Building a Phase I Unit

Timothy A. Yap MBBS PhD MRCP

Medical Director, Institute for Applied Cancer ScienceAssociate Professor, Investigational Cancer Therapeutics

and Thoracic/Head & Neck Medical Oncology DepartmentsAssociate Director of Translational Research,

Khalifa Institute for Personalized Cancer Therapy

Shanghai, ChinaNovember 2018

Disclosures

1. Employment: Medical Director of the Institute for Applied Cancer Science and Associate Director for Translational Research of the Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center. Previous employee of the Institute of Cancer Research, London, UK

2. Research support: AstraZeneca, Bayer, Pfizer, Tesaro, Jounce, Eli Lilly, Seattle Genetics, Kyowa, Constellation, EMD Serono, Ipsen, Forbius (Formation Biologics), and Vertex Pharmaceuticals

3. Scientific Advisory Board Member: Pfizer, Atrin, Bayer, Cybrexa, and Seattle Genetics

4. Consultancies: Aduro, Almac, AstraZeneca, Atrin, Bayer, Bristol-Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, Merck, Pfizer, Roche, Seattle Genetics, and Vertex Pharmaceuticals

5. Speaker Bureau: AstraZeneca, Merck, Pfizer, and Tesaro

It’s About Building Bridges

Hong Kong-Zhuhai-Macau Bridge

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Building Bridges for Drug DevelopmentThe Most Important Players

Phase I

Preclinical Clinical

Pharma Regulatory

Building Bridges for Drug DevelopmentNavigating The Roadway

• Regulatory issues

• Business office

• Contiguity

• Multidisciplinary care

• Funding

• Space

• Staff

• Training

The Cancer Center

• Integrated free-standing center with a single mission – “Making Cancer History”

• 20,000 staff members• ~1,600 outstanding scientists and

physicians• Largest number of NCI grants and grant

dollars for cancer research• Research-driven multidisciplinary care of

over 30,000 new cancer patients each year• Largest therapeutic cancer clinical trials

center internationally

MD Anderson Cancer CenterPatient Care Statistics

Total patients served ~137,000

New patients served >44,000

Patients enrolled in clinical trials >10,800

Number of clinical trials 1,255

Ambulatory care visits 1,441,403

FY17

To become the premier Investigational Cancer Therapeutics Program in the world through:• state of the art research-driven patient care• novel molecular therapeutics • biomarker-driven clinical trials

VISION

MISSION

• To translate laboratory discoveries and clinical observations into hypothesis-driven clinical trials leading to targeted, personalized cancer treatments

• To collaborate with clinicians and researchers in the DoCM and throughout the institution to: o expedite time from preclinical concept to trial o increase access to new molecular entitieso expedite discovery of right drug for right patiento expedite Phase I/II/III transition

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Department of Investigational Cancer Therapeutics (A Phase I Program)

Department of Investigational Cancer Therapeutics

Clinical Center for Targeted Therapy(CCTT Outpatient Clinic)

Dept. Core Laboratory

Clinical Translational Research Center (CTRC)

Phase I Inpatient

Departmental Resources

• Over 1500 patients enrolled on phase 1 trials in 2017• No rare tumor: 90+ tumor types seen• Competitive activation times

– Can submit before IND approval

• Competitive enrollment • Dedicated infusion unit, inpatient service, lab• Molecular profiling initiative to profile all patients

Dept. of Investigational Cancer Therapeutics Distinguishing Features

Patient Distribution by Tumor Type9/1/2014 to 8/31/2018

Trial Portfolio: Areas of Emphasis

• Studies with new first-in-human molecules– Trials that we can help develop

• Hypothesis-driven trials of new combinations of experimental or approved drugs– Combinations based on MD Anderson preclinical data

• Signal seeking histology-independent or multiple histology biomarker-selected basket trials

• Protocols using new routes of delivery of drugs• Biomarker discovery and pharmacodynamic effects

– Learning more from our trials– Responders vs non-responders– Mechanisms of acquired resistance

• IPCT Unusual responder program

Number of ICT Clinical Trials Activated and Submitted per FY

*Data as of Aug 31

Number of Active Trials by Agent & Phase

72

47

27

31

*Data as of Aug 31

Number of Active Trials by Drug Type

9078

9

*Data as of Aug 31

Unique Targets

ØAurora kinaseØDeath receptorØBRAFØCDKØEGFR familyØFarnesyltransferaseØFGFRØGamma secretaseØHDACØHIF-1aØIL-1aØIL-6ØIGFRØAnti-CD30ØTGF-bØNFkB

ØKIT kinaseØMET kinaseØMEKØmTORØPI3KØProteosomeØRAF kinaseØRET kinaseØSTAT3ØSRC KinaseØTubulinØVEGFRØEIF-4EØAKTØCHK-1,2ØNFR-1

Unique Department Organizational Structure

• Physician-based Research Teams– Each team has a study coordinator and research nurse team,

regulatory team, data team, finance Lead– Full independence– Entrepreneurial environment– Most teams have focused research themes: for example…

• Team Yap: DNA damage response (DDR); IO agents; thoracic• Team Subbiah: RET; sarcomas• Team Hong: T-cell therapies, NTRK• Team Meric: Intratumor agents• Team Naing: IO agents

Processes to Ensure Quality

• Team structure allows for accountability• Institution wide auditing process• M&M board review toxicities/SAEs• Quarterly Dose error meetings

• QIAC: centralized tumor measurements– RECIST1.1– RECIST1.1/irRC– irRC– RANO

Clinical and Translational Research Center(CTRC)

• Phlebotomy• IV infusion• Specimen processing• Research EKGs• Coordinator time-sensitive and complex research• Accommodate 24 hour PKs

Dedicated unit for intensive treatment and monitoring of patients participating in complex, early-phase clinical trials.

