Introduc)on

to Medical Oncology and Clinical Trials

Elizabeth Griths, MD Assistant Professor of Medicine Leukemia Sec>on Roswell Park Cancer Ins>tute elizabeth.griths@roswellpark.org

Outline
Burden of Disease Modes of Treatment and Successes Medical Oncology/Hematology Training and Implementa)on Developmental Therapeu)cs and Tes)ng

Deni)on and Burden of Disease

Oncology: Study of malignant tumors of lethal poten)al Malignancies can arise in any )ssue, at any age and spread by direct extension or lympha)c / vascular circula)on Cancer is the 2nd leading cause of death in the USA (1/4 US deaths), 3rd worldwide (aNer dz and infec)on)

2010 Es)mated US Cancer Cases

TOTAL (100%) Prostate Lung & Bronchus Colon &Rectum Bladder Melanoma NHL Kidney Oral/Pharynx Leukemia Pancreas Other 789,620 (100%) 217,730 (28%) 116,750 (15%) 72,090 (9%) 52,760 (7%) 38,870 (5%) 35,380 (4%) 35,370 (4%) 25,420 (3%) 24,690 (3%) 21,370 (3%) 149,190 (19%) 739,940 207,090 (28%) 105,770 (14%) 70,480 (10%) 43,470(6%) 33,930 (5%) 30,160 (4%) 29,260 (4%) 22870 (3%) 21,880 (3%) 21,770 (3%) 153,260 (21%) Breast Uterine Thyroid NHL Melanoma Kidney Ovary

2010 Es)mated US Cancer Deaths

Mortality
TOTAL (100%) Lung & Bronchus Prostate Colon &Rectum Pancreas Liver/bile duct Leukemia Esophagus NHL Bladder Kidney Other 299,200 (100%) 86,220 (29%) 32,050 (11%) 26,580 (9%) 18,770 (6%) 12, 720 (4%) 12,660 (4%) 11,650 (4%) 10,710 (4%) 10,410 (3%) 8,210 (3%) 69,220 (23%) 270,290 71,080 (26%) 39,840 (15%) 24,790 (9%) 18,030 (7%) 14,850 (5%) 9,500 (4%) 9,180 (3%) 7,950 (3%) 6,190 (2%) 5,720 (2%) 63,160 (23%) 153300/222520 (69%) 71890/424820 (17%) Breast 51370/142570 (36%) 18770/21770 (88%) Ovary NHL Leukemia Uterine Liver/bile duct Brain/Nervous

American Cancer Society, 2010

Life)me Cancer Risk

All Sites Prostate Lung/Bronchus Colon/Rectum Uterus Bladder Melanoma NHL Kidney Leukemia Ovary Oral Cavity Stomach Cervix 1 in 2 1 in 6 1 in 13 1 in 18 ----- 1 in 27 1 in 39 1 in 45 1 in 57 1 in 67 1 in 72 1 in 90 ___ Breast 1 in 3 1 in 8 1 in 16 1 in 20 1 in 40 1 in 84 1 in 58 1 in 53 ------ ------ 1 in 72 ------ ------ 1 in 145

Source: American Cancer Society, 2009

Cancer E)ology
Viral/Infec)ous Mechanisms (worldwide #1 cause , Hep B, HPV, EBV, HIV ) Gene)cs Chemical carcinogens (tobacco, benzene etc) Environmental/Industrial Carcinogens Drug-induced cancers (eg secondary neoplasia) Radia)on exposure (<1%)

Hepa>>s B and Hepatocellular Carcinoma

Chen CJ et al. JAMA. 2006;295:65-73.

