The dream of any physician and consequently every patient is to receive the right treatment in the right time with cost effectiveness. To achieve this goal, the 3 pillars: evidence based medicine, clinical research innovation & resources utilization should be integrated efficiently.
In this presentation, I'll try to comprehensively review the following:
1- How are we used to perform clinical trials in Oncology?
2- Does it fits in today’s needs?
3- Integration of biology knowledge in shaping drug development
4- New Clinical trial designs “Can they offer solution for accelerating drug development?”
5- The supporting infrastructure role in clinical trial execution
Roles and Responsibilities in Clinical Trials of Investigator, Study Coordinator, Sponsor, Monitor, a Contract research organization.
The clinical trial, definition, description, Different types of clinical trials, phases of clinical trial.
The clinical trial study team.
Requirements of the clinical trial study team.
Clinical research team role.
GCP- Good clinical practices.
The dream of any physician and consequently every patient is to receive the right treatment in the right time with cost effectiveness. To achieve this goal, the 3 pillars: evidence based medicine, clinical research innovation & resources utilization should be integrated efficiently.
In this presentation, I'll try to comprehensively review the following:
1- How are we used to perform clinical trials in Oncology?
2- Does it fits in today’s needs?
3- Integration of biology knowledge in shaping drug development
4- New Clinical trial designs “Can they offer solution for accelerating drug development?”
5- The supporting infrastructure role in clinical trial execution
Roles and Responsibilities in Clinical Trials of Investigator, Study Coordinator, Sponsor, Monitor, a Contract research organization.
The clinical trial, definition, description, Different types of clinical trials, phases of clinical trial.
The clinical trial study team.
Requirements of the clinical trial study team.
Clinical research team role.
GCP- Good clinical practices.
Superiority, Equivalence, and Non-Inferiority Trial DesignsKevin Clauson
http://bit.ly/bQKcGz This lecture was presented as part of the Drug Literature Evaluation course at Nova Southeastern University. Guided notes and an audience response system were used to augment to lecture. Context for my decision to share these slides can be found at the provided link.
This presentation provides a knowledge about Safety Pharmacology, It's aim & objectives, issues, consideration in selection and design of study and test study, duration of study, various studies involved in safety pharmacology, its guidelines, preclinical safety pharmacology. An assignment for the subject, Clinical Research and Pharmacovigilance, 1st year M.Pharm, 2nd semester.
Turacoz Healthcare Solutions provides clinical research and regulatory writing services for pharmaceutical companies. We tell you about the different components of a clinical study protocol, the document which is prepared before beginning of any clinical trial. To know more info, visit- goo.gl/C1ec0L or write to us at hello@turacoz.in and call us 011-40584280.
Superiority, Equivalence, and Non-Inferiority Trial DesignsKevin Clauson
http://bit.ly/bQKcGz This lecture was presented as part of the Drug Literature Evaluation course at Nova Southeastern University. Guided notes and an audience response system were used to augment to lecture. Context for my decision to share these slides can be found at the provided link.
This presentation provides a knowledge about Safety Pharmacology, It's aim & objectives, issues, consideration in selection and design of study and test study, duration of study, various studies involved in safety pharmacology, its guidelines, preclinical safety pharmacology. An assignment for the subject, Clinical Research and Pharmacovigilance, 1st year M.Pharm, 2nd semester.
Turacoz Healthcare Solutions provides clinical research and regulatory writing services for pharmaceutical companies. We tell you about the different components of a clinical study protocol, the document which is prepared before beginning of any clinical trial. To know more info, visit- goo.gl/C1ec0L or write to us at hello@turacoz.in and call us 011-40584280.
By preventing confounding from other circumstances, a successful clinical trial reduces the heterogeneity of the assessment and offers an objective assessment of the intervention.
With the exception of the intervention that each group receives, randomization ensures that every patient has an identical likelihood of obtaining any of the therapies being studied.
di Pier Giuseppe Pelicci, MD-PhD, Istituto Europeo di Oncologia IEO, Università degli Studi di Milano.
