scholarly journals An Integrated Safety Summary of Omadacycline, a Novel Aminomethylcycline Antibiotic

2019 ◽  
Vol 69 (Supplement_1) ◽  
pp. S40-S47 ◽  
Author(s):  
Steven Opal ◽  
Thomas M File ◽  
Tom van der Poll ◽  
Evan Tzanis ◽  
Surya Chitra ◽  
...  
Keyword(s):  
Bacterial Pneumonia ◽  
Bone Growth ◽  
Package Insert ◽  
Late Pregnancy ◽  
Phase Iii ◽  
Tooth Discoloration ◽  
Phase Iii Study ◽  
Clinical Trial Results ◽  
Muscarinic M2 Receptors ◽  
Phase Iii Studies

AbstractOmadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.

Difference between duration of treatment (DOT) and progression-free survival (PFS) as a marker of unbalanced censoring.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2548-2548
Author(s):  
Laleh Amiri-Kordestani ◽  
Julia Wilkerson ◽  
Sanjeeve Balasubramaniam ◽  
Susan Elaine Bates ◽  
Antonio Tito Fojo
Keyword(s):  
Breast Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Duration Of Treatment ◽  
Free Survival ◽  
Time To Treatment Failure ◽  
Clinical Trial Results ◽  
And Control ◽  
Phase Iii Studies ◽  
The Ideal

2548 Background: In the conduct of randomized trials Kaplan and Meier envisioned rates of censoring as similar between arms, providing accurate assessment of clinical trial results. Censoring is used when patients withdraw consent, leave study due to toxicity, or reach data cut-off without disease progression or death. Censoring can lead to erroneous conclusions as it can be either beneficial or detrimental to the arm under study. Such censoring can also explain how a statistically valid difference in PFS “disappears” when overall survival (OS) is examined. We hypothesized that censoring, especially that due to toxicity, would lead to a discrepancy between DOT and PFS since two different patient populations would be scored. Methods: We reviewed all phase III randomized studies of drugs approved by FDA since 2005 for pts with metastatic solid tumors, looking for DOT and PFS. We used standard statistical analyses using SAS. Results: We identified 55 Phase III studies conducted with abiraterone, axitinib, bevacizumab, cabazitaxel, cetuximab, eribulin, erlotinib, everolimus, ipilimumab, ixabepilone, lapatinib, panitumumab, pazopanib, sorafenib, sunitinib, temsirolimus and vandetinib. DOT was not provided in 27%. Forty-four comparisons (88 arms) were included in the analysis. The median PFS, DOT, delta PFS (difference in PFS between experimental and control arms) and delta DOT were: 161, 126, 51 and 36 days, respectively. The slopes of PFS vs DOT and delta PFS vs delta DOT were 1.16 and 1.03, respectively close to the ideal of 1.0. Five trials fell above the 90% CI boundary with delta PFS/delta DOT of 3 to 36, including two everolimus studies (PNET and breast cancer) two sunitinb studies (RCC and PNET) and one bevacizumab study (E2100, breast cancer). Conclusions: PFS and DOT as well as delta PFS and delta DOT should be concordant. The most likely explanation for a discordance between these values is toxicity-driven censoring and its occurrence raises concerns regarding the degree of efficacy. A greater utilization of “Time to Treatment Failure”, an endpoint that includes toxicity in its definition would be valuable in oncology trials, particularly those with high levels of toxicities.

A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8619-TPS8619
Author(s):  
John C. Byrd ◽  
Jacqueline Claudia Barrientos ◽  
Stephen Devereux ◽  
Jennifer R. Brown ◽  
Neil E. Kay ◽  
...  
Keyword(s):  
Package Insert ◽  
Cell Receptor ◽  
Primary Objective ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Controlled Study ◽  
Open Label ◽  
Pivotal Phase ◽  
Phase Iii Study ◽  
Line Of Therapy

TPS8619 Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with >= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count <30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.