Gene)c Suscep)bili)es
Can be gene specic risk, or popula)on specic SNPs conferring enhanced risk
Cancer Rate/100K popula;on

BRCA Muta)on Carriers

Smoking
Worldwide Smoking Prevalence (%) Women

Men

NIH.gov

Hormone Replacement Therapy

Geography and Sun Exposure

USA Australia

Site ALL Prostate Lung/Bronchus Colon/Rectum Bladder Melanoma Stomach

USA 1 in 2 1 in 6 1 in 13 1 in 18 1 in 27 1 in 39 1 in 90

Australia 1 in 3 1 in 5 1 in 12 1 in 10 1 in 39 1 in 14 1 in 55 sun H. pylori

Drug and Radia>on Induced Cancers

Allan AM and Travis LB. Nature Reviews Cancer 2005;5:943-955.

Strategies in Cancer Management

Primary Preven>on-
Tobacco, alcohol, dietary changes, environmental management, vaccina5on, an5bio5cs

Screening programs (early detec>on/2e preven>on)

Mammography, PSA/DRE, Pap Smears, Colonoscopy

Treatment-
Surgery for local control Radia5on for loco-regional management Oncology which includes cytotoxic, hormonal, immunological, targeted and suppor5ve therapies

What is Medical Oncology?

Medical Oncologist (Meh-dih-kul on-kha-lo-jist)

Doctor who specializes in diagnosing and trea)ng cancer using chemotherapy, hormone therapy or biological therapy ONen the main health care provider for someone with Cancer Provides suppor)ve care and coordinates treatment by other specialists
From the NCI Dic)onary hip://www.cancer.gov/ dic)onary/?expand=M

Medical Oncology Training

Medical School (4-8 yrs) Internal Medicine Residency ( 3 yrs) Oncology +/- Hematology Fellowship ( 3-5 yrs)

Private Prac)ce Academics

Industry

Role in Cancer Preven)on

Recogni>on of social, occupa>onal, nutri>onal, sexual prac>ces that contribute to neoplasia Educa>on of the general public in cancer preven>on Smoking is the most common correctable risk factor for cancer (worldwide also vaccina>on for HBV, HPV, preven>on of HIV) Evaluate and screen appropriately popula>ons at increased gene>c cancer risk (BRCA, HNPCC, APC, p53, Rb families)

Cancer Diagnosis
Requires histologic proof on at least one occasion New symptoms in a pa)ent with a prior history of cancer need extensive/exhaus)ve evalua)on No symptoms should be aiributed to cancer without biopsy evidence, BUT cancer should always be on the dieren)al Cancer pa)ents can also have other symptoma)c diseases

Chemotherapy
Chemicals ( usually gene-toxins, but now more targeted therapy as well) used to treat or control cancer Oncologist responsible for appropriate drug and dose combina)on Drug (s) used depend on cancer type, stage , pa)ent age and comorbidi)es Management of side eects

Principles of Treatment
Where is the tumor? What eect does it have on normal organ structure/func)on? How toxic is the treatment to surrounding/ systemic normal )ssues Is treatment poten)ally CURATIVE? Or is it PALLIATIVE (decreased sx, improved QOL)

Laws of Therapeu)cs
I- if it is working, keep it up
Primum non nocere- subject to constant reassessment in oncology. Cura5ve and sub-cura5ve strategies are almost always toxic, how much risk is worth it?

II- If it is isnt helping, stop doing it. III- if you dont know what to do, do nothing.
Ask your colleagues, go to tumor board.

IV- The treatment shouldnt be worse that the disease

Principles of Chemotherapy

Therapeu)c Approaches
Local/Regional
Surgery Radia)on, PDT Chemotherapy (eg intravesical, intrathecal, topical, hepa)c arterial chemoemboliza)on)

Systemic
Chemotherapy (cytotoxic, hormonal, immunologic, tyrosine kinase inhibitors) Suppor)ve Care (an)-eme)cs, growth factors, narco)cs

Combined Therapies

Neo-Adjuvant
Chemotherapy and/or radia)on given before surgery
Idea is to shrink the tumor to allow smaller resec)ons or organ preserva)on (eg for head and neck, breast , pancreas cancers or sarcomas) Response to treatment gives an in vivo test of chemosensi)vity/resistance (sarcomas) and can provide prognos)c informa)on in some cases May enhance the ecacy of radia)on so as to avoid the need for surgery.

