The Changing Nature of Clinical Trials

You’ve Come a Long Way Baby – The Changing Face of Clinical Trials

The clinical trial process has evolved over the years.  The first controlled clinical trial of the modern era was designed by James Lind, a Scottish physician in 1747.  While Dr. Lind was working as a ship’s doctor he was appalled by the high mortality rate of the sailors on his ship that were diagnosed with scurvy. Dr. Lind planned a comparative trial using the most promising treatments for scurvy that were available at the time. He divided 12 sailors that had scurvy into 6 treatment arms of 2 patients.  All patients were fed the same diet and were housed in the same quarters.  The only difference was the treatment they received.  Group one was given a daily quart of cider as treatment, group two twenty-five drops of sulfuric acid, group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty while the other had almost recovered. Group one also showed some effect of its treatment. It is now known that scurvy is caused by Vitamin C deficiency.

Understanding Clinical Trials

The idea of placebo was first introduced in the clinical trial process in 1863 by United States physician Austin Flint.  Placebo is a scary word for many cancer patients because it is often misunderstood when it comes to cancer trials.  A placebo is only given as a single agent to a cancer patient if there is no standard of care established. That means if your doctor’s recommendation would have been no treatment if you weren’t considering a clinical trial than a no treatment arm of a clinical trial could exist.  The other time a cancer patient may be given a placebo is when examining the effectiveness of combination therapy.  Does Drugs X + Y work better then Drug X + Placebo?  Dr. Flint planned the first clinical study comparing a placebo remedy for rheumatism to an active treatment. The idea of comparing active treatment to the “natural history of the disease” was a novel idea, but one that had merit.  Why subject a patient to a treatment that may have side-effects if the outcome with no treatment is the same? A placebo controlled trial can answer that question.

The first double blind control trial was designed in 1943 to investigate patulin treatment for the common cold. Double blind means neither patient nor doctor know which treatment arm a trial participant is assigned.  Although it was a double blind trial it was not randomized. The first randomized control trial was carried out in 1946 for treatment pulmonary tuberculosis with streptomycin. The gold standard for clinical trial design remained double blind randomized control trials until recently.

Changing Clinical Trial Design

Now is the time to innovate the clinical trial design paradigm for cancer patients. There is a need to boost trial enrollment and speed the process. With the announcements of President Obama’s Precision Medicine Initiative and the Cancer Moonshot Initiative it is time to look at new models for clinical research.  Historically clinical trials tested the effectiveness of a particular treatment in a specific cancer type.  Some treatments showed exceptional responses in a subgroup of patients while no benefit to others. What accounted for these differences in response? Could it be that although the trial participants were diagnosed with the same type of cancer and at the same stage the biology of their cancers were unique?

Years of research and advances in technology ushered in the era of Precision Medicine.  Genetically sequencing hundreds of cancer tumors and bone marrow aspirates revealed that there are more than 200 types and subtypes of cancer and even within a subtype there is heterogeneity at the molecular level.  We both may have high risk multiple myeloma, but the genetics of your disease as determined by next generation sequencing may be very different than mine.

Shift to Targeted Therapies

Cancer research has changed over the last decade too. There has been a shift in research from cytoxic agents to targeted therapies. Cytoxic agents kill fast dividing cells.  These agents don’t discriminate between the cancer cells and the cells that line your stomach. Cytoxic agents often have unpleasant GI side effects.

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecular targets.  These molecular targets can be mutations in your genes.  A growing number of experimental treatments that are being developed are targeted agents.

Strategies have been developed in recent years to adapt the traditional clinical trial design to incorporate molecular target testing.  There is no sense in testing a new targeted therapy in a patient that doesn’t have that particular target or biomarker.  Molecularly informed trials such as umbrella and basket trials are new ways of conducting clinical research involving molecular targets.

