±0.9 vs 1.34±1.0; p=0.0016); change in HGS was not statistically different. In the ECOG2 subgroup, ANAM also significantly increased LBM (0.45 vs -2.66 kg; p=0.0004); there was a trend towards improvement in FAACT and FACIT-F but this was not statistically significant. In the ANAM arm of the ECOG2 subgroup, the most frequent drug-related AE was hyperglycemia (4.5%), with few (1.1%) drug-related Grade ≥ 3 AEs. Conclusions: ANAM treatment for 12 weeks was well tolerated. In patients with ECOG2 performance status, which represents a more severe/fragile population, ANAM improved LBM, as well as anorexia-cachexia and fatigue symptoms/concerns in advanced NSCLC cachectic patients. Clinical trial information: NCT01387282.

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Comparative Susceptibilities to Fidaxomicin (OPT-80) of Isolates Collected at Baseline, Recurrence, and Failure from Patients in Two Phase III Trials of Fidaxomicin against Clostridium difficile Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00625-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5194-5199 ◽

Cited By ~ 64

Author(s):

Ellie J. C. Goldstein ◽

Diane M. Citron ◽

Pamela Sears ◽

Farah Babakhani ◽

Susan P. Sambol ◽

...

Keyword(s):

Clostridium Difficile ◽

Restriction Endonuclease Analysis ◽

Phase Iii ◽

Two Phase ◽

Double Blind ◽

Single Strain ◽

Content Type ◽

Treatment Groups ◽

Phase Iii Trials ◽

Intent To Treat

ABSTRACTA 10-day course of oral fidaxomicin (200 mg twice a day [b.i.d.]), a potent new macrocyclic drug, was compared to vancomycin (125 mg four times a day [q.i.d.]) in 1,164 adults (1,105 in the modified intent-to-treat [mITT] population) withClostridium difficileinfection in two phase III randomized, double-blind trials at sites in North America and 7 European countries. Of 1,105 mITT patients, 792 (71.7%), including 719/999 (72.0%) in the per-protocol (PP) population, provided aC. difficilestrain at baseline, of whom 356 received fidaxomicin with 330 cures (92.7%) and 363 received vancomycin with 329 cures (90.6%). The susceptibilities (MIC90) of baseline isolates did not predict clinical cure, failure, or recurrence for fidaxomicin (MIC90, 0.25 μg/ml for both; range, ≤0.007 to 1 μg/ml), but there was a one-dilution difference in the MIC90(but not the MIC50) for vancomycin (MIC90, 2 μg/ml [range, 0.25 to 8 μg/ml] for cure and 4.0 μg/ml [range, 0.5 to 4 μg/ml] for failures). A total of 65 (7.9%) “rifaximin-resistant” (MIC > 256 μg/ml) strains were isolated in both treatment groups on enrollment, which increased to 25% for failures at the end of therapy. No resistance to either fidaxomicin or vancomycin developed during treatment in either of the phase III studies, although a single strain isolated from a cured patient had an elevated fidaxomicin MIC of 16 μg/ml at the time of recurrence. All isolates were susceptible to ≤4 μg/ml of metronidazole. When analyzed by restriction endonuclease analysis (REA) type, 247/719 (34.4%) isolates were BI group isolates, and the MICs were generally higher for all four drugs tested (MIC90s: fidaxomicin, 0.5; vancomycin, 2.0; metronidazole, 2.0; and rifaximin, >256 μg/ml) than for the other REA types. There was no correlation between the MIC of a baseline clinical isolate and clinical outcome. MIC90s were generally low for fidaxomicin and vancomycin, but BI isolates had higher MICs than other REA group isolates.

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