Adjuvant Therapy
Post-Surgical Chemotherapy and/or Radia>on
Given AFTER the surgery to improve local control, decrease risk of metasta5c disease and prolong survival Can oer cure for some tumors where surgery alone has a low cure rate (ie Wilms Tumor, Osteosarcomas) Prolongs disease free interval for stage II or III breast cancer, Stage III ovarian cancers and Stage (II)/III Colon Cancers, Pancrea5c Cancers all stages, Lung Cancers Ib, II, III post surgery

Targeted Therapies
medica>ons which block the growth of cancer cells by interfering with specic molecular targets needed for carcinogeneis/growth/metasteses, rather than by genotoxic stress More eec>ve/less harmful to normal cells New Paradigms- trial design, stability vs remission
Monoclonal An5bodies Tyrosine Kinase Inhibitors Vaccines

Upfront Chemotherapy
For diseases which are not treatable with local measures For most solid tumors the goal is usually prolonga)on of survival rather than cure
systemically administered drugs to slow the growth of tumor cells, decrease the burden of metasta)c disease

BUT: Some Cancers are curable with Chemotherapy alone

Cancers Treatable/Curable with

Acute Lymphoblas>c Leukemia/Lymphoma in children Seminomas Hodgkin Lymphoma Classical Burkia Leukemia/Lymphoma Promyelocy>c Leukemia Diuse large B cell Lymphoma Hairy Cell Leukemia Chronic Myelogenous Leukemia

Curable with Combined Modality

Non-Metasta)c Carcinomas
Some early Stage lung cancers Head and neck cancers Early Stage Gastric or esophageal cancers Breast Cancer (maybe) Prostate Cancer (maybe) Ovarian Cancers (maybe) Sarcomas (some, as long as they are small)

What about the Rest??

BoVom line:
Metasta5c cancer is rarely curable Even cancers treated at early stage some5mes have micrometastases which show up later Cancers that relapse are oXen dicult to treat due to acquisi5on of resistance to chemotherapy

SO:
We try high dose therapy (i.e. auto-transplant for breast cancer) Give growth factors to try and allow higher doses of chemo, more frequently (Dose Density) Combine dierent drugs given sequen5ally to decrease toxicity and avoid resistance (PROmaceCYTABOM, CHOP, hyperCVAD) Try new drugs/drug combina5ons (CLINICAL TRIALS)

Cancer Drug Development

Steps
Novel Compound Iden)ca)on (pre-clinical) Produc)on and Formula)on Toxicology evalua)on in vivo Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials General Medical Use / Phase IV Clinical Trials

Development of An>-Cancer
Tradi&onally: Cancer Chemotherapy Na&onal Service Center established by the NCI in 1955 in order to screen compounds submi>ed by external ins&tu&ons and companies for an&-cancer ac&vity.
Example is taxol (extracted from the bark of the Pacic yew tree, Taxus brevifolia) Iden&ca&on based on EFFICACY, mechanism interrogated aOer the fact analogues developed and synthesized

Modern: drug development is based upon the idea of Ra&onal Drug Design
The TARGET is known, medicinal chemistry allows the development of compounds which are predicted to bind the target of interest.

NCI Drug Screen

Preliminary: compound incubated in vitro with 3 dierent tumor cell lines at a single concentra5on for 48 hours If ANY ac5vity In vitro screen in 60 human tumor cell lines at 5 dierent doses for 48 hours If promising Hollow Fiber Technique: 12 target tumor cell lines grown in hollow bers at two doses for 4 days And In vivo tes5ng using xenograXs: Human tumors injected sq in mice treated with various doses of compund for 30 days