Slide per l'intervento tenuto in Fondazione Giannino Bassetti in occasione del primo incontro del ciclo "La medicina di precisione", primo progetto dalla convenzione tra Università di Pavia e Fondazione Bassetti.
12 marzo 2018
Cancer Clinical Trials_ USA Scenario and Study Designs.pdfProRelix Research
Clinical trials in oncology are vital for the advancement of cancer treatments and
care. The US is at the forefront of these clinical trials, with many different study
designs being used to assess the efficacy and safety of new treatments. This article
will explore the current state of oncology clinical trial services in the US, as well as
discuss different types of study designs that are commonly used. It will provide
insight into how these trials are conducted, what data is collected, and how this
information can be used to improve patient care.
The United States Food and Drug Administration (FDA) has released
several guidance documents over the years through the Oncology Center
of Excellence to support the development of oncologic treatments and
diagnoses. Furthermore, information on the clinical trials for the treatment
of different types of cancer or specific interventions can be found on the
National Cancer Institute (NCI) website and Clinical Trials. Currently,
ClinicalTrials.gov, a website maintained by the National Library of
Medicine (NLM) and the National Institutes of Health (NIH) contains
listings of publicly and privately sponsored trials and includes information
on 91,937 studies related to cancer indicating the high volume of
research being conducted in this field.According to the World Health Organization (WHO), cancer is the leading
cause of death worldwide, with a death rate of one in six in 2020 (1).
Aside from the high mortality rate and morbidity associated with cancer, it
also negatively impacts the quality of life and poses a significant financial
burden on patients and payers making it imperative to develop effective
treatments for the disease. According to Global Cancer Observatory
(GLOBACAN), the United States accounted for 13.3% of all estimated
new cases of cancer in 2020 (2). In 2020, the single leading type of
cancer in the United States was breast cancer (11.1%) followed by lung
cancer (10%), prostrate (9,2%), colorectum (6.8%), and melanoma of the
skin (4.2%). Despite the significant prevalence of cancer and numerous
clinical trials conducted for oncology treatments, data have shown an
almost 95% attrition rate for anticancer drugs from Phase I trials until
marketing authorization. Various factors such as inaccurate preclinical
models, lack of suitable biomarkers in clinical trials, and a disconnect
between industry, academia, and regulators are responsible for the high
attrition rate (3). Therefore, it is vital to develop suitable study designs
and protocols for candidate molecules such that they obtain regulatory
approval and can be marketed. In addition to these challenges, the
development of anti-cancer agents comes at a monumental cost of an
estimated $2.8 billion. Several factors such as the choice of relevant
endpoints, the choice of appropriate biomarkers that are guided by tumor
biology, and careful patient selection are expected to improve the overall
fate of oncologic agents in the clinical trial phase
Please share this webinar with anyone who may be interested!
Watch all our webinars: https://www.youtube.com/playlist?list=PL4dDQscmFYu_ezxuxnAE61hx4JlqAKXpR
Cancer care is increasingly tailored to individual patients, who can undergo genetic or biomarker testing soon after diagnosis, to determine which treatments have the best chance of shrinking or eliminating tumours.
In this webinar, a pathologist and clinical oncologist discuss:
● how they are using these new tests,
● how they communicate results and treatment options to patients and caregivers, and
● how patients can be better informed on the kinds of tests that are in development or in use across Canada
View the video: https://youtu.be/_Wai_uMQKEQ
Follow our social media accounts:
Twitter - https://twitter.com/survivornetca
Facebook - https://www.facebook.com/CanadianSurvivorNet
Pinterest - https://www.pinterest.com/survivornetwork
YouTube - https://www.youtube.com/user/Survivornetca
We can aid decision making from the pre-clinical to the clinical setting, supporting line of sight to the clinic, by identifying and translating crucial biomarker approaches into the real world.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
2. Background
• With increasing advancements in genomics, there have been increasing
interests in biomarkers and how they can be used to improve biomedical
interventions
• Biomarker-guided trials are becoming more popular to identify therapies
that can specifically affect disease targets based on their genetic make-up
– known as ‘targeted therapies’
Adapted from Baxter C. After the double helix. Nature Reviews Genetics. 2003 Apr 1;4(4):246-7.
