Managing Clinical Trials

"Context of vulnerability" and its role in targeted drug development

Renowned cancer researcher Dr. Daniel Von Hoff and his team at TGen are fervent believers in a new approach to developing novel therapies for patients with pancreatic cancer. Their rationale, dubbed “context of vulnerability,” is a powerful new drug development paradigm that’s generating impressive results.

Medelis has just published a free downloadable interview with Dan (download it here) as part of our “Peer Perspectives in Oncology” series.  In the abstract, Dan explains how this model has already led to promising discoveries and is changing the future of oncology drug development. 

“Context of vulnerability,” a term coined by TGen’s Spryo Mousses, Ph.D., refers to the genetic configuration in a patient’s tumor that makes it susceptible to a specific drug.  “Context of vulnerability provides the genetic rationale for a targeted therapy,” Dan explains.

In the abstract, he provides examples of context of vulnerability in use.  “One way to establish the context of vulnerability is to work backwards from the result,” he says.  “For instance, in a phase I or phase II trial, you treat a certain number of patients, and when someone responds, you have to ask yourself, ‘Why did that patient respond?  What was the vulnerability in this specific tumor or patient?’  The patient either had a genetic lesion or tumor stroma that was susceptible to the drug in some way.”

Dan explains that context of vulnerability can improve a sponsor’s chance of seeing efficacy during an early-stage trial with a much smaller n.

“If you let context of vulnerability guide drug development, you would put only those patients who have the appropriate susceptibility to the drug on trial,” he emphasizes.  “It’s essentially how Herceptin® got approved with an n of 480.  If they hadn’t pre-selected patients for the context of vulnerability, estimates say that it would have taken about 23,000 patients to get the drug approved.”

Throughout the interview, Dan addresses many of the questions and opportunities presented in this model:

• How context of vulnerability provides a genetic rationale for a targeted therapy;
• How to establish a patient’s context of vulnerability;
• How using context of vulnerability to guide drug development can improve your chance of seeing efficacy with a much smaller n;
• Incorporating context of vulnerability as the oncologist’s “sixth vital sign;”
• A case study of context of vulnerability in use and how it improves patient care and new agent development;
• The gap between known contexts of vulnerability and available therapeutics;
• How CMOs can flip their drug development planning to leverage this approach;
• Feedback from the FDA, national and international groups;
• Targeted therapeutics and the future of oncology.

The abstract is the fifth in Medelis’ “Peer Perspectives in Oncology” series, and you can download the entire series here.  You’ll receive email notices when future issues are published as well.

The "Lost Opportunity” in Phase I Oncology Trials

Cancer drug developers traditionally use the phase I trial solely to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a drug.  Today, we’ve published a free new downloadable abstract, "The Lost Opportunity in Phase I Oncology Trials," an interview with renowned oncology investigator Daniel D. Von Hoff, M.D.  In the interview, Dr. Von Hoff advocates for a phase I approach that looks beyond toxicity and gleans meaningful efficacy data, creating a more compelling rationale for further investment and improved patient care.

“A Chief Medical Officer looking at the phase I typically sees it as a toxicity trial, not a therapeutic trial, because of course it is not randomized,” Dr. Von Hoff explains. “But we - doctors at the bedside and the patients themselves - do not see it that way. We are looking for improvement and survival. [The phase I] is an opportunity to look for therapeutic effect as well because it might just be there.”

Dr. Von Hoff supports an additional analysis that uses a cancer patient as his or her own control.  Rather than solely relying on the traditional data captured in normal phase I protocols, he recommends measuring the tumor’s “time to progression” on the current drug versus the tumor’s “time to progression” on the patient’s previous treatment.  This data — time to progression on each drug — should be systematically tracked in the protocol so it becomes part of each patient’s data bank.

“I have never seen a CMO plot time on a new drug versus the time on a just-prior therapy to build a story for raising money,” Dr. Von Hoff continues. “This idea of using the patient as his or her own control is a lost concept in drug development. Dr. Bob Temple at the FDA, an icon in clinical trial design, calls it a lost art. He’s referring to the ability to document changes in the natural history of a patient’s tumor, and how this information can give you a sense of whether the drug will work.”

“If you treat 30 patients and 30% stay on a new therapy for a longer time than the just-prior drug they had progressed on, then that would justify a deeper investment,” he explains.  “Patients’ tumors grow at an inexorable, ever-quickening rate. If you find an agent that can taper that growth, then it is probably doing something and should be pursued.”

“There is no question in my mind that, if a CMO started comparing time on new drug versus time on just-prior therapy, the rewards are there – both for the patients and for the progression of the drug. All it takes is a more proactive approach to the phase I. It is so simple yet I have never seen a CMO adopt this.”

In the abstract, Dr. Von Hoff answers many questions about this “lost art” in the phase I trial.  Download the full issue here; you’ll also gain access to the other issues in the series, and we’ll notify you of future publications as well.  

Personalized Genomics: The First Report of a Cancer Genome

As reported by the New York Times last week, Washington University recently completed a study that decoded the entire genome of a cancer patient. The patient, a woman in her 50s who died of leukemia, became the first cancer patient and the first female to have her entire genome decoded.

