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Genentech Seeks to Advance Basket Trial Master Protocol as New Approach to Advancing Pediatric Drugs


NEW YORK (GenomeWeb) – Genentech is working with health regulators in the US and EU to garner their go ahead for a master basket study protocol, called iMATRIX, which the company plans to use to quickly evaluate drugs across its oncology portfolio for pediatric use.

The company is also hoping that the US Food and Drug Administration and the European Medicines Agency will convene a public forum where drug companies, academics, and patient advocates can discuss pre-competitively the early data on treatments, particularly when multiple drugs in the same class are being studied for pediatric use. This can reduce unnecessary competition in pediatrics, since patients already have limited treatment options.

Genentech partnered with cooperatives, such as the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC) and Innovative Therapies for Children with Cancer European Consortium (ITCC), to design the iMATRIX clinical trial platform. And although iMATRIX is a Roche platform, Rousseau is hopeful that eventually other drugmakers will want to evaluate their drugs using it.

The first drugs being studied under the iMATRIX protocol are Tecentriq, which the FDA in May approved for metastatic urothelial cancer in adults; and Cotellic (cobimetinib), which the agency approved last year in combination with Zelboraf (vemurafenib) as an advanced melanoma treatment. 

Genentech wants to apply the iMATRIX protocol much more broadly, however, and speed up the evaluation and development of precision pediatric oncology drugs. "We're taking the view that this needs to be done quickly," Raphael Rousseau, head of Genentech's pediatrics global franchise, told GenomeWeb. "Children should not wait to have these compounds."

With the blessing of health regulators, Genentech wants to evaluate all the oncology drugs in its portfolio using its iMATRIX platform, which it believes will enable a more rational and scientific approach to advancing much needed treatments for children, particularly in the era of precision medicine.

Currently, sponsors are required to study drugs for children according to regulations under the Pediatric Research Equity Act (PREA) in the US and the Pediatric Regulation in the EU. These regulations have helped increase pediatric drug research, but there are still a limited number of drugs specifically approved for children.

According to the FDA, more than 80 percent of adult drugs were being used off-label in children without study data supporting their safety and efficacy in the population more than a decade ago. However, since laws like PREA were enacted in 2003, that number has dropped to 50 percent. 

Rousseau believes that these laws still eschew the incentives for advancing drugs for children, because the regulations obligate sponsors to study drugs in kids when their disease corresponds to an adult disease indication. As a result, many oncology drugs are commonly exempt from having to be studied in children, because the adult disease indication is so exceedingly rare or absent in kids.

"So, when a sponsor targets prostate cancer or lung cancer, these do not occur in children," Rousseau said. "Pediatric tumors are very different."

When sponsors aren't exempt from having to do pediatric studies, another challenge arises when drug firms are developing multiple drugs in the same class. Competing to bring multiple drugs in the same drug class is fine in the adult population, according to Rousseau, but it's an unnecessary hindrance in the pediatric oncology space.

"You end up competing for very rare patients in an area where clearly we should not be competitive," he said. "It's a precompetitive space. We need to get together and discuss what the best potential new medications are for these patients and focus on the right disease and right populations of patients."

A plan for children

Cancer is rare in children. In the US, around 18 per 100,000 children, compared to 631 per 100,000 adults, get cancer. Some tumor types are exceedingly rare in the pediatric population, such as neuroblastoma, which occurs in around 8 children out of a million. The growing focus on molecularly defined cancer research and treatment has only exacerbated this problem, and is further segmenting already small pediatric cancer populations.

When Rousseau joined Genentech in 2009, he and his colleagues discussed the need to go beyond the regulations governing pediatric drug development. Instead of waiting for late-stage studies to complete in adult indications, they wanted to advance drug candidates by focusing on their mechanism of action and matching them to the biology of the pediatric tumor.

The iMATRIX protocol, Genentech believes, will enable its researchers to do just that. Using the basket design, the firm hopes to quickly identify which tumor types respond to which drugs by studying them in a limited number of patients, and move forward agents to bigger studies when they show promise or retire the ones that fail to show a benefit. 

At a recent meeting of the Pediatric Subcommittee of the FDA's Oncologic Drugs Advisory Committee, Genentech presented a plan for evaluating Tecentriq in children using the iMATRIX protocol. The company will enroll 40 to 100 pediatric and young adult cancer patients under 30 years old with relapsed or refractory solid tumors (including Hodgkins and non-Hodgkins lymphoma) with known PD-L1 involvement.

Taking a cue from an adult study — where urothelial cancer patients with PD-L1 expression in tumor infiltrating immune cells derived greater benefit from Tecentriq compared to PD-L1-negative patients, but some without biomarker expression also responded — researchers are enrolling pediatric patients who express PD-L1 but also a small number of patients who don't have biomarker expression.

