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Description : Check out this medical presentation on Drug Development, which is titled "Drug Development: Basic Overview of Clinical Trials", to know about Clinical Trials from Phase I to Phase III.

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Drug Development : Basic Overview of Clinical Trials: Phase I-III Patricia Mucci LoRusso, D.O. Associate Center Director – Innovative Medicine Yale Cancer Center
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<3% of all Cancer Patients Enroll in Clinical Trials ~1.3% of African Americans Enroll in Clinical Trials Women are Underrepresented
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Aggregate Patient Recruitment Success Rates How do patients learn about trials? – CISCRP Tufts CSDD; N=3,534 Phase II-IV protocols
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*Cutting Edge Information, “Clinical Operations Benchmarking Per-Patient Costs, Staffing and Adaptive Design” 2011
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Non-performing Sites By Therapeutic Area “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015
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One Large Scale Oncology Trial “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015
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Non-Performing Sites Average $50k start-up cost Result in budget overrun Many never enroll a single patient or very few Selection of sites often carried out in a non-scientific, non-systematic way Causes delay, impacting trial schedule $334.70 million wasted on non-performing oncology sites from 2006-2011 “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015
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Potential Accrual Barriers – Patient Level Awareness of trials as an option Understanding of what trial participation involves Concerns around side effects Education about particular trial phase Education about particular treatment Fear of distrust (guinea pig) instead of trust in physician recommendations History of discrimination in medical research Inconvenience of trial logistics: travel, times, number of visits Financial burden
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How do patients learn about trials? – CISCRP
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Barriers to Enrollment – Physician Factors Concerns about potential toxicity from study treatment Concerns about comorbid conditions of patients Lack of awareness of accessible clinical trials Lack of access to clinical trials Lack of manpower necessary in clinic Physicians’ own perceptions about the relevance of the questions being addressed in the available trials Lack of time in busy practices to discuss trial options
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Potential Accrual Barriers – Provider Level Payment metrics at respective practice Time & resources required to discussing trials Fear of “losing” patients if refer to clinical trials Concerns around trial suitability for patient (eg tolerability, benefit) Belief patient should not be offered trial (not adherent, competent) Comfort with, and style of, communicating trial to patients
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Barriers to Enrollment Lack of encouragement or support from the attending physician Unaware of appropriate open trials Lack time to discuss options at length Concerned about lack of control over their patient Unrealistic, inconvenient protocol requirements Unrealistically restrictive inclusion/exclusion criteria The most motivated patients are most likely to be excluded Rejected patients often don’t try again
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Barriers to Enrollment (cont.) Politics Rivalry between physicians and/or hospital administrators Bad publicity Trials conducted unethically garner the most press Physician or hospital concerns about potential liability Insurance or HMO policies that may preclude reimbursement for care or make it difficult HIPAA restrictions Standardized order sets for “quality”
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Logistics Factors Physicians – lack of support and infrastructure (trial nurses, study coordinators, pharmacy capability, etc) to enable enrollment of patients into trials Reimbursement of costs incurred by patients during participation in clinical trials (e.g. parking) Added time off work for patient +/o caregiver Child support Patient – lack of social support to attend doctor visits (e.g. for study treatment, management of treatment-related adverse events) Language barrier
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Trial Factors Dissemination of up-to-date knowledge of available and ongoing trials and how to access them Paucity of trials for specific patient populations e.g. hepatic/renal dysfunction, elderly Changing landscape in clinical trial designs e.g. histologic and/or molecular selection including rare subsets Need for innovative and attractive clinical trials that efficiently evaluate novel agents Burden of research investigations and visits in clinical trials
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Potential Accrual Barriers – Site Level Staffing (research nursing & support staff) Redundant review processes Slow trial activation CRO relationships & issues Lack of standard processes for patient screening Lack of effective clinical trials tools