1953 1958 1980 1983 1990 1999 2003 2017 2018
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approved by the
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(Pembrolizumab)
FDA draft
guidance on
master
protocols
FDA draft
guidance
on
Complex
Innovative
Designs (CIDs)
3. Master
Protocol
A master protocol is defined as “a
protocol designed with multiple sub
studies, which may have different
objectives and involves coordinated
efforts to evaluate one or more
investigational drugs in one or more
disease subtypes within the overall trial
structure.”
• Often categorized as basket
trials, umbrella trials, and
platform trials
Master Protocols. Efficient Clinical Trial Design Strategies to Expedite Development of Oncology
Drugs and Biologics Guidance for Industry (Draft Guidance)
4. Types of Master protocols
Type of Trial Objective
Umbrella To study multiple targeted therapies in the context of
a single disease.
Basket To study a single targeted therapy in the context of
multiple diseases or disease subtypes.
Platform To study multiple targeted therapies in the context of
a single disease in a perpetual manner, with therapies
allowed to enter or leave the platform on the basis of
a decision algorithm.
Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or
Both. N Engl J Med. 2017 Jul 6;377(1):62-70. doi: 10.1056/NEJMra1510062. PMID: 28679092.
5. Rising popularity of master protocols
60
90
80
70
50
40
30
20
10
0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
Basket trials Umbrella trials
Platform trials
Number of Master Protocols over Time:
Basket Trials, Umbrella Trials, and Platform Trials
Cytel Inc. 6
Park JJ et al. BMC Trials. 2019 Dec;20(1):1-0.
Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.
Imatinib Target
Exploration
Consortium
Study B2225
6. What is a basket trial?
7
• A clinical trial that tests one or more targeted
interventions across multiple types of diseases
that share common molecular alterations and/or
other risk factors
• There are unifying eligibility criteria usually
based on predictive risk factors that combine
patients with different diseases into a single
“basket”
• Predictive risk factors are usually based on the
intervention’s mechanism of action since it can
help predict whether the patient will respond to a
specific intervention
A basket trial in cancer
• Multiple histological types of cancer
• Common targets as unifying
eligibility criteria
• Interventions agnostic to tumor and
histology
7. An illustrate example of a single-arm basket trial
Park JJH et al. 2020 Feb 7 CA: A Cancer Journal for Clinicians.
An overview of precision oncology basket and umbrella trials for clinicians
8. An illustrate example of a randomized basket trial
Park JJH et al. 2020 Feb 7 CA: A Cancer Journal for Clinicians.
An overview of precision oncology basket and umbrella trials for clinicians
9. What is an umbrella trial?
10
• A clinical trial that tests multiple targeted interventions
for a single disease based on predictive biomarkers
and/or other risk factors
• In an umbrella trial, a single disease (e.g. breast
cancer) is stratified into multiple groups
• For example, the eligibility for each group can be
defined by the intervention’s mechanism of action
An umbrella trial in cancer
• A single histological cancer type
• Multiple targets used to stratify
patients
• Multiple interventions
10. An illustrate example of a single-arm
umbrella trial
Cytel Inc.
Park JJH et al. 2020 Feb 7 CA: A Cancer Journal for Clinicians.
An overview of precision oncology basket and umbrella trials for clinicians
10
11. An illustrate example of a randomized
umbrella trial
Cytel Inc.
Park JJH et al. 2020 Feb 7 CA: A Cancer Journal for Clinicians.
An overview of precision oncology basket and umbrella trials for clinicians
11
12. Illustrations of basket and umbrella trials
Cytel Inc.
Park JJH et al. 2020 Feb 7 CA: A Cancer Journal for Clinicians.
An overview of precision oncology basket and umbrella trials for clinicians
12
13.
14. Basket and umbrella trials
14
A basket trial in cancer An umbrella trial in cancer
• Multiple histological types of
cancer
• A single histological cancer type
• Common targets as unifying
eligibility criteria
• Multiple targets used to stratify
patients
• Interventions agnostic to tumor
and histology
• Multiple sub-cancer
interventions
15. Are basket
and umbrella
trials similar
in any way?
