Clinical Research in Medical Oncology

Transcription

1 Clinical Research in Medical Oncology Adam M. Petrich, MD Northwestern University June 2, 2015

2 Objectives Why oncology? Why lymphoma? Why clinical research? Discuss various phases and objectives of clinical research (particularly early phase clinical trials) What we re doing at NM; NMDTI introduction Possible career trajectories

3 Medicine Oncology Lymphoma Clinical research Common Cold Non-Hodgkin Lymphoma Pancreatic Cancer Good Outcomes (everyone survives) Bad Outcomes (high mortality) Difference made by good care and/or clinical research* *This is not to discourage research in certain areas, nor a prediction about future success.

4 DLBCL: Still R-CHOP Dunleavy, Clin Canc Res, 2014

5 Numerous low frequency mutations can contribute to cancer cell survival no single achilles heel as a therapeutic target Some mutations may affect numerous signaling pathways Heterogeneity of cancer cells within one tumor Image credit: Cell Signaling Technology

6 Clinical Trial A type of clinical research that follows a pre-defined plan or protocol. By taking part in clinical trials, participants can not only play a more active role in their own health care, but they can also access new treatments and help others by contributing to medical research. -NIH.gov

7 Phases of clinical trials Preclinical Subject Type Tissue cultures, animals Subject Number Variable 0 Human 2-10 I Human 3-50 II Human III IV Human Human ,000+ Variable (by reporting) Features Primary Goal Testing of drug in non-human subjects, to gather efficacy, toxicity, and pharmacokinetics oral bioavailability and half-life of the drug Testing of drug on healthy volunteers for dose range Testing of drug on patients to assess efficacy and safety Testing of drug on patients to assess efficacy, effectiveness and safety Post-marketing surveillance in public use

8 Some Background Who would be the best candidate for a clinical trial? A. A 31-year-old woman with newly-diagnosed NHL with 70% cure rates with existing chemotherapy B. A 57-year-old man with relapsed NHL who still has good treatment options C. A 57-year-old man with a very rare type of NHL without known treatment options D. A 79-year-old woman in excellent shape whose NHL has returned for a 5 th time, and who has exhausted all known treatments for her disease

9 Some Background Who would be the best candidate for a clinical trial? A. A 31-year-old woman with newly-diagnosed NHL with 70% cure rates with existing chemotherapy We can almost always improve on standard of care, by either improving efficacy or reducing toxicity. Example: Standard chemotherapy plus New Drug X vs. Standard chemotherapy alone (or with placebo)

10 Some Background Who would be the best candidate for a clinical trial? D. A 79-year-old woman in excellent shape whose NHL has returned for a 5 th time, and who has exhausted all known treatments for her disease We can almost always improve on instances where no good treatments are available, by trying a new drug Example: New Drug X, or New Drug X vs. placebo (It is okay to give placebo to patients if there are no known reasonably good treatment options)

11 Problems with clinical trials Costly Time-consuming Restrictive Fitness of subjects Disease types (rare diseases frequently lack trials) Geography (most trials, particularly phase I-II, are limited to large academic medical centers) Timing (including delayed activation due to IRB approval, contracts, etc) Not necessarily well suited to the patients enrolled

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14 Addressing the Problems with clinical trials Costly Time-consuming Restrictive Fitness of subjects Disease types (rare diseases frequently lack trials) Geography (most trials, particularly phase I-II, are limited to large academic medical centers) Timing (including delayed activation due to IRB approval, contracts, etc) Not necessarily well suited to the patients enrolled

15 Pathway-Driven Treatment Lung Adenocarcinoma erlotinib or afatinib Pao et al, Nat Med 2012; 18:349 NCCN Guidelines version

16 Strategic Research Alliances Next Generation Sequencing Detection of Tumor DNA: Liquid Biopsies

17 Novartis Signature program Enrolling at 37 US sites, many in the community Two NCI-designated comprehensive cancer centers: MD Anderson Northwestern Tumor Next Generation Sequencing Target (s) identified - initial protocol approval process which must be completed in 2 weeks >40 genetic targets in the works

18 Relapsed/refractory cancer patient Actionable mutation?? The Signature Program Goal of this program is to bring the protocol to the patient New concept in clinical trial that matches investigational cancer therapies to specific genomic alterations in patient tumors. Brings the trial to the patient rather than patient traveling for this. Genetic profiling of tissue sample Genetic Profiling of tissue Sample? Re Actionable Mutation? Relapsed/refractory cancer patientrelapsed Relapsed Refractory patient Local CLIA certified laboratory

19 The Signature Program Protocol package Fixed contract Central IRB (Quorum) Standard budget Standard informed consent When a patient is identified as having an actionable mutation, their oncologist contacts Novartis Call center prequalifies the patient: (1) Protocol package sent to site (2) Expedited site visit Study open! 5.7 weeks vs 34- week* average 1 Accessed May 16, * based on internal Novartis Data

20 Cancer clinical trials: important points to consider Multifactorial etiology of cancer Is it clinically actionable Technology reproducibility/accuracy Availability of screening tests Cost Population generalizability and clinical applicability Regulatory approval for clinical use

21 Novel Agents for DLBCL and other NHL Class Target Examples Proteasome inhibitor Proteasome Bortezomib, carfilzomib, MLN9708 IMiD (multiple) Lenalidomdde, pomalidomide Monoclonal Antibody CD20 Ofatumumab, ocrelizumab, GA101, others Antibody-Drug Conjugate CD22 Inotuzumab ozogamicin Small molecule inhibitor BTK Ibrutinib Small molecule inhibitor mtor Temsirolimus, everolimus Small molecule inhibitor SYK Fostematenib, TAK-659 Small molecule inhibitor PI3Kδ Idelalesib (CAL-101/GS-1101) Small molecule inhibitor HDAC Vorinostat, abexinostat Pro-apoptosis agents Bcl-2 ABT-199

22 How to get into clinical research Eighty per cent of success is showing up. -Woody Allen, 1977

23 How to get into clinical research Do something novel as a medical student. It does not have to be in the field you eventually go into. Do something novel as a resident. It does not have to be in the field you eventually go into. Do a fellowship (clinic- or research-oriented; you ll get research experience either way). Eventually you have to specialize. Until then, at least sound like you ve chosen a specialty. People won t hold you to it.

24 TAK-659 CC-292 CC-223 mtor MAPK NFAT CC-122

25 Phase I, first in human, novel SYK inhibitor (TAK-659)

26 me with any questions: Thanks! Olivia