Ra)onal Drug Design

Target Iden5ed and recognized as the sine qua non of the cancer of interest (eg BCR-ABL tyrosine kinase muta5on gene product in CML) Use of high-throughput screening of chemical libraries to iden5fy molecules that bind/inhibit the ac5vity of the TK (iden5ca5on of 2-phenylaminopyrimidine) Compound tested and modied by addi5on of methyl and benzamide groups to improve binding to the target, solubility (ima5nib) Pre-clinical tes5ng in animal models and against human cell lines Clinical Trials demonstrate ecacy (IRIS trial, NEJM)

Produc>on, Formula>on and

Drug metabolism Chemical formula)on (issues of solubility, protein binding, absorp)on) Dose, frequency, route Toxicology in at least two animal species Large-scale produc)on plan

Inves>ga>onal New Drug Applica>ons

Required for studies involving a new agent of unproven ac5vity There are three IND types:
Inves5gator IND submiVed by a physician for a trial. A research IND proposes studying an unapproved drug, or an approved drug for a new indica5on or a new pa5ent popula5on. Emergency Use IND allows the FDA to authorize an experimental drug in an emergency situa5on. Used for pts who do not meet the criteria of an exis5ng study protocol, or if an approved study protocol does not exist. Treatment IND submiVed for experimental drugs showing promise in clinical tes5ng for serious or immediately life- threatening condi5ons while the nal clinical work is conducted and the FDA review takes place.

INDs (Contd)
Submiied either by Commercial or Research En))es IND Applica)on must contain informa)on in three broad areas: Animal Pharmacology and Toxicology Studies - establish safety for ini)al tes)ng in humans. Includes previous experience w/ drug in humans. Manufacturing Informa)on - provide info on composi)on, manufacture, stability. To assure adequate produc)on and supply of consistent drug. Clinical Protocols and Inves)gator Informa)on
Detailed protocols for proposed clinical studies to assess safety/risk. Info on the qualica)ons of the clinical inves)gators. Commitment to obtain informed consent from the research subjects, review by IRB, and adherence to IND regula)ons.

Once submiied, sponsor must wait 30 days before ini)a)ng any trials. FDA will review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

Clinical Protocols
May be designed by
Independent inves)gator Pharmaceu)cal company Mul)center coopera)ve groups

Coopera)ve Groups includes general hospitals and cancer centers based on

Specic disease areas or treatment modali)es (NSABP, RTOG) Pa)ent popula)ons (POG) Variety of cancer types (CALGB, ECOG, SWOG)

Clinical Protocols
Designed to ensure uniformity and reproducibility of procedures and research design Avoids omissions, s>pulates >mes for specic procedures and ensures standard doses, thresholds and end points All personnel should have access to a wriaen protocol specifying the regimen, inclusion criteria, stopping parameters etc Pharmacists and oncology nurses serve as addi>onal checks in the system.

Topics Covered in a Protocol

Cover sheet- names and contacts for PI/study nurse Schema and Synopsis Background and ra5onale Objec5ves Pa5ent selec5on Treatment plan w/dose adjustments Registra5on/randomiza5on info, stra5ca5on and data management/submission Required data at entry on study and at every evalua5on

Expected toxicity and management Criteria for response, progression and relapse Removal of pa5ents from theapy Drug formula5on, availability, prepara5on Adverse event/reac5on repor5ng Ancillary Therapy Sta5s5cal considera5ons References Model consent form

Phase I Trials
Toxicology IND applica5on/approval Phase I Pa5ents oXen refractory, pretreated, many dierent cancer types Goal is iden5ca5on of TOXICITY
Dose limi5ng toxicity(DLT) is irreversible grade 3 or any grade 4 toxicity Maximum tolerated dose (MTD) is highest dose at which DLT is seen in less than 33% of pa5ents at a given dose level Star5ng dose is 10% of the LD10 in the most sensi5ve non-human

Phase I Trials (cont)

Pa)ents are treated in cohorts of 3-6 people Medica)on Dose escalated aNer 3 pa)ents are treated without DLT Medica)on dose is escalated using a modied Fibonacci sequence:
Ini)al increase 100%, then 67%, then 50%, 40% then 33% each further increase