• In both trials, a common
molecular screening protocol is
used to determine eligibility
• Standardized biomarker assays are
used within the trial ecosystem –
features of master protocols
• Intervention assignment may
or may not be determined
using randomization in these
trials
15
16. Basket trials
• The inherent nature of basket trials may
be
described as “unification of diseases”
• Patients in a basket trial will represent
multiple diseases that share a common
unifying predictive risk factor
• Given that the disease sub-type is often a
prognostic factor, patient subgroups may be
defined based on the disease sub-types, but
they are usually not powered to detect
subgroups
Lung
cancer
Salivary gland
cancer
Ovarian
cancer
Biliary tract
cancer
Colorectal
cancer
Bladder
cancer
HER2 amplification
or mutation
Unification of diseases
Adapted from NCT02675829: “Trial of Ado-Trastuzumab
Emtansine for Patients With HER2 Amplified or Mutant Cancers"
Ado-trastuzumab
emtasine
17. Umbrella trials
• Umbrella trials have an inherent feature
of using multiple predictive risk factors to
stratify single-disease patients into
multiple groups (patient stratification)
• Each group is statistically powered as
each sub-study of the master protocol
Adapted from NICE’s advanced non-squamousnon-small
cell lung cancer systematic anti-cancer therapyguideline
17
18. Basket and umbrella trials: Trial design
characteristics
18
Trial design
characteristics*
Basket trials
(N = 49)
Umbrella trials
(N = 18)
Exploratory
(phase I or II)
96%
(n = 47)
89%
(n = 16)
Use of
randomization
10%
(n = 5)
44%
(n = 8)
Number of interventions
investigated
Median: 1
(IQR: 3-1 = 2)
Median: 5
(IQR: 6-4 = 2)
*Park JJ et al. BMC Trials. 2019 Dec;20(1):1-0.
Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.
Acronym: Interquartile range - IQR (Q3 –
Q1)
19. Basket and umbrella trials vs. other biomarker-guided trials
• Similar to other biomarker-guided trials, basket and
umbrella trials aim to use “omic” technologies to
define disease and eligibility criteria for improved
characterization and identification of predictive
biomarkers and targeted therapies
• Basket trials aim to identify histology-agnostic
therapies
• Traditionally, it is not uncommon for phase I trials to
recruit multiple tumors to test for the existence of
signal, but basket trials’ histology-agnostic
approaches are now being considered for phase 2
and 3 evaluations
Transcriptomics
mRNA
Proteomics
Protein
Metabolomics
Metabolite
Genomics
DNA
19
20. Basket and
umbrella
trials vs.
other
biomarker-
guided trials
• The use of a single master protocol
with standardized operating
procedures is a key difference!
• In umbrella trials, multiple histology-
dependent targeted therapies are
evaluated as different sub-studies that are
molecularly differentiated
• Use of a master protocol in an
umbrella trial allows for screening
efficiency
20
21. Screening for eligible biomarker-positive
population
Screening population
Cytel Inc.
Eligible biomarker
population
Screening
22. Basket and
umbrella trials
vs. other
biomarker-
guided trials
• For example, if we assume that 10% of
breast cancer patients will have the
biomarker of interest, an expected 1000
cancer patients will need to be screening
to reach the recruitment target of 100
patients
• In principle, each sub-study of an umbrella
trial can be conducted separately as a non-
master protocol, but conducting them
independently would require a much
larger number of patients that would
need to be screened.
23. Key design considerations for basket and umbrellatrials
23
Biological
plausibility
Accuracy of
biomarker
assays
Biospecimen
collection
Biomarker
prevalence
Sample size
calculations
Use of
randomization
24. Biological plausibility
24
Most important to consider the biological
plausibility of the targeted intervention strategies
being evaluated
It is common for cancers to have multiple genetic
mutations, but most mutations are passenger
mutations that do not affect the underlying
carcinogenic process.