A timing and process flow analysis of opening clinical trials within an oncology cooperative group setting: The case of the CALGB

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6015-6015
Author(s):  
D. M. Dilts ◽  
A. B. Sandler ◽  
M. Baker ◽  
S. Cheng ◽  
S. McGuire ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Group Setting ◽  
Calendar Time ◽  
Time Step ◽  
Center Staff ◽  
Regulatory Affairs ◽  
Decision Points ◽  
Phase Iii Study ◽  
Phase Iii Studies

6015 Background: Cooperative oncology groups are major sponsors of Phase III clinical trials, yet the number of steps and times required to setup and open such a trial have yet to be studied. This study assesses these items in the Cancer and Leukemia Group B (CALGB) for all Phase III studies opened in a 3 year period. Methods: Step 1: headquarters and statistical center staff were interviewed to discover the detailed steps required for a study to transit from initial concept submission by a potential study chair to final activation of the study. The formal procedures manuals were also reviewed. All study records and draft protocol documents were inspected to verify and identify additional setup steps. Finally, data was collected through direct contact with study chairs and disease committee chairs. Step 2: timing data for each of the major functions or processes were collected. All times are from initial initiation of the function to the final completion of the task. Times represent calendar time. Step 3: creation of stream-lined process flows, currently underway. Members from the CALGB and the Vanderbilt Center for Management Research in Healthcare (cmrhc.org) will spend 2 days creating a process to significantly reduce the time and the number of steps to opening a trial. Results: A total of 13 Phase III studies were activated during the 3 years study period. 372 processes are required to open a Phase III at CALGB, which include 314 work steps, 43 major decision points. Interesting, most of the decision points (63%) are external to CALGB. There are 23 processing loops that require repeating processes. The process map, which lists all processes, is a chart 243.5” × 41 in 8 pt font (or about the length of a 20 passenger bus). Median calendar days to activate a Phase III study at CALGB is 767 days (min = 488, max = 1,441). The three functions requiring the greatest median days are protocol development (477), forms development (434), and regulatory affairs (350). Conclusion: It can require years to open a Phase III study at a major cooperative oncology group. Using process redesign techniques, we expect to be able to significantly streamline the process. Support provided by the NCI. No significant financial relationships to disclose.

Comparison of Outcomes of Phase II Studies and Subsequent Randomized Control Studies Using Identical Chemotherapeutic Regimens

2005 ◽  
Vol 23 (28) ◽  
pp. 6982-6991 ◽  
Author(s):  
Mohammad I. Zia ◽  
Lillian L. Siu ◽  
Greg R. Pond ◽  
Eric X. Chen
Keyword(s):  
Phase Ii ◽  
English Language ◽  
Response Rates ◽  
Phase Iii ◽  
Positive Phase ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Study Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Purpose To determine whether promising results from phase II studies could be reproduced in phase III studies, and to examine which characteristics of phase II studies might be of predictive value for subsequent phase III studies. Methods We searched for all phase III studies of chemotherapy in advanced solid malignancies, published in the English language literature from July 1998 to June 2003. Each phase III study was reviewed to identify preceding phase II studies. Phase II and phase III studies included in this analysis must have used identical regimens. Data were extracted from both phase II and phase III studies. Results Of 181 phase III studies identified, 43 used therapeutic regimens identical to those in 49 preceding phase II studies. Twelve phase III studies (28%) were “positive.” The vast majority (81%) of phase III studies have lower response rates than preceding phase II studies, with a mean difference of 12.9% among all studies analyzed. None of the phase II study characteristics evaluated significantly predicted for “positive” phase III studies, but the sample size of phase II studies demonstrated a trend toward being predictive (P = .083). Conclusion Promising results from phase II studies frequently do not translate into “positive” phase III studies. Response rates in most phase III studies are lower than those in preceding phase II studies.

Chemotherapy for Hormone-Refractory Prostate Cancer: Now It's a Question of “When?”

