Therapeutic Area Workshop Oncology Angelo Tinazzi – Cytel Inc. – on behalf of PhUSE PhUSE 2013 – Bruxelles 14/10/2013

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Disclaimer

The information contained in this presentation is based on research of personal PhUSE Wiki authors. PhUSE Wiki authors may or may not be

experts in the field of the specific disease. Neither PhUSEwiki.org nor the PhUSE guarantee for the correctness of the

displayed information.

Introduction • Current/Future Role of SAS Programmers • PhUSE Wiki

Oncology • Short Overview of Disease

• Signs/Symptoms • Treatment Options

Overview

Overview

Oncology (cont.) • Endpoints – Tools used • Data Challenges • SDTM and ADaM

• Regulatory Setting

• FDA Guideline • EMA Guideline

• References

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Standards help to collaborate, the PhUSE Wiki helps to understand

SAS Programming

CDASH/annotated CRF

SDTM

ADaM

PhUSE Wiki

Standardized Analysis

Protocol, CRF, SAP

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Aim of PhUSE (TA-)Wiki

Basics

•Background Information •Etiology •Pathophysiology •Statistics •Symptoms •Treatment

options

Specific

• TA-specific •Regulatory

Setting •Endpoints •Assessment

tools • (Data)

Challenges

Standardisation

•SDTM mapping •Tumore

Response •Anti-Cancer

Medications •Survival Fup

•ADaM concepts •TTE Endpoints

•References

THE central place to share knowledge and information

PhUSE (TA-)Wiki

PhUSE (TA-)Wiki

PhUSE (TA-Onco)Wiki

Oncology - Basics

Definition (short) •Cancer is a term used for diseases in which

abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems.

•Oncology is a branch of medicine that specializes in the diagnosis and treatment of cancer. It includes medical oncology (the use of chemotherapy, hormone therapy, and other drugs to treat cancer), radiation oncology (the use of radiation therapy to treat cancer), and surgical oncology (the use of surgery and other procedures to treat cancer).

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Oncology - Basics

Source: http://en.wikipedia.org

Invasive colorectal cancer

Chest x-ray showing lung cancer in the left lung

Apoptosis is the process of programmed cell death

Cancer are caused by a series of mutations

Oncology - Basics

Epidemiology

•Cancer is a leading cause of disease worldwide with about 13 million new cancer cases occurred worldwide

• Just five cancer sites –lung, female breast, colon-rectum, stomach and prostate – accounted for half (48%) of the world’s total cancer diagnoses in 2008

•Men are more often affected than women.

Source: Cancer Research UK http://www.cancerresearchuk.org

Oncology - Basics

Risk Factors •The most common risk factors for cancer: Tobacco Sunlight Ionizing radiation Certain chemicals and other substances Some viruses and bacteria Certain hormones Family history of cancer Alcohol Poor diet, lack of physical activity, or being overweight

Oncology - Basics

Type of Cancer

•Solid Tumors Cancer involving solid tumor, typically originates in a specific body organ, such a lung, breast, ovarian, etc. Types of solid tumors includes sarcomas, carcinomas, adenocarcinomas, blastomas, carcinoid tumors

•Hematologic malignancies Arrise in the blood-forming cells; typically present as systemic disease, as blood and lymphatic organs located throughout the body are affected. Types of Hematologic malignancies includes leukemias, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MM)

Oncology - Basics

Type of Cancer

Source: US NCI – www.cancer.gov

Oncology - Basics

Diagnosis

•Not easy to diagnose •Symptoms only appears as the mass grow or ulceration E.g. mass effects from lung cancer can cause blockage of the bronchus resulting in cough or pneumonia •Metastasis when cancer spread to other locations

•Screening (Periodic Assessment) •Mammography for Breast Cancer •PSA for Prostate Cancer •Sigmoidoscopy or Colonscopy for Colorectal Cancer •Pap test for Cervix

Oncology - Basics

Diagnosis

•Primary vs Metastatic vs Recurrent Cancer

•Resistant/Refractory Cancer

•Location of the Cancer

•Stage (TNM): extent of the disease and

whether or not the cancer has spread in the

body (metastasis)

•Histology: type of normal tissue the tumor

cells most closely resemble

•Grading: cells differentiation/proliferation

Oncology - Basics

Treatment •The treatment plan depends mainly on the type of cancer, the stage of the disease, age and general health

•Treatment to Cure or Control or Reduce Symptoms •The treatment plan may change over time •The treatment plan includes

•Surgery (local therapy removes or destroys cancer)

•Radiation (to shrink or destroy a tumor) •Systemic Therapies •Vaccines to prevent and ‘cure’

Oncology - Basics

Treatment

Systemic Therapies Drugs or substances are used (through the bloodstream) to destroy cancer cells all over the body. The therapies kill or slow the growth of cancer cells that may have spread beyond the original tumor:

•Chemotherapy •Biological therapy •Monotherapy vs Combination therapies •Adjuvant vs Neo-Adjuvant Treatment

Oncology - Basics

Treatment

Therapies with molecular/biological target •Use of Biomarkers to target the population E.g. drugs used in the therapy target specific markers - Herceptin in breast cancer with HER2++ - Gefitinib in lung cancer with mutant EGFR

Oncology - Basics

Treatment Indications: Type of cancer + Line of therapy

3rd line XXXXX Treatment in relapsed YYYYY cancer patients

Oncology - Basics

Treatment •Because cancer treatments often damage healthy cells and tissues, side effects are common: Type and extent of the treatment. Side effects may not be the same for each

person, and they may change from one treatment session to the next.