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Potential Accrual Barriers – Systems Levels Overly optimistic accrual goals and/or limited accrual feasibility assessment prior to activation Inadequate recruitment planning during trial development process Limited funding & incentives for site & provider involvement (to conduct & offer trials) Trial availability & eligibility for incident patients (eg exclusion for comorbidities, prior # treatments) Massett, et al., Clin Can Res, November 2016
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Clinical Trials Clinical trial: a prospectively planned experiment for the purpose of evaluating potentially beneficial therapies or treatments In general, these studies are conducted under as many controlled conditions as possible so that they provide definitive answers to pre-determined, well-defined questions
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Why Clinical Trials? Most definitive method to ultimately determine treatment effectiveness Other designs more potential biases One cannot determine in uncontrolled setting whether intervention has made a difference in outcome Correlation versus causation
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Why Clinical Trials? Help determine incidence of side effects and complications Theory not always best path May not actually prove itself in reality May not be tolerable/ feasible solution
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Primary vs. Secondary vs Exploratory Objectives Primary most important (i.e., central question) ideally, only one stated in advance basis for design / sample size calculations/biostats focus Secondary related to primary also stated in advance limited number but usually more than one/biostats input Exploratory Typically not driven by biostats eg looking at a biomarker
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Elements of Clinical Protocols Objectives – Primary and Secondary Biostatistics Patient selection criteria – Inclusion/Exclusion Therapeutic Intervention Dose and Schedule and Mechanism/Route of Delivery Clinical Work-up and Follow-up Assessment Toxicity Toxicity criteria Dose modifications Efficacy Clinical, pharmacodynamic (PD) and QOL Analysis and interpretation Primary & secondary endpoints Correlative studies
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Questions to be Answered in Clinical Trials Why? Who? What? Which? Where? When? How (bad)? So what?
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Why: Define Trial Objectives Why are you doing this study? “The primary objective of this trial is …” Limit number of objectives Too many will limit trial success Well planned & thought out objectives Biostatistics important here Critical outcome for study a “go/no go” decisions? Define and use secondary endpoints to generate hypotheses to be explored in future research
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Why: Define Trial Objectives Remember laboratory correlative objectives “translational research” Make sure assay and tissue available Confirm reproducibility and relevance Make sure tissue/specimens handled appropriately to conduct investigation Design must take this into account when answering this question!
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Who: Patient Selection Who should enter the trial? One of the most critical factors affecting study outcome Each selection criterion should be based on a sound scientific, medical, ethical rationale Do not copy/paste from other trials! Inclusion/exclusion should be study directed Disease type Prior treatment Age, sex, organ function and other variables Measurability and disease status Proper patient selection is key for successful completion and scientific impact of your study!
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What: Trial Intervention What treatment? What dose and schedule? Which dose or schedule variations are planned? How long may the treatment last? What are specific steps in drug administration? What should be done to prepare, treat, and monitor the patient prior/during/after treatment? Will the same treatment be given to all patients? If not, what are the differing procedures? What are the methods to assess compliance with the procedures defined in your protocol?
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Which: Assessment of Critical Endpoints WHICH: Methodology is used to select patients (Performance status? Pain score? NYHA?...) Standard will be used to assess response? Instrument for evaluation of safety and toxicity Methodology to be applied for the statistical, correlative and translational endpoints?
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Where: Tumor and Response Assessment Where are primary tumor lesions to be measured? What happened to it during treatment? Location, size, density Criteria for response: RECIST vs. iRECIST vs WHO Pre-baseline assessment of progression required? Target vs. non-target lesions Other parameters of effect being studied adequately? TTP, TTF, OS, duration of response, etc. Immune response Target modulation in tumor tissue or surrogate Functional imaging
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When: Timing of Assessment When will assessments of primary, secondary and translational endpoints be performed? Do we truly know timing for translational endpoints? Is the timing of assessments compatible with the chosen endpoints? Will dose delays or modifications affect the schedule of reassessment? Will there be a sufficient number of patients to obtain adequate information? Is the chosen timing compatible with the routines of physicians, nursing staff, hospital and patient?