Lack of response in a phase I trial should not, in theory, stop further drug development

Phase Ib Trials
Expansion Cohorts
Evaluate pharmacokine)cs/pharmacodynamics at recommended phase II dose
Solid tumor biopsies add complexity to implementa)on Evaluate further tolerability at selected dose May limit to certain tumor types to preview ecacy
eg her2neu an)body (hercep)n) tested in Her2 over- expressing breast cancers

Phase II Trials
Endpoint is RESPONSE within specic tumor type Candidates should not be heavily pre treated No response in 14pts suggests drug ineec)ve
If 1 response observed, trial expanded to up to 30pts 20% response rate suggests possible clinical u)lity

BUT: eec)ve drugs can be falsely rejected (due to incorrect dose/route, heavy prior exposure, poor pa)ent PS)

Phase III Trials

Endpoint is ac5vity and toxicity rela5ve to current standard of care
Requires equipoise w.r.t. likelihood of response between the two arms

Size of the trial based on expected dierence in endpoints between the new treatment and the standard of care. POWER is the number of pa5ents needed to show sta5s5cally signicant dierences in response.
If a new treatment has response of 60% and standard has response of 40% to have a 90% chance of seeing dierences with p<0.05 you need 139 pa5ents in each arm

Phase IV Studies
Phase III studies determine standards of care Further inves)ga)on of ecacy and safety of an approved regimen or treatment or treatment in new and dierent setng Post marke)ng studies of safety

Review of Clinical Trials

Phase I: Establishes toxicity and dose-schedule Phase II: Iden)es promising therapies Phase III:
Eect of treatment rela)ve to natural history of disease (for diseases without current standard) Eect of treatment rela)ve to current standard Toxicity of treatment rela)ve to standard of care

Once Drug has Proven Ecacy

New Drug Applica5on(NDA) submiVed to the FDA
Provide data on safety and ecacy of proposed use
Animal Studies, clinical info on PK/PD informa5on

Appropriateness of proposed labeling (package insert) Methods in manufacturing and quality control

Biologic License Applica5on(BLA) submiVed to the FDA

Monoclonal an5bodies for in vivo use Cytokines, growth factors, enzymes, immunomod drugs, thromboly5cs Proteins for therapeu5c use extracted from animals or microorganisms Non-vaccine therapeu5c immunotherapies

FDA Approval
FDA approves a new drug or treatment based on Clinical Benet. Ususaly data from Phase II or Phase II trials for specic indica>ons
e.g. taxol approved for use in advanced ovarian cancer, met breast ca, and node posi5ve breast cancer, but not for lung cancer (where it is also used)

Determina>on of ecacy based on response rates or survival but can also be based on QOL measures
e.g. gemcitabine approval for pancreas cancer

FDA Approval
Once drug approved by the FDA it can be used outside its approved indica)on. (e.g. taxol used for met lung cancer) Insurers will usually reimburse for drugs used outside labeled indica)ons as long as phase II data exits demonstra)ng ecacy in that disease area.

Dierences in Developmental
Cytotoxics (Taxol) ID and Development
Brute force screening of 1000s of molecules Based on ability to kill cancer cell lines with less toxicity to normal cells Phase I- iden5fy MTD Phase II-IV similar

Targeted Inhibitors (Ima5nib) Ra5onal Design-

Specic Targets in mind

High throughput screening for small molecules that hit the target
Phase I- Iden5fy the Biologically Eec5ve Dose Phase II-IV similar

Mechanisms of Ac5on
Inhibi5on of pathways for cell division OXen eec5ve for mul5ple malignancies

Mechanism known in advance, specic targets iden5fy possible usefulness

Target malignancies w/ the target Inhibits without killing normal cells

TOXICITY
Any rapidly dividing cells

TOXITICY
Idiosyncra5c OXen less severe

QUESTIONS? elizabeth.griths@Roswellpark.org 716.845.3996