Oncology - Basics

Summary • One Disease/Several Diseases • Not easy to diagnose • Complex pattern of therapies • Challenging disease therefore challenging in

programming

Oncology – Specific

Clinical Trials in Oncology

• Placebos are never used in place of treatment when an existing standard therapy exists.

• Patient recruitment is more complicated.” • Longer follow-up

Oncology – Specific

Clinical Trials in Oncology

• Phase I • Toxicity • Optimal Dose Determination • Initial Drug Activity • PK

• Phase II • Activity Signals / Tumor Response • Confirmation about tollerability

Oncology – Specific

Clinical Trials in Oncology • Phase III

• To show better clinical risk/benefit profile based on the efficacy and safety data analysis.

• Efficacy through survival endpoints

Oncology – Specific

Phase I in Oncology

In alternative • Accelerated Titration • Intra-Patient Titration • Continuation

Reassessment Method (CRM)

Oncology – Specific

Phase I in Oncology

• A peculiarity of Oncoloy • The concept of DLT (Dose Limiting Toxicity)

and DLT period • Extended lab (hematology/chemistry)

assessments • Nadir / Time to Nadir • Recovery / Time to Recovery

• „Screening“ for future indication to develop (Phase II)

Oncology - Specific

Primary Efficacy Outcome Measures • Overall Survival (OS) is the gold standard • Several surrogate endpoints can be used in

place of OS • Best Overall Response (BOR)

• Objective Response Rate • Duration of Response

• Time to Progression (TTP) / Disease Free Survival (DFS)

• Progression Free Survival (PFS)

Oncology - Specific

Primary Efficacy Outcome Measures

http://groups.eortc.be/qol/eortc-modules

Quality of Life (EORTC QLQ-C30) and indication specific questionnaires

Oncology - Specific

Primary Efficacy Outcome Measures •Standardised Tumor response evaluation:

•RECIST for solid tumors •CHESON for Acute Myeloid Leukemia

•Modified version •Modified PFS for Prostate Cancer (PCWG2)

•mRECIST for Hepatocellular Carcinoma

Oncology - Specific

Efficacy Analysis

• Primarly survival analysis (Cox Model) • Graphical Representation

• Kaplan Meier Plot • Forest Plot • Waterfall Plot

• Sensitivity Analysis E.g. for incorrect periodicity of tumor assessment

Oncology - Specific

Efficacy Analysis •Use of Covariates (some examples)

Oncology - Specific

The concept of cycle • Commonly defined as a Number of days (or

weeks), e.g. 21 / 28 days (3/4 weeks), where treatment is repeted

• Different type of schedule

• With combinations studies drugs might have a different schedule

• The sequence of treatment is repeated (re-cycled) under certain condition usually safety and/or efficacy related.

Oncology - Specific

Exposure assessment • Usually described by means of Dose-

Intensity and Relative Dose-Intensity • Cumulative dose (mg/sqm) / Treatment

duration (weeks) • Dose Modifications e.g.:

• Delays • Reductions • Overdoses • Omissions

Oncology - Specific

Laboratory data and the CTCAE Grade • Very often Laboratory results comes from local labs • For some of the hematology, chemistry and coagulation

parameters, a categorisation of the value is possibleNCI-CTCAE criteria

• Each lab value is assigned a grade between 1 and 4 • The grade depends on the actual value and the

normal ranges defined by the labs where the sample was analyzed

• The classification can be mono or bi-directional • Hypo • Hyper • Hypo and Hyper

Oncology - Specific

CTCAE Grade for laboratory data

Oncology - Specific

Tumor response evaluation with RECIST • Tumor response measures the changes in tumor

mass, growth (progression) or shrinkage (response)

• Lesion classified as target (measurable) or non-target (non-measurable)

• Periodically assessed with CT-SCAN (every 6/8 weeks)

• Progression evaluated vs Nadir (best ‘response’ prior to current assessment)