Umbrella trials focus in on treating patients with the same type of cancer with different targeted therapies. The therapy that is selected would be based upon the presence or absence of a particular mutation or biomarker.  Umbrella trials usually have two stages.  First is the screening stage where tumors are tested for specific mutations or biomarkers.  Patients whose tumors express a targeted mutation or biomarker are then assigned to treatment based on mutation/biomarker expression. If a patient doesn’t have the mutation or biomarker being studied they are not eligible for the trial.

Trial Chart

Basket trials focus on treating patients with different cancer types (lung, skin, etc) that share a common genetic alteration with the same targeted therapy. Large basket trials such as the NCI-MATCH trial are enrolling participants from many different cancer types and are assessing targeted treatments for a variety of genetic abnormalities. NCI-MATCH wants to determine whether treating cancers according to their molecular alterations instead of the origin of their cancer will show evidence of effectiveness. NCI Match currently has 24 treatment arms. Many pharmaceutical companies are collaborating in NCI-MATCH on identifying targets and developing targeted therapies.

Clinical Trials

Researchers have learned that the genetic makeup of a tumor is as important as its location in the body. Evaluating targeted therapies in the wrong population can lead to the unnecessary failure and the possible rejection of a potentially useful treatment option. Molecularly informed trials such as umbrella and basket trials use genetic and molecular data to test new targeted therapies in the right group of patients based on their cancer genetics. Identifying the pathways that are mutated in a tumor allows for that pathway to be targeted by an anti-cancer agent hopefully leading to a positive response. Both types of trials have the potential to speed the drug development process so that the right therapies can be given to the right patient at the right time.

Basket and umbrella trials are costly due to the need to use genetic sequencing techniques to identify the correct candidates for the trial. They are also difficult to organize. For these reasons they remain in the minority of trial options available. A recent search of identified of the 229,864 studies listed 32 were basket trials and 22 were umbrella trials. There were no basket or umbrella trials listed for multiple myeloma. But myeloma patients don’t despair. The Multiple Myeloma Research Foundation recently announced its Molecular Profiling Initiative (MPI) for relapsed/refractory patients.  The goal of MPI is to determine if a relapsed/refractory myeloma patient will benefit from an existing therapy based on the molecular alterations in their tumor. Free sequencing of their myeloma cells will identify any actionable mutations and match them to a therapy if available.

Understand Your Cancer’s DNA

What does this mean for you?  Know the genetics of your cancer.  The genetics of your tumor may inform you which molecular alterations need to be targeted.  If a targeted therapy for your particular actionable mutation already exists- you may have hit the jackpot!  But it’s not that easy. It’s very likely that your tumor has more than one abnormality. Combination therapies may be needed to attack multiple alterations. Another thing to consider is what percentage of your tumor expresses a particular mutation or if the mutation is a driver or passenger mutation?  Additionally not all targets have treatments currently available to try. The initial phase of NCI-MATCH found the match rate was only 9 percent although they expect this to increase to 20% as new arms are added to the trial. Some targets exist in such a small number of people that it makes it hard to accrue enough patients to test a potential therapy’s effectiveness.  Resistance to therapy and the molecular evolution of your cancer also need to be taken into consideration.

We’ve come a long way baby, but we still have a long way to go.  The only way progress will be made is if patients enroll in clinical trials.  Clinical research provides hope and cures.

Get started and a Cure Forward Clinical Trial Navigator will help you access active clinical trial options.

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Cindy Chmielewski Precision Medicine Advocate

Cindy Chmielewski Precision Medicine Advocate

Cynthia Chmielewski was diagnosed with multiple myeloma, a blood cancer, in 2008. Cindy’s induction therapy stopped working after a few cycles and she proceeded with a stem cell transplant which failed to put her into remission. Depressed and scared she continued her fight using newly FDA-approved targeted therapies which eventually put her in remission. Cynthia continues treatment with a maintenance protocol.  Cynthia is using her passion for education to teach a new group of “students” – myeloma patients, their caregivers and others interested in myeloma.  She is a trained mentor, advocate and Patient Ambassador.
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