Intervention strategies should be targeting driver
mutations, but it can be difficult to separate
driver mutations from passenger mutations
25. Accuracy of biomarker
assays
• Conceptually, a targeted intervention should be
more efficacious against the disease with the
biomarker target versus the disease without the
target
• Given that all medical tests have some degree of
diagnostic inaccuracy, a proportion of false positive
patients are expected in basket and umbrella trials
• In exploratory biomarker-guided trials, it has
been shown that increasing false positive rates of
biomarker tests will reduce statistical power
26. Biospecimen collection
• Ensuring adequate biospecimen collection
procedures and standards across multiple
trial institutions are important
• Centralized biospecimen processing and
molecular analyses established through a
master protocol can help
• Ease of biospecimen collection,
biospecimen quality, and biospecimen yield
should be similar between different tumors
26
27. Biomarker
prevalence
• Patient recruitment is a key determinant for
any clinical trials
• Biomarker prevalence will affect the size of
eligible patient pool. If the target
biomarker has a low prevalence,
recruitment challenges can be amplified
• Planning for comprehensive recruitment
strategies to reach the target sample size
within the desired trial duration will be
essential
28. Sample size calculations
• For basket trials, sample size calculations
may be done for the overall cohort.
• It can be difficult to differentiate
’responders’ and ‘non-responders’
between different disease sub-types
• For umbrella trials, sample size calculations
may be done for each of the sub-studies
given that multiple targeted interventions
are being evaluated
29. Use of randomization
• Randomization is generally preferable, as it can help determine
whether the risk factors being used as part of the targeted
intervention strategies are indeed predictive
• In single-arm basket and umbrella trials, it can be difficult to
differentiate between predictive and prognostic factors
• Statistical adjustments may be made on disease sub-types and/or
other prognostic risk factors, but adjustments are difficult in
smaller data sets
30. Use of
randomization
• Choice in control arm:
• If there are multiple standard-of-
care across different tumors, it
might be difficult to pick a single
control in a basket trial
• In an umbrella trial, each sub-study
can have its own control and
powered accordingly
32. Vemurafenib in Nonmelanoma Cancers Harboring BRAF
V600 Mutations
• *ECD = Erdheim-Chester
disease; LCH = Langerhans cell
histiocytosis.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E,
Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med.
2015 Aug 20;373(8):726-36. doi: 10.1056/NEJMoa1502309. Erratum in: N Engl J Med. 2018 Oct 18;379(16)
34. Signature program: a platform of basket trials
• A series of 8 phase 2, agent-specific basket protocols.
• Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib,
sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic
malignancies and an actionable mutation.
• The primary endpoint - clinical benefit rate (ie, complete or partial response, or
stable disease) at 16 weeks.
• The most common tumor types among the 595 treated patients were colorectal
(9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%).
• Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial
or complete responses were observed with 6 compounds in 16 tumor types.
35. Agents Target Mutations Required Tumor Types Excluded
Buparlisib (BKM120) Pan-Pl3K PIK3CA mutation/amplification, PTEN
mutation/loss, or PIK3R1 mutation
Endometrial, glioblastoma, NSCLC,
prostate, breast
Dovitinib (TKI258) Various RTKs FGFR1-3, FLT3, or c-
KIT mutation/amplification
or PDGFRα/β, VEGFR1-
2, RET, TrkA (NTRK1), or CSF-
1R mutation
Multiple myeloma, urothelial, AML
(FLT3+), hepatocellular, endometrial,
renal cell, breast (metastatic),
squamous NSCLC
Binimetinib
(MEK162)
MEK (RAS pathway) RAS, RAF, MEK1/MEK2, or NF1 Pancreatic, biliary, colorectal, ovarian
(low-grade serous), melanoma
Encorafenib
(LGX818)
BRAF BRAF V600E Melanoma, colorectal, primary CNS
Ceritinib (LDK378) ALK/ROS1 ALK/ROS1 mutation/amplification/tra
nslocation/rearrangement
ALK+ NSCLC
Signature program: a platform of basket trials
36. BATTLE trial
Design-
• BATTLE was a randomized phase II, single-center, open-label study
in patients with advanced NSCLC refractory to prior chemotherapy.
