Sviluppo di disegni sperimentali: esperienze e proposte. Gianluca Fincato Medical Director BU Oncology Novartis Farma SpA

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1 Sviluppo di disegni sperimentali: esperienze e proposte Gianluca Fincato Medical Director BU Oncology Novartis Farma SpA ISS Roma, 17/11/2017

2 Use of This Slide Deck This material, and all contents cited within, is intended to provide free medical information for physicians. The objective is to share scientific data allowing each HCP to draw autonomous conclusions and make autonomous decisions from the material provided. The scientific information may include data/information on investigational uses of compounds/drugs that have not been approved by regulatory authorities. Efficacy and safety have not been established. There is no guarantee these compounds will become commercially available. This material may contain recommendations outside the approved labeling of Novartis products, but it is not intended to promote or recommend any indication, dosage, regimen or any claim not covered in the licensed product information (SPC). BU ONCOLOGY

3 From R&D strategy to trial design

4 Our strategy is defined by patient selection, novel combinations and understanding resistance New targets and combinations Pathway analysis and drug sensitivity Understanding resistance Clinical trial design Genetic analysis of responders and non-responders Patient preselection with genetic and pathway biomarkers

5 Patient selection is critical for efficient, successful cancer drug development Drives: Improved patient benefit Increased probability of success Faster time to market with lower development cost Highest social benefit All early development conducted with patient selection Companion diagnostics underway for all relevant full development programs (Genoptix) Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

6 Novartis drug development model NIBR TCO Target selection Compound selection IND-enabling studies First human studies Proof of Concept Full Development Registration GDD NIBR = Novartis Institute for BioMedical Research TCO = Translational Clinical Oncology GGD = Global Drug Development Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

7 Patient selection can markedly shorten development timelines TKI258 HCD122 Phase I FPFV 65 months 60 months POC POC AUY months POC BKM120 LDE months 18 months POC POC LDK months POC (April 24) Tasigna LGX818 6 mo 5 mo POC POC No selection Selection at MTD Selection at FPFV Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

8 Alternative trial design: adaptive studies

9 Types of adaptation in clinical trials Chow and Chang (2007)

10 Motivations and definition Motivations Increase the probability of success for identifying the clinical benefit of the treatment under investigation. Reduce costs of drug development programs through more efficient study designs. Definition and Features Adaptive design is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study (FDA, 2010). Aim to enhance the trial, not a remedy for inadequate planning Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

11 Phase I/II in oncology: Novartis approach

12 From the Traditional 3+3 design... New cohort at a new dose level: Enroll 3 patients DLT =0/3 DLT =1/3 DLT >1/3 Go to next higher dose level or same dose if highest dose level Enroll 3 additional pts at the same dose level Go to next lower dose level or declare MTD at next lower dose level if 6 pts already tested (never re-escalate) DLT =1/6 DLT >1/6 Go to next higher untested dose level or declare MTD otherwise Go to next lower dose level or declare MTD at next lower dose level if 6 pts already tested (never re-escalate) Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

13 ...to a Bayesian model: combination of clinical and statistical expertise Informed decisions: clinical data, historical knowledge and Statistics Historical Data (prior info) Clinical Expertise Trial Data 0/3,0/3,1/3,... DLT rates p 1, p 2,...,p MTD,... (uncertainty!) Dose recommendations Model based dose-dlt relationship Decisions Dose Escalation Decision Gianluca Fincato, Novartis Farma S.p.A., Sviluppo di disegni sperimentali - ISS, 17/11/2017

14 Phase I/II: adaptive study: a Novartis example combining phase I bayesian and two stage phase II Phase I Phase II

15 Phase I/II: adaptive study Primary objective - dose escalation arm To determine the MTD of AUY922 as a single agent when administered IV on a once weekly schedule to adult patients with advanced solid tumors, whose disease has progressed despite standard therapy or for whom no standard therapy exists.

