Design of Early-Phase Trials
ABSTRACT The development of new agents for children with relapsed ALL represents a unique challenge. Given that attainment of remission
is a prerequisite for cure, and given that regimens composed of standard agent combinations remain effective in achieving
morphologic remission for many patients following relapse, treating physicians and investigators faced with a child in relapse
of ALL are understandably reluctant to turn to a new agent or combination of new agents with no proven efficacy. The poor
accrual to single-agent phase I studies of new agents in childhood ALL reflects this reluctance. Thus, the successful evaluation
of new agents against childhood ALL requires novel trial designs that take into account the desire of treating physicians
to utilize standard agents while simultaneously allowing for the demonstration of activity and the evaluation of toxicity
of the new drug(s) under study. Clinical trial designs that simultaneously allow for the attainment of both objectives have
been developed and are now in use in the Children’s Oncology Group.
- Journal of Clinical Oncology 09/2004; 22(16):3432-3. · 18.04 Impact Factor
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ABSTRACT: The Continual Reassessment Method (CRM) is a Bayesian phase I design whose purpose is to estimate the maximum tolerated dose of a drug that will be used in subsequent phase II and III studies. Its acceptance has been hindered by the greater duration of CRM designs compared to standard methods, as well as by concerns with excessive experimentation at high dosage levels, and with more frequent and severe toxicity. This paper presents the results of a simulation study in which one assigns more than one subject at a time to each dose level, and each dose increase is limited to one level. We show that these modifications address all of the most serious criticisms of the CRM, reducing the duration of the trial by 50-67 per cent, reducing toxicity incidence by 20-35 per cent, and lowering toxicity severity. These are achieved with minimal effects on accuracy. Most important, based on our experience at our institution, such modifications make the CRM acceptable to clinical investigators.Statistics in Medicine 07/1995; 14(11):1149-61. · 2.04 Impact Factor
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ABSTRACT: Despite improvements in the treatment of pediatric acute lymphoblastic leukemia, approximately one in five patients will develop recurrent disease. The majority of these patients do not survive. This limited institution study sought to improve event-free survival (EFS) by intensification of chemotherapy. Twenty-one patients with either an isolated marrow (n = 16) or a combined marrow and central nervous system relapse (n = 5) received treatment according to Children's Hospital of Philadelphia protocol CHP-540. Six patients had an initial remission of <36 months, and five patients had relapsed within 1 year of completion of phase III therapy. Induction and reinduction therapy consisted of idarubicin, vincristine, dexamethasone, asparaginase, and triple intrathecal chemotherapy. Consolidation and reconsolidation therapy employed high-dose cytarabine, etoposide, and asparaginase given in a sequential manner. Maintenance therapy included courses of high- or low-dose cytarabine followed by sequential etoposide and asparaginase pulse, moderate-dose methotrexate with delayed leukovorin rescue, and vincristine/dexamethasone pulses. Therapy continued for 2 years from the start of interim maintenance in the 16 patients who did not receive a bone marrow transplant (BMT). Two patients underwent an HLA-identical sibling BMT specified by protocol. Four received a nonprotocol-prescribed alternative donor BMT. The complete remission induction rate was 95%. With a median follow-up from date of relapse of 49 months in survivors, the actuarial EFS based on intent to treat is 75%. There were three toxic deaths in patients in CR and two deaths from relapse. This regimen is toxic but effective and deserves study in a larger setting.Medical and Pediatric Oncology 05/2000; 34(5):313-8.