CTRC “Fast Facts”

28-bed and 4-chair Total full-time employees: CTRC Treatment Center: 44CTRC Laboratory = 54 (and 2 part-time)

Protocol enrollments (Sep 2012 – Aug 2017) § 8,552 total enrollments to CTRC studies § 701 enrollments on NIH-sponsored, Cooperative Group § 18 CCSG programs served in last 5 years

FDA approved 76 drugs studied in the CTRC in last 5 years

Investigator-Initiated Trials in ICT Bringing a concept from bench to bedside

Scientific concept

From concept to trial design

Build study team and write letter

of intent

Pharmaceutical partnership or other support

Trial implementation

What Metrics are Important?

• Quality of work:– Data quality – accurate and on time– Lack of protocol deviation and violations– Meeting deadlines– Outstanding care and follow up of patients– Professionalism and attitude of team

• Accrual• Efficiency • Scientific input and engagement• Cost

Integrating translational medicine capability

Doc, you must know everything!

Requirements for Handling NGS “Big Data”1. Inhouse resource that provides physicians with a clear understanding of which genomic

alterations are actionable at a gene and variant level (i.e. don’t leave it up to the physicians to guess!)

2. Resource that matches clinically available therapies with specific genotypes (at a variant level)

3. Resource that provides concise representation of the level of evidence associated with each therapy within the patient’s genomic and tumor context (keep it simple and evidence-based)

4. Resource for identifying genotype-relevant clinical trials (ideally open access for all)

5. Simplified reporting scheme that incorporates all this information in a patient-specific report (simple and user friendly)

6. Timely proactive notification of actionable genomic alterations identified and potential courses of action (must be in real time and must be a plan of action, e.g. trial or no trial)

Precision Oncology Decision Support System (PODSS) set up to improve clinical utilization of molecular testing

Institute for Personalized Cancer TherapiesGenomics Decision Support

• Prospective tumor characterization for patient enrichment in targeted therapy trials and validation of predictive biomarkers– Clearinghouse study

• Discovery of biomarkers of sensitivity and resistance in ongoing trials and in standard of care therapy– Unusual responder program

• Identifying potential actionable aberrations• Incorporating patient and previous treatment information• Leveraging information in published literature and other

online biomedical data • Prioritization of mutations/targets• Identifying optimal approved or investigational treatment

Institute for Personalized Cancer TherapiesGenomics Decision Support

1. Resource that provides physicians with a clear understanding of which genomic alterations are actionable at a gene and variant level

2. Resource that matches clinically available therapies with specific genotypes

3. Resource that provides concise representation of the level of evidence associated with each therapy within the patient’s genomic context

4. Resource for identifying genotype-relevant clinical trials

5. Simplified reporting scheme that incorporates all this information in a patient-specific report

6. Timely proactive notification of actionable genomic alterations identified and potential courses of action

Precision Oncology Decision Support CASE STUDY

Decision Support Requires More that Delivery of Mutation Information

How can we help clinicians interpretresults and rapidly identify the best

treatment options available?

First 14K patients tested = >6,000mutations found

Molecular Reports issued by MDL include genes altered (pg. 2) with specific alterations listed (pg. 3 and beyond)

Unmatched therapy Matched therapy

Institute for Personalized Cancer TherapiesGenomics Decision Support

Ann Bailey, PhDJia Zeng, PhD Vijaykumar Holla, PhD Amber Johnson, PhD

Beate Litzenburger, PhD

Yekaterina Khotskaya, PhD

Precision Oncology Decision Support (PODS) Team

Nora Sanchez, PhD Lauren Brusco, PhD

REAL PEOPLE, NOT MACHINES

Communicating Annotations in Real Time in Effective Reporting Format

Level I Indication: standard of care

Resistance mutations clearly highlighted

Variants of unknown significance are deprioritized

Personalizedcancertherapy.org

Website: 33 genes fully annotated>1,025 functionally significant SNVs>15,000 SNVs reviewed

Single Patient Annotation Effort: 3200 Single patients annotated

Drug Curation Effort: 1504 drugs annotated

Clinical Trial Curation Effort: 3240 cancer clinical trials annotated

Precision Oncology Decision Support (PODS) Team

Strategy 1. Data in real time: Patient Report within 1 business day

Clear Alteration-Level Actionability Calls

Aggregated Frequencies

Emailed and Deposited into EHRClear Functional

Significance Call

Variant-level annotations

Trials retrieved only if targets a potentially actionable or actionable alteration

Strategy 2. Patient Report: Are There Clinical Trials Available? (that are active & have open slots)

Display only what is relevant to patient

Relevant drug underlined

Based on Variant Actionability

On-demand link for screening

Strategy 3. Clinical Trial Email Alert to Patient’s Oncologist and Trial PI

Thank you

MD Anderson Department of Investigational Cancer Therapeutics (A Phase I Program)

tyap@mdanderson.org