16 Phase I/II: adaptive study Primary objective - breast cancer dose expansion arm At the MTD two further arms will be expanded to assess response (according to a two stage multinomial design) in the following breast cancer patient populations: 1. Patients with HER2 positive inoperable locally advanced or metastatic breast cancer must have: History of trastuzumab resistance, defined as either local or systemic disease progression on treatment with at least 8 weeks of a trastuzumab containing regimen. Received up to 3 prior anti HER2 based regimens (i.e. trastuzumab and/or lapatinib in combination with other agents) and up to 2 lines of cytotoxic therapy for advanced disease. Patients who develop metastases while receiving adjuvant or neo-adjuvant trastuzumab are eligible. 2. Patients with ER positive inoperable locally advanced or metastatic breast cancer whose disease has progressed on at least one and up to 3 lines of standard sequence endocrine therapy and who received up to 2 lines of ct for adv. disease.

17 Phase I/II: adaptive study Secondary objectives To characterize the safety and tolerability of AUY922 treatment. To characterize the pharmacokinetic (PK) profiles of AUY922 To assess changes in target and downstream PD markers in pre- and post- AUY922 dosing in PBMCs as a measure of HSP90 inhibition, including such markers as HSP70, CDK4, and HSP90/p23 complex dissociation. To assess changes in target and downstream PD markers in pre- and post AUY922 dosing in tumor tissue biopsies (where available and accessible) as a measure of HSP90 inhibition, including such markers as HSP70, AKT, pakt, and CDK4. To assess changes in relevant client proteins in pre- and post- AUY922 dosing in biopsies of tumor tissue (where available and accessible). These client proteins may include HER2 and ER To assess changes in cellular response markers in pre- and post- AUY922 dosing in tumor tissue biopsies (where available and accessible), including (Ki67) for proliferation and cleaved caspase 3 and M30 for apoptosis. To asses changes in cellular response markers in pre- and post- AUY922 dosing in peripheral blood including M30 and M65 for apoptosis. To quantitate the number of circulating tumor cells (CTC) and analyze either a pharmacodynamic marker (HSP70) or client protein expression (HER2) in pre- and post AUY922 therapy peripheral blood of patients with locally advanced or metastatic breast cancer

18 Phase I/II: adaptive study -> need for patient selection Selection criteria 9 inclusion criteria 18 exclusion criteria mbc patients MBC HER2+/HR+ 1-2 anti HER2 o 1 hormono previous treatments Tumor tissue sample Other selection criteria Eligible patients

19 Our colleague Tom Marsilje the acknowledged discoverer of Zykadia (ceritinib), died Tuesday afternoon of colon cancer at a hospital in San Diego. He was 45. Although he had already begun his battle with colon cancer, he was continuing his drug research efforts. He could view his role both as a researcher and as a patient. So today, as you dash off that , make that presentation, arrange that meeting, please pause and take a moment to remember Tom, his family and the effort he put forth to make life better for patients and their families. 1

20 LDK378: a successful example of adaptive design and pts selection -> a phase I efficacy study (130 pts) LDK378 exhibits potent antitumor activity in ALK+ NSCLC, including in patients previously treated with CRZ Response rates in patients treated with LDK mg/day: Patients CR n (%) CR + PR n (%) CR + PR + upr n (%) NSCLC, 400 mg/d (n=59) NSCLC + prior CRZ, 400 mg/d (n=45) 1 (2) 24 (41) 42 (71) 1 (2) 21 (47) 36 (80) CNS activity of LDK378 was seen in NSCLC patients with brain metastases Median duration of response (patients with 1 PR [n=44]) was 7.4 months Duration of response was 6 months in 71% of patients Data to be updated at ASCO 2013 CNS, central nervous system; CR, complete response; PR, partial response; upr, PR documented only once to date. Shaw AT, et al. ESMO 2012; Abstr 440O.