• Response evaluated vs Baseline • Best Overall Response as the best response

assessed since the subject is on-study (on-treatment) Applicable to Solid Tumors

Oncology - Specific

Tumor response evaluation with RECIST

Applicable to Solid Tumors

Oncology - Specific

Data Challenges • Use of Local Labs • Advers Events and Treatment Emergent

Definition • Periodic Tumor Assessments • Tumor Assesment and Treatment having

different schedule • Blinded Tumor Assessments (Independent

Review) • Follow-up when OS is primary endpoint • Use of Biomarkers in the analysis

Oncology - Specific

Summary • Choice of endpoints depends on

several factors • Efficacy evaluation of response is

standardised and validated for solid tumors and for certain non-solid tumors (e.g. AML)

• Revised standard for specific cancer-type

• Peculiarity in handling Safety and Exposure

Oncology - Standardisation

CDISC •SDTM version 3.1.3 contains oncology specific data domains for tumor response evaluation

•TU: Tumor Identification •TR: Tumor Results •RS: Tumor Response

•Upcoming version of SDTM •PR: Procedures •SS: Subject Status (Follow-up) •TS: Trial Design Assessment

RG02: “CDISC Journey on Solid Tumor Studies using RECIST” Kevin Lee, ; PhUSE 2013

Oncology - Standardisation

CDISC ADaM • No specific oncology-standard have

been developped • ADTTE for most of efficacy

endpoints (time-to-event) including composite endpoints

Oncology - Standardisation

CRF SDTM ADaM TLF PFS as a composite endpoints

EVENT

Progression

Death

From Tumor Assessment / Response

From Survival Follo-up

CENSOR

Last Tumor Assessment

From Tumor Assessment / Response

Oncology - Standardisation

CRF SDTM ADaM TLF PFS as a composite endpoints

Oncology - Standardisation

CRF SDTM ADaM TLF PFS as a composite endpoints

Oncology - Standardisation

CDISC – Oncology Open Questions • [SDTM] Where to store prior anti-cancer

therapiesCommon approach is to store them in CM with appropriate CMCAT and CMSCAT

• [SDTM] Prior Cancer history stored in several different domain e.g. MH, CM, SUPPQUAL of MH, sponsor domains

• [SDTM] Follow-up in DSLack of details • [SDTM] The use of Oncology Domains to store

non-efficacy information • [ADaM] Cycles date as TRxxSDT/TRxxEDT?

Oncology - Standardisation

CDISC – Coming Version (SDTM 3.1.4)

• PR Procedures For Prior prior/post anti-cancer treatments • SS Subject Status

For survival follow-up • TD Trial Disease Assessments

For efficacy schedule of assessments

Oncology - Standardisation

Analysis Display (Survival Estimates)

Oncology - Standardisation

Analysis Display (Forest Plot)

Oncology - Standardisation

Analysis Display (Tumor Shrinkage)

Oncology – Regulatory

Regulatory Setting (FDA) FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007)

General regulatory requirements for efficacy Detailed description of endpoints and how they can be used in various clinical settings • Pros and Cons • Protocol and SAP design requirements • Data Collection for Tumor Measurement

Oncology – Regulatory

Regulatory Setting (FDA)

• Issues to consider in PFS analysis • Progression and Censoring Date • How to handle Missing Data • Lesions evaluation • Sensitivity Analysis

• ………

Oncology – Regulatory

Regulatory Setting (EMA) Guideline on the evaluation of anticancer medical products in man

All stages of clinical drug development Appendices covering methodologial aspects related to: • Use of Progression Free Survival (PFS) and

Disease Free Survival (DFS) in confirmatory trials • Confirmatory Studies in Haematological Malignancies • Condition specific Guidance such as NSCLC, Prostate

The EMA is also planning to provide an additional appendix for Quality of Life/Patient Reported Outcome.

Oncology - Bibliography

Oncology - Bibliography

Regulatory Guidance

Oncology - Bibliography

Oncology Specific

Oncology - Bibliography

Oncology and Programming

Oncology – Bibliography (PhUSE 2013)

Oncology and Programming

Oncology

Overall Summary •Cancer one diseases, several diseases •Complex study endpoints derivation in efficacy but also in safety

•Unsual concepts e.g. a „cycle“ is not a „visit“

•If you get involved in a Oncology-study you may take a look at the PhUSE Wiki before you start

What next •Seeking for feedback

•Structure, Sections, Topics covered •Enough or more details •Link to source or source

•Seeking for contributions •Complete sections, provide missing details •Review •Maintenance

PhUSE (TA-Onco)Wiki

What next to develop •Identify tumor type specific characteristics from the data and analysis point of view •E.g. What make different colorectal cancer from lung cancer?

•Key requirements for submission •E.g. Differences between indications, type of cancer and / or line of therapy

•Complete the following area: •Phase II and Phase III design •Statistical Analysis •Quality of Life •Any missing important item?

PhUSE (TA-Onco)Wiki

Oncology

Everyone is invited to contribute! http://www.phusewiki.org For further information: wikiadmin@phusewiki.org angelo.tinazzi@cytel.com

Oncology

Any questions?