2005 ◽  
Vol 23 (32) ◽  
pp. 8242-8246 ◽  
Author(s):  
Charles J. Ryan ◽  
Mario Eisenberger
Keyword(s):  
Prostate Cancer ◽  
Phase Iii ◽  
Refractory Disease ◽  
Hormone Refractory Prostate Cancer ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Potential Benefits ◽  
Phase Iii Study ◽  
Hormone Refractory ◽  
Phase Iii Studies

Recently, data from two randomized phase III studies that compared docetaxel-based chemotherapy to mitoxantrone-based therapy demonstrated that treatment with docetaxel can prolong life in a significant way for patients with hormone-refractory prostate cancer. For many patients who experience disease progression after androgen-deprivation therapy, however, chemotherapy may not be immediately indicated. Such cases include those individuals with hormone-refractory disease in the absence of clinical metastases, and those with asymptomatic metastatic disease, for example. As a result, clinicians treating patients with hormone-refractory disease must weigh the benefits of earlier chemotherapy against its risks, and may consider other therapies such as secondary hormonal approaches before initiating chemotherapy. This decision is further complicated by the fact that a phase III study designed to compare secondary hormonal therapy with chemotherapy has failed due to lack of accrual. Furthermore, the limitations of chemotherapy for prostate cancer are being clarified and include a lack of standard second-line therapy as well as uncertain benefits for those with nonmetastatic disease. In this review, we will highlight some of the issues that impact on the decision of when to start chemotherapy and in whom as well as the potential benefits of secondary hormonal approaches.

Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics

2009 ◽  
Vol 27 (25) ◽  
pp. 4103-4108 ◽  
Author(s):  
Laurent Claret ◽  
Pascal Girard ◽  
Paulo M. Hoff ◽  
Eric Van Cutsem ◽  
Klaas P. Zuideveld ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Time ◽  
Phase Ii ◽  
Tumor Size ◽  
Prediction Interval ◽  
Phase Iii ◽  
Antitumor Response ◽  
Phase Iii Study ◽  
Phase Iii Studies ◽  
Size Data

PurposeWe developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.MethodsWe developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.ResultsThe TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, −21 to 110 days) versus 35 days observed was predicted for capecitabine.ConclusionThe modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.

Triticum vulgare mouthwashes (TVM) for patients (pts) with oral mucositis (OM) induced by chemotherapy and chemoradiotherapy (ONCOLGroup study)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20570-e20570
Author(s):  
E. Carrasco-Chaumel ◽  
A. F. Cardona ◽  
E. G. Ospina ◽  
L. M. Montaño ◽  
R. Noemí ◽  
...  
Keyword(s):  
Weight Loss ◽  
Analogue Scale ◽  
Phase Iii ◽  
Triticum Vulgare ◽  
Reduce Weight Loss ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Previous Clinical Trial ◽  
Mucosal Bleeding ◽  
Clinical Trial Results

e20570 Background: OM is a frequent complication of cancer therapy in Colombia. Triticum vulgare has been reported to effectively treat mucosal and skin disturbances. Methods: To evaluate the safety and efficacy of TVM for the control of OM induced by chemoradiotherapy in pts with head and neck cancer (HNC) and by chemotherapy in pts with haematological malignancies (HM). Thirty-one pts received TVM delivered in a spray four times daily to the whole oral cavity until the OM being resolved. The primary endpoint was the OM grade evaluated daily using the Nebraska scale (NS). Secondary endpoints were OM duration, weight loss, pain and TVM tolerance; the latter two were evaluated using a visual analogue scale (VAS). Results were compared with data from 42 pts with OM treated with saline mouthwashes (SM) in a previous clinical trial. Results: Nineteen pts had HM and 12 had HNC; those with HM developed OM on day 9 of chemotherapy (range, 7–14), whilst those having HNC did so towards day 17 of chemoradiation (range, 13–26). Using NS 38% of pts developed GI OM, 46% GII OM and 16% GIII OM. Moderate and severe OM occurred more frequently amongst HNC pts (8 vs 1, p = 0.047), mean OM duration in HNC pts was 12±4.5 days, whilst it was 7 ±3 days (p = 0.047) in pts with HM. Median OM duration in pts treated with TVM was 5.4 days (range, 2–9) vs 7 days (range 1–17) for pts treated with SM (p = 0.048). TVM appears to reduce weight loss, especially in pts with HNC (p = 0.058); however, no changes were documented regarding saliva characteristics and production, mucosal bleeding and voice properties. Evaluation of pain did not reveal differences between the groups (VAS 5.5 for the TV compared to VAS 6.2 for SM; p = 0.27) but the proportion of pts suffering from pain VAS≥7 differed between both populations (8% TV vs 23% SM; p = 0.043). There are no significant adverse events with TVM. Conclusions: TVM is safe and has therapeutic activity against OM. Further phase III study is needed to confirm these results. No significant financial relationships to disclose.

Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11000-11000 ◽  
Author(s):  
Sant P. Chawla ◽  
Kristen N. Ganjoo ◽  
Scott Schuetze ◽  
Zsuzsanna Papai ◽  
Brian Andrew Van Tine ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Package Insert ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Open Label Study ◽  
Tumor Environment ◽  
Phase Iii Study ◽  
Novel Drug

11000 Background: Aldoxorubicin (A) is a novel drug that binds covalently to albumin in the circulation, accumulates in tumors and releases doxorubicin in the acidic tumor environment. It has demonstrated enhanced antitumor activity in several murine models and in a phase IIb STS study when compared with doxorubicin. Trial Design: Phase III open-label study evaluating efficacy and safety of A compared to investigators' choice (IC) of treatment in subjects with soft tissue sarcomas (STS) who have relapsed or were refractory to prior chemotherapy. Objectives: (1) Primary: Efficacy of A vs IC: progression-free survival (PFS); (2) Secondary: Efficacy of A vs IC: tumor response (ORR), disease control rate (DCR; CR+PR+SD > 4 months), overall survival (OS) and safety. Methods: A: 350 mg/m2 (260 mg/m2dox. equiv.) iv q3 wks. IC drugs: dacarbazine, doxorubicin, pazopanib, ifosfamide, gemcitabine/docetaxel administered per package insert or study site's standard practice; provided, with G-CSF, by the sponsor. AEs, serum chemistries, CBCs, EKG and ECHOs obtained frequently. CT scans every 6 weeks for 30 weeks, then every 12 weeks; analyzed using RECIST 1.1 by Blinded Independent Central Review. Results: Randomized 433 subjects; 79 countries; 313 (72%) in North America (NA) and 121 (28%) in Rest of World (ROW). Leiomyosarcoma 42.5%, liposarcoma 15%, synovial sarcoma 9%, others 33.5%, L-sarcomas (lipo+leiomyo) 57.5%. Median PFS Total Pop. (months): A= 4.06; IC= 2.96; p = 0.12; HR = 0.82 (0.64-1.06). Median PFS NA (months): A= 4.21; IC= 2.96; p = 0.027; HR = 0.71 (0.53-0.97). Median PFS L-sarcomas (months): A= 5.32; IC= 2.96; p = 0.007; HR = 0.62 (0.44-0.88). DCR Total Pop.(%): A= 30.3; IC= 20.9; p = 0.028; DCR NA (%): A= 32.9; IC= 19.2; p = 0.007; DCR L-Sarcomas (%): A= 37.5; IC= 23.0; p = 0.018. ORR and OS will be reported. TEAEs gr 3 or 4 (%): A= 61.0; IC= 46.4. Trtmt Rel. SAEs (%): A= 27.0; IC= 14.0. TEAEs leading to Drug Discontinue (%): A= 4.2; IC= 6.3. Trtmt Related Deaths (#); A= 3; IC= 0; LVEF < 50% expected (%): A= 2.8%;Dox = 12.8%. Conclusions: Aldox is an active, well-tolerated drug for treating relapsed or refractory STS and is significantly better than standard treatments for patients with L-sarcomas. Clinical trial information: NCT02049905.

scholarly journals Using phase II data for the analysis of phase III studies: An application in rare diseases

2017 ◽  
Vol 14 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Simon Wandel ◽  
Beat Neuenschwander ◽  
Christian Röver ◽  
Tim Friede
Keyword(s):  
Drug Development ◽  
Phase Ii ◽  
Interim Analysis ◽  
Large Scale ◽  
Drug Approval ◽  
Phase Iii ◽  
Orphan Diseases ◽  
Operating Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Background: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. Methods: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. Results: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. Conclusion: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

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