Study groups-
• Following molecular tumor biomarker assessments, patients were
randomly assigned to oral treatment with erlotinib (150 mg once
daily), vandetanib (300 mg once daily), erlotinib (150 mg once daily)
plus bexarotene (400 mg/m2 once daily), or sorafenib (400 mg
twice daily)
37. BATTLE trial
Primary end point- disease control rate (DCR) at eight weeks.
Secondary end points-
• Included response rate
• Progression-free survival (PFS)
• Overall survival (OS)
• Toxicity.
Planned exploratory objectives were each treatment's efficacy in
relation to patient biomarker profiles.
38.
39.
40. Results
• Sorafenib was active against tumors with
mutated or wild-type KRAS, but had a
worse DCR (compared with other study
agents) in patients with EGFR mutations.
• Erlotinib was beneficial in patients with
mutated-EGFR tumors. Erlotinib plus
bexarotene improved DC in patients with a
higher expression of cyclin D1 and also
improved DC in the KRAS-mutant patient
population.
43. • FOCUS4-D has shown no evidence of efficacy of single-agent EGFR,
HER2, and HER3 inhibition with AZD8931 (Sapitinib) in patients with
advanced colorectal cancer whose tumours are wild-type for BRAF,
PIK3CA, KRAS, and NRAS after first-line induction therapy.
FOCUS 4 Conclusion
44. Platform Trials
• A randomized design with a common control
arm and many different experimental arms
that enter and exit the trial as futility or
efficacy are demonstrated, often according to
Bayesian decision rules.
45. Platform
Trials
• The trial itself then comprises a platform or
standing infrastructure to which novel
therapies may be added or from which they
may be dropped.
• Adaptive randomization, i.e. mid-trial shifts
in the randomization ratios for patients with
a given biomarker signature to favor the
treatment showing the most promise in that
signature, may also be present.
46.
47. I-SPY 2 TRIAL (Investigation of Serial studies to Predict The Therapeutic
Response with Imaging and Molecular Analysis 2, NCT01042379)
• Multicenter, open-label, adaptive phase 2 clinical trial design for women with high-risk clinical
stage II or III breast cancer.
• Goal- I-SPY 2 trial is to target rapid, focused, and individualized clinical development of promising
agents or agent combinations based upon breast cancer biomarker subtypes.
• The trial classifies breast cancer into 10 subtypes based on ER, HER2, and MammaPrint scores.
• Study population – Women with invasive tumor. ≥ 2.5 cm in Diameter.
48. I-SPY 2 TRIAL
• The control group receives standard neoadjuvant therapy consisting
of weekly intravenous paclitaxel (T) at a dose of 80 mg per m2 of
body surface area for 12 cycles, followed by 4 cycles of doxorubicin
(A) at a dose of 60 mg per m2 and cyclophosphamide (C) at a dose
of 600 mg per m2 , administered intravenously every 2 weeks to 3
weeks.
• The primary endpoint - pCR, defined as elimination of invasive
cancer in the breast and lymph nodes at the time of surgery.
• Drugs that increase pCR rates within a specific molecular subtype
will be preferentially assigned to new patients entering the trial with
that particular subtype allowing for a more rapid determination of
success. On the other hand, drugs doing poorly within a particular
subtype will be less likely assigned to that subtype.
49. I-SPY 2 TRIAL
• Criteria for Stopping enrolment in an experimental group-
Bayesian predictive probability of success reaches a
prespecified threshold (usually 85%) for any biomarker
signature- Agent/combination is deemed as “graduated”
from the trial.
Futility - if the probability falls to below 10% for all
biomarker signatures.
50. The steps involved in the enrollment, randomization, and treatment
process.
54. Summary
• There is great promise that use of the Master Protocol design to
discover, explore, and test multiple biomarkers and therapeutic
regimens under one study mechanism will result in getting new and
effective therapies to patients more quickly.
• Methodological advancements in basket and umbrella trials will help
catalyze the adoption of precision medicine and oncology into clinical
practice.
• There are some important considerations that are need to be made
for these trials.