Precision medicinebased clinical trials Clara Natoli Drug discovery

Precision medicine-based clinical trials Clara Natoli

Drug discovery and development timeline 3 -5 years 5 -7 years 2 -3 years http: //www. yourgenome. org/facts/how-are-drugs-designed-and-developed

CLINICAL TRIALS PITTFALLS Ø Only 5% of cancer patients actually join clinical trials Ø 37% of clinical trials fail to reach their recruitment goals Ø 11% of sites fail to recruit a single patient

New trends of drug development EMPIRICAL ONCOLOGY 1980 MOLECULAR ONCOLOGY 1990 Phase I -II Phase II 2010 Phase III

About 90% of topselling medicines only work for 30% to 50% of patients. Side effects and adverse reactions caused by medications, account for 30% of acute hospital admissions every year. Nature 520, 609– 611; 2015

Genomic Landscape of 5, 000 Human Cancers Source: Mac. Conaill, L, et. al. , J Mol Diagn 2014, 16: 660 -672

Precision medicine should ensure delivery of the right intervention to the right patient at the right time

Precision Oncology Treatment genomically selected trials

Development of reliable endpoints to allow an early recognition of clinical benefit ENDPOINTS Effect on molecular target Circulating tumor cells Circulating tumor DNA Functional imaging Wilson et al. Lancet Oncol 2015

so, what do we need? ‘select the trial for the patient, not the patient for the trial’

The precision medicine trials aim to indicate a treatment individually A few studies have been published, and a few more are ongoing… Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.

NSCLC … but only few of these targets have agents with FDAEMA approval

The NCI has put forth a national strategy for precision medicine with two broad components The first is the exceptional responder initiative (ERI), which seeks to evaluate the genomics of tumor from patients who had an exceptional response to a drug that were not effective for most other patients. In order to be eligible, patients must have received a treatment in which <10% of patients had a complete or durable partial response. The malignant (and normal if available) tissue from these exceptional responders will undergo whole exome sequencing and/or m. RNA sequencing. . [NCT 02243592]. https: //clinicaltrials. gov/ct 2/show/NCT 00243592? term=NCT 02243592&rank=1

The NCI has put forth a national strategy for precision medicine with two broad components The second is the NCI Molecular Analysis for Therapy Choice (MATCH) trial which screens for molecular features that may predict response to a drug with a given mechanism of action. This trial design is in response to the observation that certain driver mutations which may be common in a particular tumor type are mutated in other diseases at low frequency (<10%). In low frequency mutations, testing the utility of certain targeted therapy requires screening large numbers of patients.

New Precision Medicine Trials Design Umbrella trials Basket trials Adaptive Design Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.

December 8, 2016. doi: 10. 1001/jamaoncol. 2016. 5299

ü One type of cancer ü Different genetic mutation https: //www. bhdsyndrome. org/forum/bhd-research-blog/genetic-sequencing-approaches-to-cancer-clinical-trials/

ü Multiple types of cancer ü 1 common genetic mutation https: //www. bhdsyndrome. org/forum/bhd-research-blog/genetic-sequencing-approaches-to-cancer-clinical-trials/

BASKET TRIAL across tumor types, selected by single marker or for a single candidate drug L. A. Renfro et al. / Cancer Treatment Reviews 43 (2016) 74– 82

NCI MATCH study design will target molecule abnormalities directed by next generation sequencing and will “match” patients with appropriate targeted agents http: //meetinglibrary. asco. org/content/114000071 -144

NCI-MATCH TRIAL

However, no control arms are included, which could dramatically affect the interpretation of the final results …

Relying on efficacy results from uncontrolled clinical trials can result in expedited drug approval, but the disadvantages of this practice must be taken into account. For example, the apparent improvements in outcomes observed in an early single-arm trial of a new therapy might reflect the prognostic nature of the target, rather than a true treatment effect. Moreover, the predictive role of biomarkers can be definitively ascertained only randomly assigning patients to a control arm.

NCI M-PACT: Molecular Profiling Based Assignment of Cancer Therapy R

NCI M-PACT: Molecular Profiling Based Assignment of Cancer Therapy actionable mutations of interest (a. MOIs)

New Precision Medicine Trials Design Basket trials Umbrella trials Adaptive Design New trials design Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.