21 Shaw, A., NEJM, 370(13),

22 LDK 378: FDA Breakthrough Designation Phase I Study (LDK 378 X2101) 80 % of objective responses in 70 NSCLC pats Activity found also on brain metastasis Phase II studies: LDK378 A2201 ( 3L, after CT & crizotinib) LDK378 A2203 ( 2L, after CT) Phase III study: LDK378 A2301 (1L, pts naïve) LDK378 A2303 (3L, after CT & crizotinib)

23 Overview of CTL019 Therapy in the Clinic 1. Leukapheresis: patient s T cells are collected T cells are genetically transduced ex vivo with a lentiviral vector encoding the anti-cd19 CAR 1,3 3. CTL019 cells undergo ex vivo expansion on magnetic antibodycoated beads Lymphodepleting chemotherapy: the patient may receive a preparative lymphodepleting regimen before T cell infusion 1-3 Copyright Novartis Corporation 5. CTL019 cells are infused into the patient Porter DL, et al. N Engl J Med. 2011;365: ; 2. Porter DL, et al. J Cancer. 2011;2: ; 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73. Image from Levine BL. Cancer Gene Ther. 2015;22: Business Use Only

24 Adaptive design in phase I/II: need for new approaches Recent advances in molecular biology have led to the development of a myriad of anticancer agents that specifically target aberrant pathways and other proteins that are relatively specific for tumor cells. The number of agents available for testing dictates that a more efficient system aimed at quickly and accurately identifying promising agents for phase III testing be developed. This will allow investigators to efficiently discard non efficacious agents and devote time to the development of the more promising agents, thus conserving financial and human resources. A barrier to achieving this goal is the lack of good surrogates of true patient benefit, which in oncology is improvement in overall survival. In addition to identifying good surrogates, which could be imaging biomarkers or biochemical, genetic, or molecular biology biomarkers, novel approaches to phase II study design need to be tested. Alex A. Adjei, Clin Cancer Res 2009

25 Adaptive design in phase I/II: need for new approaches Until recently, the phase II trial in oncology generally took the form of the single-arm two-stage design, for which the typical end point was objective tumor response (by RECIST) A two-stage design was frequently constructed to distinguish between a study-level response rate felt to indicate a lack of promise and a response rate that would indicate promising activity. The dominant use of this design was based on the premise that an agent that could not produce a tumor response was not likely to produce a clinically meaningful overall survival (OS) or progression-freesurvival (PFS) benefit in subsequent phase III testing. The recent rapid evolution in oncology drug development has challenged these previously accepted paradigms. Target agents not always are likely to produce or improve tumor response rates; rather that such agents will improve PFS or OS. Larry Rubinstein, Clin Cancer Res 2009

26 Benefits and disadvantages of adaptive design Benefits Increase of information value given the same number of patients Less patients needed compared to classical non-adaptive designs Hurdles Adaptations at an interim analysis may lead to operational bias, thus resulting in a slight change of the study population. Statistical inferences such as confidence interval and/or p- values on the treatment effect of the test treatment under study may not be reliable. Introduction to Pharmaceutical Statistics IIS China Adaptive Clinical Trials

27 Practical issues: regulatory perspective Regulatory requirements for adaptive designs in Phase I or II trials are very different to those for Phase III trials It is mandatory to control the overall Type I error rate in the strong sense and maintain trial integrity for Phase III trials EMEA Reflection Paper (2007) on Methodological issues in confirmatory clinical trials planned with an adaptive design FDA Draft Guidance for Industry (2010) on Adaptive design clinical trials for drugs and biologics

28 Summary and conclusions The potential advantages offered by adaptive designs should be viewed in balance against any perceived risks or complexities. Strict control of processes for handling interim data and restricting information, and documentation that are followed, will be critical. Some types of adaptations convey limited information for which it seems difficult to envision how the trial might be compromised. Others convey more information, but perhaps we can implement extra steps to mitigate the risk. Introduction to Pharmaceutical Statistics IIS China Adaptive Clinical Trials