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Pink Sheet – Colon Cancer Community Weighs “Master Protocol” Approach

Pink Sheet – Colon Cancer Community Weighs “Master Protocol” Approach

Building on enthusiasm for the multi-sponsor, multi-drug clinical trial due to get underway in lung cancer soon, stakeholders in academia, industry, government and the patient community have begun discussions about a similar, biomarker-driven trial in colon cancer.

The concept of a clinical trial “master protocol” is expanding into other disease areas even before the inaugural trial in lung cancer enrolls its first patient.

Representatives from academia, industry, the patient community and government have begun discussions about a biomarker-driven trial in colon cancer.

Although the talks are very preliminary, sources said, there is considerable interest across the colon cancer community in the master protocol concept, which would allow for large numbers of patients to be screened and enrolled in a multi-arm, multi-drug study based upon tumor mutations.

With the potential for greater efficiency and speed in the conduct of clinical trials and late-stage drug development, particularly for therapies targeting rare tumor mutations, enthusiasm in the master protocol approach is expected to spread to other oncology settings as well, although how the approach fares with the initial lung cancer project could impact interest in the idea.

More Efficiency, Less Expense

The master protocol concept has been described as a paradigm-changing approach to drug development, particularly in oncology, where patient populations are becoming increasingly segmented based upon the molecular characterization of tumors (“Lung Cancer “Master Protocol” Eyed As Paradigm-Changing Approach To Drug Development” — “The Pink Sheet,” Nov. 18, 2013).

The idea is getting off the ground with a trial in second-line squamous cell non-small cell lung cancer (Lung-MAP) that was designed through a public/private partnership.

Patients will be screened for specific tumor mutations using a next-generation sequencing platform and assigned to randomized treatment arms based upon mutation status. Five compounds fromAmgen Inc.AstraZeneca PLC and its MedImmune LLC division, Genentech Inc. and Pfizer Inc.have been chosen for initial study, although protocol designers envision that compounds will rotate in and out of the trial down the road. The Phase II/III trial is designed to provide data sufficient to support drug registration.

When details about the master protocol were announced at the Conference on Clinical Cancer Research in November 2013, the study’s leaders said they hoped to begin enrollment this March. Although that date has slipped, the current target to begin enrollment is May.

Costs of the trial will be shared by the participating pharmaceutical sponsors. The master protocol approach is expected to cost significantly less on a per-patient basis than if a company studied its own drug in a dedicated registration trial.

In an interview, Friends of Cancer Research Executive Director Jeff Allen said that although study details are still being finalized, the per-patient cost of the lung cancer trial is expected to be about $35,000, “which is less than what an industry registration-quality trial would be.” FOCR is playing a lead role in development and implementation of the master protocol approach.

The study designers have been able to capitalize on a number of efficiencies, Allen said, including use of an existing infrastructure through the National Cancer Institute cooperative groups, spreading data monitoring costs across sponsors and use of a common genomic screening tool for all patients.

Allen also pointed to the efficiencies created with the all-comers, mass-screening approach, particularly for tumor mutations of relatively low prevalence. For companies whose drugs target such rare mutations, “it may be extremely difficult to do a trial independently because of the sheer number of patients that you would have to screen in order to identify those with the alteration. You’d have to pay for screening in so many test-negative patients that it would really increase your costs significantly. It also could be a limiting step as far as companies determining which molecules they may want to prioritize or move forward with. I expect that will be a big factor for companies large and small that may be considering if this particular trial could be part of their development program as we move ahead.”

FDA, NCI Involvement

The colon cancer community will be watching the initiation of Lung-MAP with interest as it tries to reach consensus on the major design elements of its own master protocol, such as line of treatment, when targeted therapy should be introduced, mutation targets and study endpoints.

On March 7, FOCR hosted a planning meeting on the design of a colon cancer master protocol that was attended by representatives from academia, industry, patient groups and NCI. FDA representatives included Center for Drug Evaluation and Research Director Janet Woodcock, an enthusiastic supporter of the lung cancer master protocol, and Steven Lemery, a lead medical officer in the Division of Oncology Products II.

FDA is advising the working group regarding regulatory issues related to the protocol, including devices, the agency told “The Pink Sheet.”

One of the academic leaders working to develop a master protocol is Stanley Hamilton, head of the Division of Pathology and Laboratory Medicine at MD Anderson Cancer Center. Colon cancer is second only to lung cancer as the most common cause of cancer-related deaths in the U.S., “making it a logical tumor type to address with the master protocol approach,” Hamilton said in an email.

Many of the challenges are similar for lung and colorectal cancer, “including the complexity of the logistics to acquire a biopsy specimen and provide genomic results for the patients with short turnaround time so that therapy can be started,” he said.

However, there are important biological and practical differences between the two cancers.

“Colorectal cancers in general appear to have a wider spectrum of driver abnormalities and less oncogene dependence than does lung cancer. Combination of agents may therefore be necessary at the outset, rather than single agents,” he said.

“Another difference is a practical one: a biopsy of a recurrence is not considered by all oncologists to be standard of care for colorectal cancer patients, in contrast to lung cancer patients where biopsy is routine.”

Hamilton highlighted some of the efficiencies associated with a master protocol approach.

“A master protocol that identifies multiple, and we hope numerous, small subsets of patients who have each target for which there is a targeted agent in the trial and can be entered into a clinical trial arm that is likely to produce benefit provides economies of scale over trying to screen a large population of patients for a single small subset,” he said. “In addition, the master protocol approach increases the number of patients who will qualify for an arm in the trial.”

A patient advocate involved in the discussions said the idea of increasing the efficiency of clinical trials, particularly when it comes to targeting rare mutations, is appealing to the patient community.

“I see huge logistical benefits, and I also think ultimately personalized medicine is going to be the answer to cancer …. and we don’t know how to do that yet in colorectal cancer,” the advocate said.

However, careful thought needs to be given to logistical issues and it is important that the approach is workable for community-level oncologists, not just those in academic centers, because a large number of patients will be needed for screening, the advocate said.…