Larry H Bernstein, MD, FCAP
Pharmaceutical Intelligence
UPDATED 4/23/2020: New Design for Phase 1 pediatric oncology trials to expedite dose escalation studies.
Clinical Trials Revisited
http://pharmaceuticalintelligence.com/2013/04/03/clinical-trials-revisit/
Cancer Clinical Trials of Tomorrow
Advances in genomics and cancer biology will alter the design of human cancer studies
Smaller, more precise trials ahead
New challenges
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UPDATED 4/23/2020: New Design for Phase 1 pediatric oncology trials to expedite dose escalation studies.
REVIEW
Ushering in the next generation of precision trials for pediatric cancer
Steven G. DuBois, Laura B. Corson, Kimberly Stegmaier, Katherine A. Janeway
Science 15 Mar 2019:Vol. 363, Issue 6432, pp. 1175-1181 DOI: 10.1126/science.aaw4153
Abstract
Cancer treatment decisions are increasingly based on the genomic profile of the patient’s tumor, a strategy called “precision oncology.” Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.
Some terms from the bibliography:
3+3 design: A commonly used rule-based design for phase 1 clinical trials in which patients are enrolled in cohorts of three patients, and decisions to increase or decrease the dose level for the next three participants are based on toxicities observed in those three patients.
Basket trial: A precision oncology trial design in which patients with many different cancer types are enrolled, the tumor is tested for a set of biomarkers of interest, and then patients are assigned to one of several clinical trial subprotocols based on the presence of a biomarker corresponding to a particular molecularly targeted therapy.
Bayesian model–based trial designs: A broad class of trial designs that use data known before the trial as well as data obtained during the conduct of the trial to adapt trial parameters as more information becomes available
Continual reassessment method: One example of a Bayesian model–based trial design in which an initial mathematical model of the relationship between drug dose and probability of unacceptable toxicity is continually updated as new information becomes available to assign subsequent patients to a dose anticipated to have an unacceptable toxicity rate below a set rate.
First-in-child trial: The first clinical trial of a specific agent to include a pediatric population, traditionally considered patients <18 years of age.
Rolling 6 design: A variation of the 3+3 design in which up to six participants may be enrolled to a dosing cohort before enrollment pauses to assess toxicity.
Safety run-in: An initial component of a phase 2 or phase 3 trial in which a small group of patients are treated with a previously untested regimen to evaluate toxicity before opening the trial to a larger group of participants.
Umbrella trial: A precision oncology trial design in which patients with a specific cancer type are enrolled, tumor is tested for a set of biomarkers of interest, and then patients are assigned to one of several clinical trial subprotocols based on the presence of a biomarker corresponding to a particular molecularly targeted therapy.
In this review article, DuBois et al describe new paradigms for pediatric precision oncology trial design and how these designs should be contrasted with the old models and differentiate from the design for these types of trials in the adult. As the genomic landscape of pediatric tumors is becoming clearer (1, 2) the authors noticed two themes which are becoming evident:
- Pediatric cancers harbor certain genomic mutations rarely seen in adult cancers
- Pediatric cancers share some genomic alterations and mutational gene signatures with adult tumors
However there is only a small number of pediatric clinical trials to investigate if specific genetic mutations predict outcome to a given personalized therapy.
Thus, there an urgent need for precision clinical trials in pediatric cancers.
Several reviews have described numerous ongoing and recently completed trials however most are phase 1 dose escalation trials including basket trials and umbrella trials but based on previous data from adult trials using the same precision drug. For example, pediatric trials involving the TRK inhibitor laratrectinib in tumors harboring a NTRK fusion gene or a pediatric crizotinib trial for pediatric glioblastomas having an ALK fusion protein have shown great success yet most of the early phase 1 work was based on adults or carried out in a way that does not take advantage of the new regulatory framework designed to expedite new drugs for adult precision medicines.
Speeding up the early phase trials in pediatric cancers: new trial design paradigms
Dose escalation phase I trials have, traditionally been the starting point for clinical development of new pediatric anticancer drugs however these first in child trials have seriously lagged their adult counterparts by many years. These trials relied on the standard 3 x 3 or rolling six trial design, and doses escalated until a pediatric MTD (maximum tolerated dose) was achieved. In recent years new precision medicine pediatric trial design has been adopted to expedite the process, based on the fundamental shift in thinking that many new oncology agents will not have a true MTD when tested in adults.
