CLINICAL TRIALS - A PATHWAY TO A CURE CanSurvive Monthly Support Group February 19th, 2017 Anna Burton, BSN, RN

OBJECTIVES Be able to describe the phases of a clinical trial Be aware of the current clinical trials at UAB GYN Oncology

Why we use phases Phases help define and describe the type of study. Important for supporting the licensing of a drug.

Basic Information: A protocol is a document describing the rationale, materials, and methods for conducting a research study. A well designed protocol provides the clinical research team instructions and directions that are strongly supported by scientific rationale for conducting the study

Pre-clinical Trial Purpose: To identify a new drug or treatment that could be suitable in humans.

Phase 1 Clinical Trial Clinical Trials start at Phase 1: Focus is on safety and tolerability. Seeks safest dose, bioavailability rather than efficacy. Usually single dose or increasing dose to discover the maximum tolerated dose Could be first in humans Small number of participants (usually <50). 6-18 months to complete 40% of new drugs fail in Phase 1 trials

Phase 2 Clinical Trial Phase 2 trials are focused on determining the efficacy of the drug in a larger number of patients (perhaps several hundred) suffering from the condition that the drug is intended to treat These trials may be performed globally and give information on efficacy and allow for a further estimation of safety in a larger population 6 months to 2-3 years to complete 62 % of the phase 1 drugs in phase 2 trials will fail.

Phase 3 Clinical Trials Assuming satisfactory results from phase 2 studies, the drug will enter phase 3 clinical trials 2-4 years or longer to complete Usually randomized, double-blind; compares new treatment to standard or control The trials would routinely involve several thousand patients and compare the investigational drug with drugs that are currently in use for the treatment of the target disease (“comparators”) 40% of phase 2 drugs will fail in phase 3 studies. The results from these trials essentially form the basis of the risk/benefit analysis that will be submitted to the regulatory authorities

The protocol is complete! The endpoints are obtained, the data is analyzed and the final report is prepared. The manuscript(s) is written and published.

NDA: New Drug Application Submitted to FDA Summary of all work done to date, including: Data from IND Clinical Trial Results Additional data on preclinical, drug substance and product manufacturing and animal studies Proposed product labeling One NDA can have up to 15 sections and over 100,000 pages. The review process can take up to 18 months

FDA Approval The Food and Drug Administration can grant either regular or accelerated marketing approval for oncology drugs. Regular approval is based on endpoints demonstrating that the drug provides a clinical benefit, such as longer life, enhanced quality of life, or a favorable effect on an established surrogate for longer or better life, such as long-term complete responses

Phase 4 Clinical Trial These trials are often referred to as post-marketing studies and they are performed after the medicine has been approved These give a greater idea of long term risk and benefit and may give indications as to how use can be modified The trials may involve many thousands of patients and go on for many years Such trials may assist in indicating other uses for the medicine

So What Will Oncology Clinical Trials of Tomorrow Look Like?? Emphasis has begun to shift from large scale studies of relatively unselected patients to smaller studies selecting more narrowly targeted to molecularly characterized populations. A more personalized or precision approach Advances in genomics and cancer biology over the last decade have provided viable targets for cancer treatment.

Smaller, More Precise Trials Ahead There is a rise in the number of trials that incorporate molecular tumor testing prior to treatment, with the selection made by the molecular features of each individuals cancer. These “personalized” trials have the potential to yield better outcomes by increasing the probability of response with less toxicity. Clinical trials should get much smaller – fewer participants are needed when therapeutic benefit is larger.

2014 Targeted Therapy Approvals Accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) BRAF + Melanoma Approved olaparib capsules (Lynparza, AstraZeneca Pharmaceuticals LP) BRCA mutated Ovarian CA Approved lanreotide (Somatuline Depot Injection, Ipsen Pharma) Approved ramucirumab (Cyramza Injection, Eli Lilly and Company) EGFR Inhibitor, Stomach CA Approved ruxolitinib (Jakafi, Incyte Corporation) JAK 2 inhibitor, Polycythemia Vera Accelerated approval for blinatumomab (BLINCYTO, Amgen Inc.) Philadelphia chromosome Neg R/R ALL

2014 Targeted Therapy Approvals Accelerated approval to pembrolizumab (KEYTRUDA, Merck Sharp & Dohme Corp.) BRAF + Melanoma Approved idelalisib (Zydelig tablets, GileadSciences, Inc.) PI3K Kinase Inhibitor, CLL Accelerated approval to belinostat (BELEODAQ, Spectrum Pharmaceuticals, Inc.) HDAC Inhibitor, T-cell Lymphoma Accelerated approval to ceritinib (ZYKADIA, Novartis Pharmaceuticals Corporation) ALK + NSCLC Accelerated approval to ibrutinib (IMBRUVICA, Pharmacyclics, Inc.) BTK Inhibitor, CLL Accelerated approval to trametinib (Mekinist tablets, GlaxoSmithKline, LLC) and dabrafenib (Tafinlar capsules, GlaxoSmithKline, LLC) BRAF + Melanoma

Current UAB Research Studies for Ovarian Cancer Phase 1 Celsion – Neo Adjuvent Chemotherapy after biopsy (UAB1534) Phase 1B – Plexxicon Oral TKI + Weekly Taxol (UAB1571) Phase 2/3 OXiGENE – FOCUS – Chemotherapy + Avastin + vascular disrupting agent OX3425 (UAB1647) Phase 3 Abbvie/GOG – Neo Adjuvant or Adjuvent Chemotherapy PARP Inhibitor (Veliparib) (UAB1558) Phase 3 SOLO3 for BRCA+ -- Third line treatment with a Parp Inhibitor (Olaparib) (UAB14109)

Questions