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Advocacy >  An Advocate's Perspective on Participation in Phase I Trials  

Last update: 12/01/2015

Background 

When might we patients reasonably consider a phase I study?  | How to decide?

 Related Information | Phase I Lymphoma and CLL trials on ClinicalTrials.gov 

 Comment or Question?


The purpose of clinical trials from the scientist's perspective is to test new therapies in a way that reliably guides the care of future patients or advances clinical science.  Patients considering participation, however, have a different purpose: the hope to address our unmet clinical needs. 

Here is an overview of the phases of clinical studies and how we patients might think about them, with a focus on when phase I study participation might be considered a reasonable clinical decision -- guided by our treating physicians. 

The phases of studies focus on different questions. 

Phase I – what is the highest dose of the study drug that’s safe?

       "The dose is usually increased a little at a time in order to find the highest
        dose that does not cause harmful side effects"  (NCI)


Phase II – does the study drug have clinical activity at that dose?

Phase III – does it provide meaningful clinical benefit?

       Testing if the activity against the disease exceed the side effects … compared to?

There are overlapping purposes for each phase:

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A phase I study will also look for signals of clinical activity

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A phase II study will continue to look for and record rates of side effects.

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A phase III study assesses both good and bad effects and also
asks if the net effect provides meaningful clinical benefit compared to the regular approach.

Comparative studies are needed to advance and inform best practice –  and to test the study approach against the current standard of care.

The words “activity” and “benefit” have special meanings in clinical research.

Clinical activity (in this discussion) refers to a response of the tumors – such as if the tumor shrinks in size, or remains stable when it was previously increasing, or if it goes away (a complete response). 

It's important to emphasize that clinical activity does not mean benefit. A tumor might shrink for a short while and then grow faster. The bad effects of the study drug might be more significant overall than the good effects.  The study drug showing "activity" in preclinical studies might not be safe to give to people at an active dose.

Benefit is when the activity of the drug against the tumors offsets the risks and toxicities. Here the study drug demonstrated by well designed studies a positive risk/benefit effect. Meaningful clinical benefit also requires that the good effects are lasting.

To demonstrate that a study drug provides benefit is very challenging and takes time. It generally requires a large comparative study -- where the assignment to the study and control arms is randomized to ensure that risks factors of the participants are balanced (by age, stage, counts etc.).

* Exceptions can be made for “breakthrough drugs”, where the activity in phase II studies is compelling relative to the regular approach.

* TERMINOLOGY DISCUSSION:
I’ve defined the word activity as a response by the tumor.  This could be a nonstandard use of the word; efficacy is also used for this purpose.  I’ve stayed clear of the word efficacy intentionally, because it suggests benefit more than the word activity.  The FDA defines clinical benefit as the result of an intervention that improves survival or quality of life. Tumor shrinkage (a response) is sometimes used as a surrogate endpoint that might reasonably predict benefit in some cases, depending on the duration of the response and the side effects of the treatment.    See Glossary


When might we patients reasonably consider taking part in a phase I study?

That we are eligible for a phase I study does not mean it's a good fit for us -- as each patient will have unique clinical circumstances and preferences.   The potential benefits and risks of each study can also be unique.

Phase I studies may be considered:

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When standard therapies are not considered appropriate due to resistance or toxicities.

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When the study drug has a unique mechanism of action and standard approaches
are not working for us (if we have treatment refractory lymphoma).

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When the study drug is given with a standard drug AND the standard drug is appropriate for us,
and, perhaps, when the science suggests that the study drug might enhance the standard treatment.

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When the type (class) of study drug seems promising and unlikely to have serious toxicities -
(participation is unlikely to burn treatment bridges).

Other considerations:

Some phase I studies test different doses of the study drug in the same patient (intra-patient dose escalations). This design improves the odds of getting a clinically active dose of the study drug, but this design also increases the risk of toxicity.

Increasingly, phase I studies will select patients based on biomarkers that may predict response to the study drug, increasing the odds that the study drug will be active.  (Your tumor has this genetic change. This drug was designed to target that. However, it should be emphasized that mechanism of action is not evidence of benefit ... or even that the active dose of the study drug can be given safely -- which is the question the phase I study is asking.)

Some phase I studies will test new compounds that *appear* to have a unique potential to inhibit key drivers of the disease involved in resistance to standard therapies.  The preliminary science might suggests that this could help overcome treatment-resistant disease and this is your situation.

Historically, phase I studies uncommonly helped the patient directly. The purpose was to help advance clinical science. But as drug design is based increasingly on insights into the biology of tumors, the odds of benefiting in phase I studies is increasing. Some patients, for example, in the earliest phases of CART 19 studies apparently benefited from taking part.

Overall, the chance of benefiting in phase I studies is low 2, even if improving.  However, it should be noted that lymphoma and CLL (blood cell cancers) appear to have a greater intrinsic potential to be treated effectively with single agents -- even when at an advanced stage - compared to many other types of cancer.  Arguably, this improves the odds that lymphoma patients can benefit from a novel study approaches in safety studies.  

... It's also important to note that every approved therapy was first studied for safety, and that additional progress against lymphoma depends on participation in early-phase studies. 

Finally the risks and potential benefits from participation in a phase I study must be weighed against comfort care (palliative care) - which is given not to treat the lymphoma but to improve how we feel and our quality of life. Our performance, age, and general health also enters into the decision about study participation. 


How to decide?


It's very important to seek independent expert guidance on trial participation.  That we are eligible for a study is not in itself a reason to take part. When you consult a specialist, he or she will have first-hand information about your clinical circumstances, your treatment goals, your preferences, and also knowledge of available standard and investigational options.

For this reason, we provide the Trial Talk list below.

Trial Talk - experts to consult for second opinions and to inquire about clinical trials


Related Information

  1. Phase I lymphoma OR CLL studies- List Results - ClinicalTrials.gov
  2. Therapeutic Misconception, Misestimation and Optimism in Subjects Enrolled in Phase I Trials http://1.usa.gov/1VsjsPP
  3. Rethinking Risk-Benefit Assessment for Phase I Cancer Trials http://bit.ly/1jAyF5w
  4. JCO 2006 Patients' Decision-Making Process Regarding Participation in Phase I Oncology Research http://bit.ly/1KQJppi
  5. Getting the dose right  PAL
  6. Phase I trial, defined (NCI) cancer.gov/

    The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.
  7. Glossary of Related terms

    safety
    Monitoring - checking for negative activity of the study drug on a regular schedule
    Looking for signs of toxicity (from lab tests) and by patient reporting
    Some effects may be mild and temporary; others may last a long time or never go away. Some may be severe.
    (Reporting changes is important! The dose can be adjusted, or the symptoms managed with medications.)

    activity (can be positive and/or negative)
    = on target clinical activity is when the study drug binds to the desired cell target
    Both on and off-target binding of study drug can cause side effects
    (A drug can be active without efficacy! Such as when the target is not as important as it was hoped to be)

    efficacy
    = study drug leads to killing of tumor cells – a response
    (A drug can kill tumor cells without providing benefit!)

    benefit
    improved survival and/or quality of life
    (Study drug has efficacy. The killing of tumor cells is measurable, lasting. Positive effects outweigh side effects)

    endpoints
    how efficacy is measured in clinical trials
    (Overall response rate (ORR), complete response (CR) rate, improvement in progression free survival (PFS), improvement in overall survival (OS))

    surrogate endpoints
    measures that are not directly related to survival, but might predict improved survival
    (ORR, CR rate, PFS)

     




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