Genentech is taking this approach to better characterize the cutoff for PD-L1 expression in the pediatric population. In an effort to improve understanding of the predictive utility of PD-L1 in pediatric tumors, researchers are also conducting retrospective biomarker analysis in 100 samples. This retrospective analysis may even identify a biomarker signature beyond PD-L1, according to Rousseau. He noted that if a biomarker is retrospectively defined in the pediatric population in the Phase I/II portion of this study, it will be used to stratify patients in Phase II investigations.

The whole idea behind using a basket trial approach to evaluate Tecentriq is to move the pediatric development program along at a faster clip. To date, more than 70 patients have been enrolled in the Tecentriq study over six months. In pediatrics, this is a "remarkable" enrollment timeline, Rousseau said. He also highlighted that Genentech recently opened enrollment under the iMATRIX protocol for Cotellic and there is already one pediatric patient enrolled in that study

For Tecentriq, Genentech is enrolling patients across eight "baskets" focusing on specific tumor types. Researchers will perform an initial response evaluation when at least 10 patients are enrolled in each basket and follow them for around six months. For some baskets, as few as two patients will have to respond to Tecentriq for that indication to be evaluated in an expanded cohort. "If we don't see a response, then the next patients with the same type of tumor are offered another kind of compound," Rousseau said.

By end of summer, researchers should know whether Tecentriq has single-agent activity in certain tumor types, and which tumor cohorts they will study further. The FDA advisory committee responded positively to Genentech's protocol and advised that the sponsor also test out combinations of drugs on pediatric patients.

"You don't cure cancer with one drug," Rousseau said. "Combinations make perfect sense in pediatrics as well."

Because the children enrolled in the iMATRIX platform will be refractory and advanced cancer patients with limited treatment options, Genentech will take a flexible approach to using molecular markers for enrollment. As with the Tecentriq study, if patients have a predictive marker known to be associated with a certain kind of drug, that will be used to match them to a treatment.

But, generally, researchers will try to assign patients to treatments based on their tumor biology, the mechanism of action of the drug, and preclinical study data. They will collect biological samples from patients and retrospectively define a biomarker signature for the pediatric population that can be used to prospectively stratify patients in later studies.

Need for precompetitive dialogue

Currently, the pediatric studies for Tecentriq and Cotellic are standalone trials but under the aegis of iMATRIX. "What we hope is that by the end of this year, the [iMATRIX] concept itself will be approved, so it will go much faster," Rousseau said, "so we can add on or remove compounds very quickly, and optimize data collection, interpretation, and administrative burdens."

The company is discussing the master protocol with the FDA and EMA, and according to Rousseau, they've been supportive of the concept so far. Genentech is ironing out a number of issues with health authorities, for example, how much data they need from single agents before they can move into combination drug studies, as well as the use of data from modeling and simulations to limit exposing too many children to the toxicities of investigational agents.

"I hope that we can convince health authorities that ultimately what's important is the safety of the combination," Rousseau said. "We'd like to come to an agreement with health authorities, academic partners, and parents [about] what constitutes the minimal data package for a single agent and rapidly move into combinations. I think this is where the efficiency of the platform will be seen."  

The EMA and FDA will meet at the end of August to jointly evaluate and qualify the master protocol. "What we hope ultimately, when it is approved, is for other sponsors, academic or industry to use it as well, so we all gain speed," he said.

Genentech would also like the health authorities to organize a public forum so stakeholders can have a dialogue about how best to advance drugs in pediatrics, particularly when there are multiple agents in the same class. When regulators have asked competing drug firms to run the same type of studies for similar drugs in the pediatric setting, the outcome has been disappointing, Rousseau noted.

For example, health regulators asked at least three firms to study their BRAF inhibitors — approved for metastatic melanoma in adults — for advanced melanoma in adolescents. Because the disease is so rare in adolescents, "asking three companies to run the exact same trial is counterproductive," Rousseau said. "If you ask parents and children, they just want one BRAF inhibitor, they don't need six."

Genentech enrolled six patients in five years in a study for its BRAF inhibitor Zelboraf (vemurafenib) in children and had to close it. The company is now discussing cancelling the entire pediatric development plan for Zelboraf with the EMA, which initially sought to enroll 26 patients. "If we don't solve this issue, I promise you, the BRAF [inhibitor] fiasco will happen again," Rousseau said.

For example, in the immunotherapy setting, FDA has approved two PD-1 inhibitors (Keytruda and Opdivo) and Genentech's PD-L1 inhibitor Tecentriq in adult cancer indications, but there are three pediatric Phase I/II programs investigating anti-PD-1/PD-L1 drugs. Rousseau thinks it would be in the best interest of children if the different drug sponsors sat down and discussed openly with all the stakeholders which agents to advance into late-stage studies.

Drug companies inherently compete with each other and this is healthy when developing drugs for the adult setting, Rousseau acknowledged, but applying the same market dynamics when developing treatments for children doesn't make much sense to him. "The spirit of precompetitiveness is really important for children," he said.