Overview
 Identifying and testing of new promising therapies
 Targeted therapies
 Molecular testing of tumors
Phases of Clinical Trials
 Preclinical Research (academic centers, pharma)
 IND (Investigational New Drug) application filed with the
FDA
 Phase 1
 Phase 2
 Phase 3
 FDA Approval
Time to preclinical research to drug approval can take up to
10 years or more!
Phase 1 Clinical Trial
 Testing of a new agent with the primary goal being
to determine the safety profile of a new drug
 Drug is dose escalated until toxicity to determine the
safest dose range
 May be the first time a drug is administered to
humans
 Typically small numbers of patients (10-20)
 Primarily done in academic research centers
Phase 2 Clinical Trial
 New treatment given to larger groups of patients to
see if it is effective and to more thoroughly evaluate
the side effects.
 Typically 100-200 patients
 Typical time frame to completion is 2 years
Phase 3 Clinical Trial
 Typically a randomized trial where the new treatment is given
to some patients and other patients receive standard
treatment.
 The goal of the trial is to further determine the effectiveness,
safety of the new treatment compared to standard therapy.
 Large trials involving hundreds to thousands of patients
 May be up to 5 years until study results known
Clinical Trials
 New drugs/therapies initially tested in patients with
Stage 4 disease (metastatic)
 If the new drug/therapy is effective in patients with
stage IV disease, clinical trials then start assessing
response in patients with earlier stage disease (stage
1, 2 and 3) to determine if the cure rate can be
improved upon
Chemotherapy
 Has improved the cure rate for many early stage
cancers-breast, colon, ovarian, stomach, brain,
lymphoma, leukemia, testicular, etc.
 Can prolong life for many incurable cancers
 Damages cells that are “rapidly growing and
dividing”
 Can’t distinguish between cancer cells and normal
cells
Chemotherapy
 Side effects of chemo include GI, hair loss, low blood
counts (rapidly growing “normal cells”)
 Normal cells have a greater capacity to recover from
the damaging effects of chemotherapy than cancer
cells do
Targeted Therapies
Targeted Therapies
 Specifically designed drugs that TARGET specific
molecules within the cancer cell that drives tumor
growth and progression
 Primary goal is to fight cancer cells with more
precision and hopefully fewer side effects
First Reported Targeted
Agent
 Chronic Myeloid Leukemia
 Caused by a specific alteration in bone marrow cells in
which an abnormal gene is created (BCR-ABL gene)
 The abnormal gene produces a protein that constantly
activates another protein (tyrosine kinase) that causes
unregulated cell division (leukemia)
First Reported Targeted
Agents
 An oral agent, STI-571 (now called imatinib or
gleevac) was specifically designed to inhibit the
protein that was “turned on” in chronic myeloid
leukemia.
 It inhibited the abnormal protein (the tyrosine
kinase), hence “tyrosine kinase inhibitor”
 The initial study was first published in 2003
Survival with CML
Targeted Therapies
 Two Broad Categories
 Small Molecules (drugs ending in –ib)
 Enter into cancer cell and inhibit the function of proteins
that are important for cell growth
 Monoclonal Antibodies (drugs ending in –mab)
 Typically work by affecting proteins on the surface of
cancer cells that are important for cell growth
Targeted Therapies
 Block cell proliferation
 Alter gene expression
 Induce cells to die
 Help the immune system to destroy cancer cells
 Deliver toxic molecules directly to the cancer cells
 Inihibit blood vessel formation
 (Anti-angiogenesis)
Chronic Myeloid Leukemia
 Imatinib (Gleevac)
 Dasatinib
 Nilotinib
 Bosutinib
 Ponatinib
Breast Cancer
 Trastuzumab (Herceptin)
 Pertuzumab (Perjeta)
 T-DM1 (Kadcyla)
 Lapatinib
 Everolimus (Afinitor)
 Palbociclib (Ibrance)
Renal Cell Cancer
 Sunitinib (Sutent)
 Sorafenib (Nexavar)
 Pazopanib (Votrient)
 Axitinib (Inlyta)
 Temsirolimus (Torisel)
 Everolimus (Afinitor)
 Bevacizumab (Avastin)
Melanoma
 Vemurafinib (Zelboraf)
 Dabrafenib (Tafinlar)
 Trametinib (Mekinist)
 Ipilumumab (Yervoy)
 Pembrolizumab (Keytruda)
 Nivolumab (Opdivo)
PD1 Antibody therapies
PD-1 Antibody
Response to Vemurafenib
Chronic
Leukemia/Lymphoma
 Rituximab (Rituxan)
 Alemtuzumab (Campath)
 Ofatumumab
 Tositumomab (Bexxar)
 Ibritumomab (Zevalin)
 Brentuximab
 Obinutuzumab (Gazyva)
 Ibrutinib (Imbruvica)
 Idelalisib (Zydelig)
Ovarian Cancer
 Bevacizumab (Avastin)
 Olaparib (Lynparza)-most active in BRCA carriers
 Lung Cancer
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Gefitinib (Iressa)
Erlotinib (Tarceva)
Crizotinib
Ramucirumab
 Colon Cancer
 Cetuximab
 Panitumumab
 Bevacizumab
 Head and Neck Cancer
 Cetuximab
12 Weeks on Crizotinib
Molecular Testing of
Tumors
 Tumors can be tested to identify a molecular target
 Caris Life Sciences
 Foundation One
 How these results guide therapy is still uncertain,
but promising
Foundation One Result
Additional New Advances
 Genetic counseling and testing
 Improved Screening
 Local treatments
 Supportive Therapies
 Survivorship Issues
Clinicaltrials.gov
 The largest clinical trial data base
 Registry of clinical trials run by the United States
National Library of Medicine at the National Institute
of Health (NIH)
 Over 130,000 clinical trials in over 170 countries
Rocky Mountain Cancer
Centers
 Active research program in both radiation oncology
and medical oncology
 Clinical trials available through cooperative research
groups funded by the National Cancer Institute as
well as trials funded through pharmaceutical
companies with US oncology
 Over 100 trials available, with the majority utilizing
new targeted agents in both early and advanced
disease.
Questions and Answers