Umbrella Studies Within 1 tumor type, selected by different markers for single or multiple candidate drugs • Efficiency in drug evaluation compared with traditional histology driven sequential studies • Evaluate large effects of targeted agents on relatively rare targets • Different types with shared molecular aberrations may be more similar than tumors from same type lacking molecular features Sleijfer, S et al. Designing Transformative Clinical Trials in the Cancer Genome Era. J Clin Oncol 31: 1834 -184

ONCOGENIC PATHWAYS CURRENTLY BEING TARGETED IN NON-SMALL CELL LUNG CANCER Front. Med. , 10 April 2017 https: //doi. org/10. 3389/fmed. 2017. 00039

National Lung Matrix Trial The UK trial recruits patients with stage IV disease, or stage III disease not amenable to surgery or radical radiotherapy, and allocates them to a treatment arm according to their molecular phenotype as determined by the Stratified Medicine pre-screening Programme 2. NLMT is a multi-arm multi-stage trial currently recruiting to 21 clinical arms.

Lung-MAP protocol (NCT 02154490)

Sub-studies currently open in the Lung-MAP protocol (NCT 02154490) Multiple sub-studies that independently evaluate investigational therapies

Lung-MAP design principles ü New sub-studies can enter the trial at any time when relevant drug-biomarker pairs with sufficient proof-of concept become available. ü According to the results of the futility analysis in the phase II portion, the sub-studies can be quickly closed or move to a phase III registration trial. ü This strategy significantly reduces time, number of patients, and cost needed to bring promising agents to the clinical setting. The use of a common and detailed genotype platform facilitates broad screening and efficient allocation of patients to biomarker-specific sub-studies. ü The presence of a “non-match” arm, allow for all eligible patients to be accrued. ü The master protocol is flexible and adaptable, allowing for incorporation of “new standards” in an evolving field.

AURORA – Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer Patients will be treated according to physician’s choice or will be given the opportunity to enter clinical trials based on the genotype of their disease. In both cases, patients enrolled in AURORA will be followed with collection of clinical data and plasma and serum samples every 6 months to determine response and clinical outcome end points for a period of 10 years. © 2014 Cancer Research UK. British Journal of Cancer (2014) 111, 1881 -1887; doi: 10. 1038/bjc. 2014. 341

New Precision Medicine Trials Design basket trials umbrella trials Adaptive Design Sharp A, Harper-Wynne C (2014) Treatment of Advanced Breast Cancer (ABC): The Expanding Landscape of Targeted Therapies. J Cancer Biol Res 2(1): 1036.

Adaptive Trial Designs Chow, SC and Chang, M. Adaptive design methods in clinical trials – a review. Orphanet Journal of Rare Diseases 2008, 3: 11

Biomarker design with response-adaptive (D) adaptive enrichment design randomization L. A. Renfro et al. / Cancer Treatment Reviews 43 (2016) 74– 82

Adaptive Trial Designs ü Allows researchers to analyze accumulating study data at prospective interim time points and to alter the course of a single patient’s study plan or trial itself, without undermining the validity and integrity of the trial ü Stopping early/extending accrual with a conclusion of either superiority or futility üAdaptively assigning doses to more efficiently assess the dose outcome relationship ü Dropping/adding arms or doses ü Seamless phases of drug development within a single trial ü Changing proportion of patients randomized to each arm and accrual rate

Adaptive Trial Designs ü Potential to speed up the process of drug development üPotential to receive marketing approval for multiple indications from a single successfull trial ü Shorter clinical time lines than conventional approaches ü A feasible way to conduct clinical trials in rare cancers BUT …. . üOften less statistically efficient than fixed plans üStatistical methods for the design and analysis are more complex than those associated with conventional designs

PRECISION MEDICINE OPEN ISSUES Bruce Chabner: ‘Underlying this new effort is my conviction that genomic medicine is neither totally precise nor completely rational at this point in its development. ’ The Oncologist 2016

The scope of publications will include all types of clinical research (basket trials, exceptional response results, informatics, mechanism- and evidence-based case reports, and small series of educational value), provide a forum for novel multi-institutional databases to advance outcomes measurements, and include extensive expert driven commentary, editorials, and reviews considering the challenges and value of targeted therapies based on genomic analyses.

Oncologists await historic first: a pan-tumor predictive marker, for immunotherapy • Ken Garber Nature Biotechnology 35, 297– 298 (2017) doi: 10. 1038/nbt 0417 -297 a FDA Approves First Cancer Treatment for Any Solid Tumor With a Specific Genetic Feature FDA News Release May 23, 2017 The U. S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature, biomarker. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. Pembrolizumab is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or mismatch repair deficient (d. MMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with chemotherapy drugs.

n engl j med 372; 26 nejm. org june 25, 2015 A phase 2 study recruiting patients with hereditary nonpolyposis colo-rectal cancer (i. e. Lynch-syndrome) and with sporadic mismatch repair–deficient tumors, a condition that causes MSI.

CONCLUSIONS