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How (bad): Safety and Toxicity To what degree does treatment interfere with patient well-being? How assessed (CTCAE? QoL? Self-made instrument?) What modifications are incorporated to avoid or minimize the risk or severity of toxicity? Dose reduction Dose delay Dose omission Supportive care (prophylaxis, intervention, secondary prevention) Discontinuation of individual treatment? Termination from the study (specify criteria!)
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So What: Analysis and Interpretation Has study design been followed, is the trial “mature”? Evaluate the compliance of all involved parties What do the results and observations mean? Primary endpoint reflects the hypothesis tested Secondary endpoints reflect hypotheses generated Have the appropriate statistical tools been used? Beware of sporadic “significant” results that result from multiple, unplanned comparisons Beware of retrospective subgroup analyses Given the results, how should we move forward (go/no go; generate confirmatory evidence in laboratory models; additional clinical trials…)?
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Definitions
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Definitions Single Blind Study: A clinical trial where the participant does not know the identity of the treatment received Double Blind Study: A clinical trial in which neither the patient nor the treating investigators know the identity of the treatment being administered.
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Definitions Placebo: Used as a control treatment 1. An inert substance made up to physically resemble a treatment being investigated 2. Best standard of care if “placebo” unethical 3. “Sham control” 4. Used in Randomized trials
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Definitions Adverse event: An incident in which harm resulted to a person receiving health care. Examples: Death, damage to liver, nausea, drop in white cells or platelets Not always easy to specify in advance because many variables will be measured May be known adverse effects from earlier trials or preclinical toxicology studies Animals and man different – can’t always predefine Not necessarily linked to assigned treatment Important to decipher if drug effect
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Adverse Events (AEs) Challenges Long term follow-up versus early benefit Rare AEs may be seen only with very large numbers of exposed patients and/or long term follow-up Example – COX II inhibitors Vioxx & Celebrex Immediate pain reduction versus longer term increase in cardiovascular risk
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Phase I Trial Primary Objective : Determine an acceptable range of dose(s) & schedule(s) for a new drug Determine toxicities (dose-limiting and others) Secondary Objectives: Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity Usually seeking maximum tolerated dose or target dose based on pre-clinical exposure Maximum biological dose Participants have often failed other treatments Important to have adequate performance status & “normal” organ function (except organ dysfxn trials) Not an alternative to Hospice
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Pharmacokinetics (PK): “what the body does to the drug” ADME: absorption, distribution, metabolism and excretion PK parameters: Cmax, AUC (drug exposure), t1/2, Clearance, etc. Pharmacodynamics (PD): “what the drug does to the body” e.g. nadir counts, non-hematologic toxicity, molecular correlates, biomarker changes, imaging endpoints Definitions of Key Concepts in Phase 1 Trials
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Phase I Design Strategy Designs often based on tradition Typically do some sort of dose escalation to reach targeted endpoint (MTD, OBD, MFD) Has been shown to be safe and reasonably effective Dose escalation based on mathematical model: Fibonacci, 2-fold escalation, Continuous Reassessment Method, etc.
