scholarly journals Ipilimumab Pharmacotherapy in Patients with Metastatic Melanoma

2012 ◽  
Vol 6 ◽  
pp. CMO.S7245 ◽  
Author(s):  
Joanne M. Jeter ◽  
Lee D. Cranmer ◽  
Evan M. Hersh
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Clinical Trials ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Phase Iii ◽  
Preclinical Evaluation ◽  
Investigational Therapies ◽  
Alternative Means ◽  
Phase Iii Studies

Immune augmentation with ipilimumab, an anti-CTLA-4 monoclonal antibody, has joined the ranks of approved immunologic agents for the treatment of metastatic melanoma. Phase III studies of ipilimumab in metastatic melanoma have demonstrated an overall survival advantage as compared to other approved and investigational therapies. However, the adverse effects associated with this medication are unique and often require management with steroids or other immunosuppressants. In addition, the time to response differs with ipilimumab as compared to traditional chemotherapy, and alternative means of assessment of response have been proposed. In this review, we will summarize the basic science of this treatment, its preclinical evaluation, and the clinical trials leading to its approval. We will also discuss the details regarding its use, assessment of response to this drug and other immune-related therapies, and further directions for investigation.

scholarly journals Ipilimumab, a Promising Immunotherapy with Increased Overall Survival in Metastatic Melanoma?

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Gérald E. Piérard ◽  
François Aubin ◽  
Philippe Humbert
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
T Cells ◽  
Skin Cancer ◽  
Malignant Melanoma ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Cytotoxic T Cells ◽  
Therapeutic Options ◽  
Life Threatening

Malignant melanoma (MM) is one of the most aggressive skin cancer. The therapeutic options remain limited for advanced MM, and those directed to the neoplastic cells have not brought major survival advantage so far. Immunotherapy is another targeted option. Ipilimumab, a monoclonal antibody directed to CTLA-4 present on cytotoxic T cells boosts immunity, particularly its anti-MM activity. Under treatment, the overall survival of patients with MM metastases is moderately but significantly increased. The immuno-related adverse effects may be severe and life threatening.

Potential of Mirabegron and its Extended-release Formulations for the Treatment of Overactive Bladder Syndrome

2020 ◽  
Vol 21 (2) ◽  
pp. 79-88 ◽  
Author(s):  
Pankaj Mandpe ◽  
Bala Prabhakar ◽  
Pravin Shende
Keyword(s):  
Clinical Trials ◽  
Overactive Bladder ◽  
Adverse Effects ◽  
Symptomatic Relief ◽  
Phase Iii ◽  
Overactive Bladder Syndrome ◽  
Modified Release ◽  
Blurred Vision ◽  
Antimuscarinic Drugs ◽  
Tablet Dosage

Background: Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. The commonly used antimuscarinic drugs show poor patient compliance because of unsatisfactory potency, tolerability and high occurrence of adverse effects such as dry mouth, blurred vision, constipation, dizziness etc. Mirabegron is the first approved β3-adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. Objective: The present review provides an insight into the mechanism, pharmacokinetics, toxicokinetics, clinical trials and the development of various conventional and modified-release dosage forms of mirabegron for the treatment of overactive bladder syndrome. Results: The clinical trials of phase II and phase III of mirabegron demonstrated symptomatic relief from the overactive bladder without disturbing the micturition cycle. To date, mirabegron showed promising results for safety, tolerability and efficacy in patients with overactive bladder syndrome. The modified-release tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs like Oxybutyline chloride ER, Detrol LA, VESIcare, etc. Conclusion: Mirabegron shows a distinct mode of action, i.e., targeting β3-adrenoreceptors and improving bladder storage without altering void contractions. The limited side effects, high safety, efficacy and tolerability of mirabegron present an adequate substitute to antimuscarinics. However, long-term analysis and clinical studies are prerequisites for assessing the safety, tolerability and efficacy profile of mirabegron.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

scholarly journals Trends in clinical trials for stroke by cell therapy: data mining ClinicalTrials.gov and the ICTRP portal site

