Drug candidates aren't the only innovations being tested in a wave of trials using new "basket" designs. Three large-scale basket trials are gearing up that will be crucial tests of a paradigm-shifting approach to clinical trial conduct and enrollment.

The trials – the National Cancer Institute-MATCH study, Novartis AG's SIGNATURE program, and the American Society for Clinical Oncology's TAPUR trial – will take advantage of a revolution in sequencing technology. As next-generation sequencing (NGS) moves genomic screening toward routine medical practice, clinical trial enrollment and screening can be much more widely disseminated than before.

"During the past five years, rapid technological progress has allowed us to analyze a person’s microbiome, hormones, genome, and epigenome at wholesale scales, a stark contrast from the past, when each would have been analyzed one at a time," the American Association for Cancer Research noted in its annual Cancer Progress Report, released Sept. 16.

NGS technology is new to the market – the first, Illumina Inc.’s MySeq diagnostics platform, was approved in November 2013 – but rapid advances in the field are forcing FDA to re-evaluate its regulatory paradigm for molecularly targeted therapy: a specific companion diagnostic test approved by FDA's device center alongside a therapeutic from the drug center. FDA is exploring new approaches to qualifying tests done on a new scale (see sidebar).

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Researchers are using newly available genetic information as the basis for basket trials, an emerging histology-independent trial design that enrolls patients based on biomarkers instead of tumor site. Basket trials are emerging as a potentially valuable signal-finding tool, although early experience suggests that they may not be the foundation of totally histology-independent drug development ([A#00150914015]).

The genetic screening is also the basis of another type of new clinical trial also aimed at quicker signal detection and more efficient drug development. So-called umbrella trials screen a cohort of patients with a common cancer type and enroll to various drug arms based on their genetic signatures, such as the National Institutes of Health’s Lung-MAP Also see "Lung-MAP Patient Screening Should Translate To Cost-Savings" - Pink Sheet, 23 June, 2014..

Riding A Wave Of Enthusiasm For 'Precision Medicine'

"Since many gene mutations in tumors are infrequent or unique, screening for individual mutations is not cost-effective or efficient in clinical trials," the National Cancer Institute explained when announcing the MATCH trial, which started in summer 2015. Instead, NCI-MATCH will use a single DNA sequencing test developed by the NCI Molecular Characterization Laboratory to look for more than 4,000 variants across 143 genes. The basket trial will assign patients with actionable mutations to targeted therapy in 10 arms to start, with plans to expand to 20-25 arms (see chart).

NCI-MATCH
The NCI-MATCH trial aims to enroll 1,000 patients in 20-25 substudies. The trial started in summer 2015 with 10 drug/genetic variant pairings.
Pfizer's Xalkori (crizotinib) for ALK rearrangements and for ROS1 translocations	Verastem's VS6063 for NF2 loss
Novartis' Tafinlar (dabrafenib) plus Mekinist (trametinib) for BRAF V600E or V600K mutations	Pfizer's Sutent (sunitinib) for cKIT mutations
Novartis' Tafinlar (dabrafenib) for BRAF fusions or non-V600E, non-V600K mutations	AstraZeneca's AZD9291 (EGFR T790M or rare EGFR activating mutations)
Boehringer Ingelheim's Gilotrif (afatanib) for EGFR activating mutations and for HER2 activating mutations	Roche's Kadcyla (ado-trastuzumab emtansine, TDM1) for HER2 amplification
Source: NCI National Clinical Trials Network

The National Institutes of Health effort is benefiting from widespread interest in what used to be called personalized medicine, and is in line for substantial funding under President Obama's Precision Medicine Initiative ([A#00150209016]).

NCI-MATCH is leveraging NCI's extensive efforts to build and support clinical trial networks at the institutional and now the community level. Enrollment will be through the NCI Community Oncology Research Program (NCORP), a national network of investigators, care providers and institutions, as well as the National Clinical Trials Network (NCTN), NCI's framework for established clinical trial groups like ECOG-ACRIN, which will lead the NCI-MATCH study.

NCI expects 2,400 sites to enroll patients in NCI-MATCH. "Large numbers of patient tumors will need to be screened because most gene mutations occur in 10% or less of cancer patients," the institute noted.

In order to "ensure quality control" over biopsies from the 3,000 patients who will be screened for NCI-MATCH, specimens will all be sent to the ECOG-ACRIN Central Biorepository and Pathology Facility at the MD Anderson Cancer Center. "The use of a unique kit for specimen collection, shipment, and centralized tissue processing, assures high-quality analysis,” the NCI announcement declared. DNA sequencing analysis will be done at a network of four molecular diagnostics labs, and "pilot testing of specimens across the four locations showed remarkable reproducibility of the molecular results – another important aspect of quality assurance in trials of this scope and scale."