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Typical Scheme 1. Enter 3 patients at a given dose 2. If no toxicity, go to next dosage and repeat Step 1 3. a. If 1 patient has serious toxicity, add 3 more patients at that does (go to Step 4) b. If 1/6 have serious toxicity, consider MTD 4. a. If 2 or more of 6 patients have toxicity, drop down 1 dose to confirm safety b. If 1 of 6 has toxicity, increase dose and go back to step 1
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AACR March 31st, 2019 A Phase 1b Study of CD40 Agonistic Monoclonal Antibody APX005M Together with Gemcitabine and nab-Paclitaxel with or without Nivolumab in Untreated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) Patients PICI0002 (PRINCE) Mark H. O’Hara, Eileen M. O’Reilly, Rosemarie Mick, Gauri Varadhachary, Zev A. Wainberg, Andrew Ko, George Fisher, Osama Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Erica L. Carpenter, Travis Hollmann, Pier Federico Gherardini, Lacey Kitch, Cheryl Selinsky, Theresa LaVallee, Jingying Xu,Ovid C. Trifan, Ute Dugan, Vanessa M. Hubbard-Lucey, Ramy Ibrahim, Robert H. Vonderheide
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Study Design Cohort B1: 6 Subjects Gem, NP + APX005M 0.1 mg/kg Phase 1b Cohort C2: 6 Subjects Gem, NP + nivo + APX005M 0.3 mg/kg Cohort C1: 6 Subjects Gem, NP + nivo + APX005M 0.1 mg/kg Cohort B2: 6 Subjects Gem, NP + APX005M 0.3 mg/kg ClinicalTrials.gov Identifier: NCT03214250 Phase I Investigation of novel CD40 targeted agent in front-line metastatic pancreatic cancer
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Clinical Snapshot date: 05MAR19Safety-evaluable Population Percent Change in Sum of Target Lesions (Best Response) Cohort B1: Gem/NP/APX005M 0.1 mg/kg Cohort B2: Gem/NP/APX005M 0.3 mg/kgCohort C1: Gem/NP/APX005M 0.1 mg/kg + nivo Cohort C2: Gem/NP/APX005M 0.3 mg/kg + nivo
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Phase II Trials Objective: To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources. Doses and schedules may not be optimum Begin to focus on population for whom this drug will likely show favorable effect
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Phase II Trials Goal Screen for therapeutic activity Further evaluate toxicity Test using MTD or defined Dose(s) & Schedule(s) from Phase I (RP2D) Make go/no-go decisions for Phase III trials Perform translational work Might also randomize patients into multiple arms each with a different dose and/or schedule can then get a dose response curve
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Phase III Trial Objective : To compare experimental or new therapies with standard therapy or competitive therapies Often large & expensive studies Typically required by FDA for drug approval If drug approved, often followed by Phase IV trials to follow-up on long-range adverse events – concern is safety
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The foundation for the design of controlled experiments established for agricultural experiments The need for control groups in clinical studies recognized, but not widely accepted until 1950s No comparison groups (and hence no Phase III randomization) needed when results dramatic: Vismodegib in Advanced Basal Cell Carcinoma Use of proper control group necessary due to: Natural history of most diseases Variability of a patient's response to intervention Phase III Trial Designs
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Purpose of Control Group To allow discrimination of patient outcomes caused by test treatment vs those caused by other factors Natural progression of disease Observer/patient expectations Other treatment Fair comparisons Necessary to be informative
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Use of Placebo Control The “placebo effect” is well documented Could be No treatment + placebo Standard care + placebo Matched placebos necessary so patients & investigators cannot decode the treatment assignment eg. Vitamin C trial for common cold Placebo was used, but was distinguishable Many on placebo dropped out of study – not blinded Those who knew they were on vitamin C reported fewer cold symptoms and duration than those on vitamin who didn't know
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A new treatment used in a series of subjects Outcome compared with previous comparable subjects Non-randomized Rapid, inexpensive, good for initial testing of new treatments Vulnerable to biases Different underlying populations Criteria for selecting patients Patient care Diagnostic or evaluating criteria Not most updated treatment intervention Historical Control Study
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Comparing Treatments Fundamental principle Groups must be alike in all important aspects and only differ in the treatment each group receives In practical terms, “comparable treatment groups” means“alike on the average” Randomization Each patient has the same chance of receiving any of thetreatments under study Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned Blinding Avoidance of psychological influence Fair evaluation of outcomes