Doses in phase 1 trials for targeted therapies like those in precision medicine are usually escalated based on considerations other than toxicity, like pharmacodynamics or biomarker analysis. A pediatric phase 1 dose escalation trial may require more subjects than an adult trial. But
although these newer approaches to early-phase trial design more efficiently establish a pediatric dose, they do little to advance our understanding of with patients are most likely to benefit from a new therapy.
Thus the need for good biomarkers to be included early on in these initial trial designs. For example, Dana Farber’s first in child clinical trial NCT03654716, a Phase 1 Study of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer (as a possible treatment for resistant (refractory) solid tumor, brain tumor, lymphoma or leukemia), are reducing the time children are waiting for entry into a trial, as unselected patients can enroll and the biomarker, increased MDM2 expression is used to determine those patients who go on to phase 2 dose escalation. In other cases, such as NCI Children’s Oncology Group basket trials, they have completely supplanted formal phase 1 trial design and instead incorporated molecularly targeted therapies based on adult doses but adjusted for patient size. The use of combinations with traditional therapies in trial design is also helping to speed up the process for enrollment. The authors also suggest that tumor profiling is pertinent however should be put in trial design so the costs to patients can be covered by the trial funds.
Figure 1Fig. 1 Evolution of precision trials for pediatric cancer.
Illustration: Kellie Holoski/Science
Source: Ushering in the next generation of precision trials for pediatric cancer BY STEVEN G. DUBOIS, LAURA B. CORSON, KIMBERLY STEGMAIER, KATHERINE A. JANEWAY SCIENCE 15 MAR 2019 : 1175-1181 https://science.sciencemag.org/content/363/6432/1175
- S. N. Gröbner, B. C. Worst, J. Weischenfeldt, I. Buchhalter, K. Kleinheinz, V. A. Rudneva, P. D. Johann, G. P. Balasubramanian, M. Segura-Wang, S. Brabetz, S. Bender, B. Hutter, D. Sturm, E. Pfaff, D. Hübschmann, G. Zipprich, M. Heinold, J. Eils, C. Lawerenz, S. Erkek, S. Lambo, S. Waszak, C. Blattmann, A. Borkhardt, M. Kuhlen, A. Eggert, S. Fulda, M. Gessler, J. Wegert, R. Kappler, D. Baumhoer, S. Burdach, R. Kirschner-Schwabe, U. Kontny, A. E. Kulozik, D. Lohmann, S. Hettmer, C. Eckert, S. Bielack, M. Nathrath, C. Niemeyer, G. H. Richter, J. Schulte, R. Siebert, F. Westermann, J. J. Molenaar, G. Vassal, H. Witt, B. Burkhardt, C. P. Kratz, O. Witt, C. M. van Tilburg, C. M. Kramm, G. Fleischhack, U. Dirksen, S. Rutkowski, M. Frühwald, K. von Hoff, S. Wolf, T. Klingebiel, E. Koscielniak, P. Landgraf, J. Koster, A. C. Resnick, J. Zhang, Y. Liu, X. Zhou, A. J. Waanders, D. A. Zwijnenburg, P. Raman, B. Brors, U. D. Weber, P. A. Northcott, K. W. Pajtler, M. Kool, R. M. Piro, J. O. Korbel, M. Schlesner, R. Eils, D. T. W. Jones, P. Lichter, L. Chavez, M. Zapatka, S. M. Pfister, ICGC PedBrain-Seq Project, ICGC MMML-Seq Project, The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). 10.1038/nature25480pmid:29489754
2. X. Ma, Y. Liu, Y. Liu, L. B. Alexandrov, M. N. Edmonson, C. Gawad, X. Zhou, Y. Li, M. C. Rusch, J. Easton, R. Huether, V. Gonzalez-Pena, M. R. Wilkinson, L. C. Hermida, S. Davis, E. Sioson, S. Pounds, X. Cao, R. E. Ries, Z. Wang, X. Chen, L. Dong, S. J. Diskin, M. A. Smith, J. M. Guidry Auvil, P. S. Meltzer, C. C. Lau, E. J. Perlman, J. M. Maris, S. Meshinchi, S. P. Hunger, D. S. Gerhard, J. Zhang, Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555, 371–376 (2018). 10.1038/nature25795pmid:29489755
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