A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence 6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers.

A male infant was diagnosed prenatally with a partial ornithine transcarbamylase (OTC) gene deletion and managed from birth. However, he displayed neurological abnormalities and developed pleural effusions, ascites and anasarca not solely explained by OTC deficiency (OTCD). Further evaluation of the gene locus using exon-specific PCR and high density SNP array copy number analysis revealed a 3.9Mb deletion from Xp11.4 to Xp21.1 including five additional gene deletions, three causing the known genetic diseases: Retinitis pigmentosa (RP3), X-linked chronic granulomatous disease (CGD) and McLeod syndrome. The case illustrates (1) the complexities of managing a patient withneonatal onset OTCD, CGD, RP3 and McLeod syndrome, (2) the need for detailed evaluation in seemingly "isolated" gene deletions and (3) the clinical utility of high density copy number analysis for rapidly characterizing chromosomal lesions.

Phase I clinical trials play a crucial role in development of therapeutics for cancer patients. During phase I clinical trials common toxicities are delineated, dose limiting toxicities (DLT) are determined and a dose for phase II studies is recommended. However, reviews of the phase I population indicate a younger group of participants with a median age of 50-55. No data exists on the performance of octogenarians on phase I trials. Concerns for enrollment of this patient population, relates to presence of comorbidities and possibly altered pharmacokinetics in the setting of unknown potential toxicities. We present herein the largest review of octogenarians on phase I trials. Twenty-two octogenarian patients with a median age of 83 were enrolled on phase I clinical trials. More than 50% of them were chemotherapy-naïve most likely indicative of the fact that treating physicians believed standard therapy to be potentially toxic to this population. These 22 patients were otherwise matched in terms of performance status and other parameters to a control group of participants < 80. This includes a similar number of cycles administered. Patients ≥80 had a 3 fold higher rate of achieving DLT (p=0.06) compared to the control group enrolled at the same dose level. The toxicities observed include cardiovascular, gastrointestinal and infectious complications. Three patients were enrolled on molecular targeted treatments with no significant toxicities. We conclude that enrollment of patients ≥80 on phase I trials of chemotherapy agents is most likely associated with higher risk of DLT.

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