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Redesigning Cancer Trials: Stage 1
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Oncology Clinical Trial Designs Bui & Kummar Jnl Mol Med, 2018
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Master Protocols Overarching protocol with multiple objectives that involve coordinated efforts to evaluate one or more investigational products in one or more patient populations within the overall trial structure. In general, the RP2D has been established for investigational agent(s)
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Oncology Clinical Trial Designs Bui & Kummar Jnl Mol Med, 2018
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Master Protocols: Umbrella Trials One type of cancer with multiple drugs and predictive biomarkers Patients are matched based on biomarker analysis
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Master Protocols: Basket Trials Biomarker-driven approach: enroll patients across many different tumor types into discreet, biomarker defined baskets Hyman DM et al NEJM 2015 Examples: VE-Match NCI MATCH ASCO TAPUR
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TRK fusions found in diverse cancer histologies Brain cancers (glioma, GBM, astrocytoma) Salivary (MASC) Lung cancer Secretory breast cancer Melanoma Colon Sarcoma (multiple) 66 Infantile fibrosarcoma Gliomas Thyroid cancer Congenital nephroma Sarcoma (multiple) Common cancer with low TRK fusion frequency Rare cancer with high TRK fusion frequency Cholangiocarcinoma Pancreatic GIST Thyroid cancer Spitz nevi Hyman, LBA2501 Estimated 1,500–5,000 patients harbor TRK fusion-positive cancers in the United States annually
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Larotrectinib TRK fusion development program N=55 TRK fusion patients n=8 n=12 n=35 TRK fusion status determined by local CLIA (or similarly accredited) laboratories Primary endpoint Best objective response rate (ORR) RECIST v1.1 per investigator assessment Secondary endpoints Duration of response (DOR) Progression-free survival (PFS) Safety Dosing Single-agent larotrectinib, administered predominantly at 100 mg BID continuously Treatment beyond progression permitted if patient continuing to benefit Adult phase I Age ≥18 years Advanced solid tumors SCOUT: pediatric phase I/II Age ≤21 years Advanced solid tumors NAVIGATE: adult/adolescent phase II ‘basket’ trial Age ≥12 years Advanced solid tumors TRK fusion positive 67 Data cut-off: April 14, 2017 Hyman, LBA2501
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Efficacy of larotrectinib in TRK fusion cancers *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; #Pathologic CR Note: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recorded. 68 Hyman, LBA2501
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All Patients N = 1235 Advanced NSCLC n = 550 Cohort F1 (Randomized) PD-L1+ Treatment naive n = 101 Cohort F3 PD-L1+ ≥1 prior therapy 2 mg/kg Q3W n = 55 2 mg/kg Q3W n = 6 10 mg/kg Q3W n = 49 10 mg/kg Q2W n = 46 Advanced Melanoma n = 655 Cohort B1 Nonrandomized n = 135 Cohorts B2, B3, D Randomized n = 520 IPI Naive n = 87 IPI treated n = 48 Cohort DIPI naive n = 103 Cohort B2 IPI refractory n = 173 10 mg/kg Q2W n = 41 10 mg/kg Q3W n = 24 2 mg/kg Q3W n = 22 10 mg/kg Q2W n = 16 10 mg/kg Q3W n = 32 2 mg/kg Q3W n = 51 10 mg/kg Q3W n = 52 2 mg/kg Q3W n = 89 10 mg/kg Q3W n = 84 Cohort B3 IPI naive or IPI treated n = 244 10 mg/kg Q3W n = 122 10 mg/kg Q2W n = 122 Cohort A Advanced solid tumors n = 30 1 mg/kg Q2W n = 4 10 mg/kg Q2W n = 10 3 mg/kg Q2W n = 3 2 mg/kg Q3W n = 7 10 mg/kg Q3W n = 6 Cohort C Any PD-L1≥2 prior therapies 10 mg/kg Q3W n = 38 Cohort F2 Previously Treated n = 356 Nonrandomized PD-L1+ ≥2 prior therapies 10 mg/kg Q3W n = 33 Randomized PD-L1+ ≥1 prior therapy n = 280 Nonrandomized PD-L1– ≥2 prior therapies 10 mg/kg Q2W n = 43 10 mg/kg Q3W n = 167 10 mg/kg Q2W n = 113 Clinical Trial Development of Keytruda - FIH with Multiple Expansion Cohorts Keynote-001 N=1255
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Conclusions Clinical Trials are a necessary component of cancer drug development There are discrete developmental phases of clinical drug development, often with some endpoint overlap (1o or 2o): Phase I Trials, although many different types, are typically answering questions for one of the first times in man Phase II Trials are focused on efficacy Phase III Trials help determine benefit over Stand of Care treatment
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We must work together in the fight against Cancer – please encourage patients and caregivers to consider treatment on a clinical trial
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THANK YOU!!!