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Takaharu Negoro ◽  
Hanayuki Okura ◽  
Midori Maehata ◽  
Shigekazu Hayashi ◽  
Satoru Yoshida ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Therapy ◽  
Chronic Phase ◽  
Cell Types ◽  
Phase Iii ◽  
Definitive Treatment ◽  
Stroke Treatment ◽  
Portal Site ◽  
Therapy Studies ◽  
Phase Iii Studies

Abstract Definitive treatment of stroke constitutes an important thesis of regenerative medicine in the cerebrovascular field. However, to date, no cell therapy products for stroke are yet on the market. In this study, we examined the clinical research trends related to cell therapy products in the stroke field based on data obtained from the ClinicalTrials.gov website and International Clinical Trials Research Platform (ICTRP) portal site. These data do not offer results of clinical trials comprehensively but provide information regarding various attributes of planned clinical trials including work in progress. We selected 78 cell therapy studies related to the field of stroke treatment from ClinicalTrial.gov and ICTRP. These were analyzed according to, e.g., the reporting countries, origin (autologous or allogeneic), of cell used, cell types and source organs, the progress of translational phases, target phase of the disease (acute or chronic stroke), and route of administration. This analysis revealed a trend whereby in the acute phase, mesenchymal stem cells were administered intravenously at a relatively higher dose, whereas in the chronic phase a small number of cells were administered intracranially. Only two randomized controlled Phase III studies with over 100 patients are registered, but none of them has been completed. Thus, cell therapy against stroke appears to constitute a premature area compared with cartilage repair as assessed in our previous report. In addition, tracking by means of the ID number of each trial via PubMed revealed that 44% of clinical studies in this field have corresponding published results, which was also discussed.

scholarly journals Chronic lymphocytic leukemia paradigm continues to be refined: news from the American Society of Hematology 2018 annual meeting

2019 ◽  
Vol 8 (2) ◽  
pp. IJH14
Author(s):  
Stefano Molica
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Standard Of Care ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Prospective Phase ◽  
American Society ◽  
Anti Cd20

There were a number of important updates and advances presented at the 2018 Annual American Society of Hematology meeting. With respect to the treatment of chronic lymphocytic leukemia, the American Society of Hematology 2018 was notable for an improved understanding of ibrutinib-based therapies. In fact, three prospective Phase III trials presented at the meeting indicate, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard of care for chronic lymphocytic leukemia. However, additional clinical trials comparing chemo-immunotherapy with ibrutinib alone or in association with an anti-CD20 monoclonal antibody remain a reasonable avenue to complete results of these large studies.

Use of placebo in cancer medicine: The experience of a National Clinical Trials organization

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6104-6104
Author(s):  
J. L. Pater ◽  
W. Parulekar
Keyword(s):  
Clinical Trials ◽  
Supportive Care ◽  
Study Design ◽  
Standard Of Care ◽  
Phase Iii ◽  
Design Data ◽  
Standard Of Care Treatment ◽  
Prevention Trials ◽  
The Impact ◽  
Phase Iii Studies

6104 Background: The use of placebos in cancer clinical trials requires careful evaluation. Factors that must be considered include the impact of placebo on endpoint measurement, the efficacy of placebo relative to standard of care treatment, patient altruism/acceptance of a non-active intervention and the resulting increase in complexity of study conduct with respect to randomization, drug supply, data management, analysis and the unblinding process. Methods: We reviewed the experience of the National Cancer Institute of Canada Clinical Trials Group with the use of placebo in the randomized phase III setting from 1982–2005. Results: Since 1982, 34 studies were identified that utilized a placebo as part of study design. Data is presented below according to the type of study and date of study activation. The numbers in brackets represent those studies in which placebo was used alone in the control arm. Supportive care studies were the most common type of study employing a placebo as part of study design and constituted almost 50% of our Group’s experience. Therapeutic studies involving placebo were conducted in multiple sites including breast (4), lung (6), myeloma (1), melanoma (1), ovary (1) and pancreas (1). Conclusion: Phase III studies involving a placebo constitute an important part of our clinical trial activity and cross the spectrum of supportive care, therapeutic and prevention trials. The use of placebo in cancer studies may increase due to the relative ease of blinding in studies that evaluate targeted, oral therapies with minimal toxicities as well as the need for unbiased assessment of increasingly used endpoints such as time to progression. [Table: see text] No significant financial relationships to disclose.

Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7108-7108 ◽  
Author(s):  
R. K. Bagai ◽  
A. Dowlati
Keyword(s):  
Clinical Trials ◽  
Survival Time ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Improvement In Survival ◽  
Phase Ii And Iii ◽  
Phase Iii Studies

7108 Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data. [Table: see text] No significant financial relationships to disclose.

Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8514-8514 ◽  
Author(s):  
Sapna Pradyuman Patel ◽  
Wen-Jen Hwu ◽  
Kevin B. Kim ◽  
Nicholas E. Papadopoulos ◽  
Patrick Hwu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Cell Function ◽  
Performance Status ◽  
Phase Iii ◽  
Induction Phase ◽  
Ecog Performance Status ◽  
Two Phase

8514 Background: Ipilimumab (Ipi) alters the immune system balance by inhibiting the suppression of T-cell function. In two phase III trials, Ipi has shown an overall survival benefit alone and in combination with dacarbazine in previously treated and treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We performed a single-institution, phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM. Methods: Pts between the ages of 18 and 75 with previously untreated unresectable stage III or stage IV MM and an ECOG Performance Status of 0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on Days 1 – 4 every 3 weeks for 4 doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks and oral Tem 200 mg/m2 on Days 1 – 5 starting week 12 and repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS) rate at 6 months. Responses were evaluated using immune-related response criteria. Results: Sixty-four pts were enrolled and received at least one dose of study drug. All pts were included in the analysis. With a median follow-up of 8.5 months, the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%, and the median PFS was 5.1 months. There were 10 (15.6%) confirmed complete responses and 8 (12.5%) confirmed partial responses. At the time of this analysis, median overall survival has not been reached. Immune-related adverse events (irAEs) were experienced by 88% of pts, most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis (45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis (5%). Constipation occurred in 70% of pts and was the most common gastrointestinal (GI) toxicity. There were no GI perforations or deaths on study due to treatment. Conclusions: At a median follow-up of 8.5 months, the best overall response rate in this study is 28%. Ipi at 10 mg/kg in combination with Tem given in an induction followed by maintenance fashion is safe, well-tolerated, and efficacious in MM.

Nonstandard first-line therapy and survival in patients (pts) with recurrent/metastatic head and neck cancer (RMHNSCC): Experience of 194 pts in a single institution.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16036-e16036
Author(s):  
Jerome Fayette ◽  
Valentine Polivka ◽  
Sylvie Chabaud ◽  
Bertrand Favier ◽  
Severine Racadot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Alternative Therapy ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
First Line Therapy ◽  
Phase Iii Studies ◽  
Line Chemotherapy

e16036 Background: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Methods: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Results: At initiation of palliative chemotherapy, median age was 62 [29-87]; PS was 0, 1, 2, 3 in 13%, 59%, 16% and 11% of pts, respectively. First line chemotherapy consists in combination cisplatin+taxanes (CIST) 24%, caboplatin+taxanes (CART) 33%, cisplatin or carboplatin without taxanes (NOT) 15% or others (OTH) 28%. Median OS was estimated to 9.6 months CI95%=[8.1-11.4], with 39% of pts; CI95%=[32-47] still alive at 1-year. Second line of treatment has been initiated in 61% of pts. Some of them have even been able to have up to 3, 4 or more than 4 lines of treatment in 19%, 11% and 4% of pts, respectively. In the subgroup analysis, which represents a population similar to those included in [ref1], first line chemotherapy was CIST, CART, NOT or OTH in 30%, 30%, 18% and 22%, respectively. Median OS was 13.0 months, CI95%=[11.2-17.7] reaching up to 15.3 months for CIST subgroup. Second line of treatment was initiated in 73% of pts, with 20%, 15% and 5% of pts having a third, a fourth, and a fifth line, respectively. Conclusions: We can reach for unselected pts the best OS published in phase III studies. The use in first line of combination of platinum and taxanes, followed by monotherapies with cetuximab, capecitabine and methotrexate allows reaching OS of 13 months.

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