To protect the patient’s identity, the data will be available to scientists only.

While the finding won’t help patients right away, the controversial project, funded primarily by a private donor, could open the door to entirely new approaches to treat cancer.

A cancer expert not involved with the study, Dr. Stephen Nimer, chief of the hematology service at Memorial Sloan-Kettering Cancer Center, called the research a “tour de force” and the report “a wonderful paper.” He said the whole-genome approach seemed likely to yield important information about other types of cancer as well as leukemia.

While scientists have debated the validity of sequencing the whole cancer genome, the study was possible due to recent advances in technology that have made it easier and cheaper to analyze 100 million DNA snippets.

Dr. Richard K. Wilson, director of Washington University’s Genome Sequencing Center and the senior author of the study, sees a bright future for DNA sequencing. “That’s personalized genomics, personalized medicine in a box,” he said. “It’s holy grail sort of stuff, but I think it’s not out of the realm of possibility.”

Dr. Wilson said he hoped that in 5 to 20 years, DNA sequencing for cancer patients would consist of dropping a spot of blood onto a chip that slides into a desktop computer that produces a report suggesting which drugs will work best for each patient.

Some feel that this study signals a change in the oncology drug development landscape. If personalized medicine for oncology becomes a reality, it could signal the end of the “one-size-fits-all” oncology blockbuster drug. Patient survival rates should increase, because cancer patients and oncologists will have a greater selection of drugs and more data to predict efficacy.

The real change will be in the drug development process: Biotech and pharma will need to create more varieties of drugs that affect different genomes. Efficacy rates should improve, but each drug will treat far fewer patients. Clinical trials will be smaller and faster, as many of the drugs should receive FDA Fast Track and/or Orphan Drug status.

That puts quite a burden on oncology drug developers. Not only do they need to shoulder the additional costs of creating more drugs (that will produce lower revenues per drug), but they will also have to create more efficient trial designs to handle the larger number of smaller, quicker trials for each drug.

One way to accomplish this is to run phase I and/or phase II trials in parallel instead of running multiple separate trials. For a deeper discussion of this strategy, check out Dr. Daniel Von Hoff’s 'The Complete Phase Ib' Insider Abstract.

But the biotech and pharma industries will adapt. If the personalized genomic predictions are correct, the burden will be worth it when powerful treatments are developed to match common genomes.

Oncology clinical research scientist recommends a nuanced preclinical study process to speed drug development

Medelis has just published the third issue of "Peer Perspectives in Oncology," our free Q&A series focused on issues that face Chief Medical Officers today: rising costs, optimum patient accrual, targeted therapeutics, patient safety, FDA regulations, efficacy, budgets, and timelines.

In "Preclinical Trials:  A Nuanced Approach to Get Into the Clinic Faster," Dr. Mike McGarry describes a nuanced preclinical process that can help a CMO get into the clinic faster.  This approach hinges on a strategic, well-defined rodent model, quality data, and ongoing integration between the pre-clinical, regulatory and clinical teams.

Dr. McGarry, VP of Preclinical Studies at Medelis, is a preclinical research scientist with 35 years of experience generating high quality animal-based data.  In the interview, he provides a detailed inside look at the issues that can speed or derail the oncology preclinical phase:

• Critical factors for a CMO to understand and evaluate during this step in the drug development process
• Regulatory assessments and how to avoid hitting a preclinical wall
• The nuances and complexities of animal models, tumor selection, and other variables
• How to keep the preclinical, regulatory and clinical teams involved in feasibility dialogue
• The typical preclinical process and the questions a CMO should be asking at each step
• Additional requirements unique to oncology preclinical trials
• What to look for in an outside preclinical team.

The abstract is free, and you can download it here.  You can also download the first two issues in the series, "The Complete Phase 1b:  A Proven Approach to Getting to Phase II Faster," an interview with Dr. Dan Von Hoff, and "Patient Safety in Clinical Trials," a discussion with Dr. James Gourzis.

Can the internet fuel drug development?

What happens when some cancer patients become frustrated with their treatment options?  They search for a cure on their own. Some raise money to build awareness; others donate to further research.

Dr. Jay Tenenbaum, an e-commerce pioneer who is battling melanoma that spread to his liver, took a different approach:  he created a company to allow patients to discover new drugs with the help of the internet. 

CollabRx builds and operates "virtual biotechs" for people seeking cures on their own.  The CollabRx platform connects researchers to one another and to a network of scientific services.  Wealthy individuals, foundations and patient groups can join in to financially support specific research activities.  The system encourages researchers to share information and collaborate, going against the grain of the traditional scientific process.

While it’s unclear whether the concept will work, CollabRx highlights how the internet is starting to affect drug development.  Some of our sponsors are starting to recognize how the internet can help them recruit patients for their trials.  While pharmaceutical companies may be slow to pick up on the power of the web, patients seem to be a few steps ahead.

Amy Dockser Marcus provides a detailed look at CollabRx in yesterday’s Wall Street Journal.  She also provides excellent tips for patients who want to make a difference in the search for a cure.