walking our talk – the road from the laboratory to phase I clinical trials

The following post is written by Dr. Michael Jensen, Director of the Ben Towne Center for Childhood Cancer Research. Here, Dr. Jensen carefully lays out in layman’s terms the path research takes from the lab to clinical trials. Currently the Center is conducting a FDA approved phase I trial for relapsed acute lymphoblastic leukemia. In the months and years to come there will be similar trials running concurrently for neuroblastoma, brain tumors and sarcomas. It is a difficult and bold task, as Dr. Jensen attests to here, but we continue to believe that we can and will change the way all childhood cancers are treated and cured. 

Walking Our Talk– The Road from the Laboratory to Phase I Clinical Trials

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We have arrived at that pivotal moment. 

When the carefully designed experiments in the research laboratory were completed and the PLAT-01 trial got the green light from the FDA, a deep collective breath was taken by our Ben Towne Center for Childhood Cancer Research team — now the hard work begins.

What lies ahead is the real world application of our laboratory research to the very serious circumstances of children, sick and fragile children with relapsed leukemia. As with all new therapies, the work in the clinic begins with a Phase I study. A Phase I trial by its very nature is a first step evaluation of how a new therapy will be tolerated in patients. It is the initial stage of a multi-phased process wherein the safety of a new type of treatment is established. For researchers at the BTCCCR, to have our efforts come to this juncture is both exhilarating but also nerve racking.

I liken it to what the Apollo lunar landing team must have felt (in the pit of their collective stomachs) when the hatch was opened and Neil Armstrong descended to the moon’s surface. Will the space suit protect the human inside in the harsh extremes of space? Will the safety systems and plans for emergencies hold up when attempted on the moon? Phase I trials are much the same within the microcosm of a patient’s body. 

Phase I oncology trials are often reserved for those patients who have exhausted all the established forms of treatment. These patients are often the very same children who have accumulated the most side-effects from prior rounds of surgery, chemotherapy and radiation. The fragility of their body’s life support systems makes our patients particularly susceptible to side effects caused by experimental new treatments. This is the “risk-benefit” balance when it comes to clinical trials at their earliest stages, when neither the potential for positive results, nor the risk of potentially severe toxicities are known.

For our PLAT-01 (PLAT stands for Pediatric Leukemia Adoptive Therapy) trial, headed by Dr. Rebecca Gardner and spearheaded by Dr. Julie Park’s Phase I clinical trials team at Seattle Children’s Hospital, the new medicine is reprogrammed T cells which we isolate from a blood sample from the patient. We genetically modify and grow each patient’s T cells to several billion cells in number over the course of two-three weeks. The genetic modification is a key step as the reprogrammed T cells are engineered to make an artificial receptor that binds to the CD19 molecule present on the surface of cancerous B cells of acute lymphoblastic leukemia, the most common form of cancer the afflicts children. One key assessment to be made in the conduct of the PLAT-01 trial is to determine how often we are successful in manufacturing a patient’s reprogrammed T cells.

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Phase I trials are designed to first expose the initial groups of patients (referred to as cohorts) to very small doses of a new medicine. As the trial proceeds, higher and higher doses are given to subsequent cohorts of patients (the cohorts are typically three patients in size). This established methodology of starting with very low doses then sequentially treating groups of patients with higher and higher doses is based on identifying significant side-effects–  if this can be accomplished when the side effect is not full blown based on the patient receiving a small dose, then we have done our job to push the risk-benefit equation in favor of our patients. Based on carefully designed “stopping rules” the trial continues until unwanted side effects are observed. Then the “maximal tolerated dose” is established and the Phase I trial has achieved its primary goal.  Knowing the maximal tolerated dose (referred to in oncologist’s jargon as the “MTD”) is the starting point for being able to commence with larger Phase II trials that ask the question, “When patients are treated at the MTD does the therapy result in anti-tumor responses? If so are the responses complete and lasting?”

In many ways, the Phase I trial is the most challenging stage of translational research (i.e. research to apply advances in laboratory research to the treatment of patients in the clinic). While in the initial stages of a Phase I trial the outcomes are likely to be disappointing as patients treated in early cohorts who receive small doses of T cells may not show beneficial effects (have the leukemia go in to remission). At later stages we might encounter significant side effects in some of our treated patients. This is the hard road forward and I try my best to prepare my research team for the roller coaster-like sequence of events that are to come.  

This blog is my opportunity to prepare you too. As supporters of our work, I can imagine that you want us to make the jump from the test tube directly to having this new form of therapy be a cure without complications. In reality, to get to that objective we must march through the clinical trials process. This is when the going gets tough and there will be setbacks and hopefully bright spots in the months to come for our patients who participate on these trials. Where I think we are heading is a much better understanding of what will work well and what we need to do back in the lab to make the therapy as reliable and safe as possible. If we do our work well, we will gain valuable insights in how to apply this new immunotherapy safely to children with advanced relapsed leukemia.

We feel a palpable sense of urgency. Yes we are impatient, but the careful stepwise testing of our T cell therapies in clinical trials at Seattle Children’s Hospital is paramount to maximizing both the safety of our patients and achieving our goal of making this new immunotherapy emerge from clinical testing as safe, effective, and available to children everywhere. So, we are on this journey with all of you, our Ben Towne Foundation supporters — together, I am confident we will get to that time and place we all want to be: a cure for all children diagnosed with acute lymphoblastic leukemia.