Mining Clinical Experience

Targeted therapy has produced new drug approvals at an unprecedented pace. "From Jan. 1, 2011, through July 31, 2015, 32 additional therapeutics targeting molecules involved in the development and progression of cancer were discovered and approved for patient benefit, which is more than in the entire four prior decades,” the AACR 2015 Cancer Progress Report observes. And since physicians are not limited in prescribing to FDA-approved labeling, the explosion of targeted drug options combined with the rapid adoption of NGS screening is the source of extensive off-label use ([A#00150831009]).

That real-world off-label experience also represents a huge amount of information that could be extremely valuable to drug development.

The American Society for Clinical Oncology saw in this off-label experience the opportunity for the association's first-ever clinical trial. The TAPUR basket study aims "to learn from the real-world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target," ASCO Chief Medical Officer Richard Schilsky explained when introducing the study at the ASCO annual meeting in June.

TAPUR will enroll patients with advanced solid tumors, B-cell non-Hodgkin lymphoma and multiple myeloma for whom no standard therapy exists, if they have genomic test results from a certified and accredited lab that show a genetic variant known to be a target for a commercially available drug. TAPUR will provide enrolled patients with drugs free of charge under its agreements with five pharmaceutical companies to provide 13 drugs that address 20 genomic variants. Participating companies are AstraZeneca PLC, Bristol-Myers Squibb Co., Eli Lilly & Co., Genentech Inc., and Pfizer Inc.

Genentech and its parent Roche are conducting basket trials of their own products as well ([A#00150914012]). Roche has invested heavily in biomarker-driven research and genomically-informed drug development under its "comprehensive diagnostics" strategy to leverage its strengths in both therapeutics and diagnostics Also see "Roche's Oncology Strategy: The Long Game Comes Into Focus" - Pink Sheet, 15 June, 2015..

Without NCI's centralized laboratory and established clinical trial management infrastructure, ASCO looked to technology companies Illumina and Syapse for the TAPUR trial's data collection and analysis. Illumina's NextBio platform classifies and aggregates phenotypic and clinical data "within a single environment and allows analysis of that data at unprecedented speed and scale," according to the company.

Physician practices participating in TAPUR will use Syapse's Precision Medicine Platform to "integrate study participants’ genomic profile, treatment history, and clinical outcomes and report the data to the researchers," Syapse said. The platform "will enable the TAPUR study to standardize study workflows that include retrieval and review of molecular test results," the company said, and "structured data from a growing network of participating health networks will be centralized" to allow the study "to better identify signals of drug activity."

Swift identification of signals of activity is a keystone of the new basket trials, which rely on adaptive statistical designs to respond flexibly to data while the study is under way (see sidebar).

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Novartis Building Central Infrastructure For SIGNATURE

Novartis' SIGNATURE basket trial is looking for signals of efficacy with eight of the company’s drugs in the most ambitious histology-independent program launched by an individual company ([A#00150914009]).

The trial is also establishing a "working model" for fast and efficient signal-finding early in drug development, Novartis Senior VP-Head of US Oncology Clinical Development and Medical Affairs August Salvado said in an interview with "The Pink Sheet."

Like TAPUR, the SIGNATURE program will identify patients by local testing in certified labs. "You allow the physicians to identify the patients rather than have a specific fixed number of sites," Salvado said. "Having a large footprint like that where physicians are aware of the trial and are able to identify the right patients … really should allow us to be more efficient in trial accrual."

SIGNATURE uses protocols approved by a central IRB, Salvado noted, "so we didn’t have to go through a long approval process at various institutions." Novartis aims to avoid getting bogged down in negotiations by using "a contract from which we would not deviate … in each of the study protocols," he said. "We tried to be very careful in terms of looking at the assessments that were to be done in each of these studies and to look at the average costs and not to deviate or negotiate a long time around that budget."

Novartis has implemented SIGNATURE "efficiently and quickly and we have done that both in a community setting as well as in an academic setting with these studies," Salvado said. At the ASCO annual meeting, SIGNATURE investigator Julio Antonio Peguaro, Oncology Consultants PA, Houston, Texas, reported that 368 patients were dosed through January 2015 in SIGNATURE at 16 academic centers and 151 unique community/network sites.

"The average startup timeline was 5.2 weeks," Peguaro reported.

That should translate into even faster drug development for molecularly targeted drugs, AACR noted.

"This new era of clinical trials offers the promise to accelerate the pace at which new anticancer therapeutics are tested in the clinic and reduce the number of patients that need to be enrolled in clinical trials, both of which may drive down costs," the Cancer Progress report states.

Genomics-Driven Trials Built To Be Fast And Flexible

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