Lenalidomide is well tolerated in pediatric patients with CNS tumors at doses up to 116 mg/m2/d. The MTD was not established. The major toxicity observed in our study was myelosuppression, similar to the adult trials. There was no clear dose relationship with acute toxicity. However, long-term tolerability and toxicity may be dose limiting.
Previous investigational studies of lenalidomide have not clearly established a dose relationship with acute toxicity. Several of the early studies were performed in patients with bone marrow disease or in a population that was heavily pretreated, complicating the assessment of myelosuppression as a primary toxicity. In a phase I clinical trial of lenalidomide in patients with heavily pretreated multiple myeloma (including autologous stem-cell transplantation in 15 of 24 patients) treated for 28 days at doses of 5 to 50 mg/d, one patient treated at 10 mg/d had a DLT characterized by grade 3 leukopenia and neutropenia; no other DLTs were observed in the first course of therapy, including in 13 patients treated at 50 mg/d.24
However, 12 of 13 patients treated at 50 mg/d developed grade 3 or 4 myelosuppression after day 28. In a study of adult patients with advanced cancers, 20 heavily pretreated patients were enrolled and tolerated lenalidomide doses up to 50 mg/d.19
The majority of adverse events were classified as grade 1 or 2, and no serious adverse events were attributed to lenalidomide therapy. In a phase I trial of lenalidomide in adults with recurrent ovarian and primary peritoneal carcinoma, patients were treated with 25 mg/d for 21 days of a 28-day cycle.14
Twenty patients were enrolled and received 70 completed cycles of therapy. The majority of events were grade 1 or 2. No grade 4 toxicities were observed.
In a dose-escalation study of lenalidomide, adults with solid tumors (primarily melanoma and renal cell carcinoma) received daily lenalidomide doses of 5 to 150 mg/d.17
Adverse events, including myelosuppression, were not obviously related to dose. In a study of adults with refractory metastatic cancer, dosing for 21 of 28 days was better tolerated.22
Doses up to 35 mg/d (21 days on, 7 days off) were well tolerated, and the authors concluded that tolerability to myelosuppression may be better in patients without hematologic malignancies. In a phase I study in adults with recurrent high-grade gliomas,10
lenalidomide 40 mg/d for 21 days was well tolerated, and no MTD was defined. Myelosuppressive events consisted of one episode of grade 2 leukopenia at dose level 1 (2.5 mg/m2
/d for 21 days, with a 7-day rest) and one episode of grade 3 neutropenia at dose level 1.
A phase I study of lenalidomide was recently performed by the Children's Oncology Group in pediatric patients with relapsed or refractory solid tumors or myelodysplastic syndrome (ADVL0319).25
The primary objectives were to determine the MTD and recommended phase II dose for children with refractory solid tumors and describe the toxicities in this population. Doses up to 70 mg/m2
/d for 21 days followed by a 7-day rest were evaluated. Although six episodes of DLT were observed, they were sporadic and not clearly associated with dose. The MTD was not reached. The majority of patients on this study did not receive more than one course of therapy.
The disposition of lenalidomide in children was similar to that observed in adults.10,24
Absorption was relatively slow, with a time to maximum concentration ranging from 2 to 4 hours (1 to 4 hours in adults). In adults, the lenalidomide systemic exposure (AUC from time 0 to infinity) increased with dosage,10
but a relationship only up to 20 mg/m2
has been reported. In the present study, we observed a linear relationship between lenalidomide systemic exposure (AUC from time 0 to infinity) and lenalidomide actual dosage up to a dosage of 116 mg/m2
. Similarly, we observed a relationship with lenalidomide maximum concentration and actual dosage, which has been observed in adult studies. As with other oral drugs studied in children, we observed a wide range (approximately six-fold) in lenalidomide apparent oral clearance.
Early-phase clinical trials of noncytotoxic (eg, antiangiogenic) agents in patients with brain tumors are complicated by several issues. Conventional end points in phase I trials are defined by predetermined toxicity criteria to define an MTD or, more recently, by biologic end points to define a biologically effective dose. Standard phase I studies are designed to best identify acute, rather than long-term, toxicities. Antiangiogenic agents frequently have little acute toxicity and may need to be administered chronically. They may be effective at doses well below the MTD, and therefore, dose escalations to the MTD may be unnecessary. However, defining a biologically effective dose is difficult because there is a lack of validated biologic surrogate markers. In the case of lenalidomide, this is further complicated by the lack of complete understanding of its antitumor mechanisms.
There is preliminary evidence of activity of lenalidomide in this population, particularly in patients with progressive low-grade gliomas who had a 12-month PFS rate of 67% ± 13% on this study. Although this could be attributed to the inconsistent growth rates of these tumors, all patients had recurrent, refractory, or progressive disease at study entry, and this 12-month PFS rate compares favorably to other studies in this population.26
It is unclear whether this antitumor activity is dose related, although there is some suggestion that this is the case given that the two objective responses occurred at the higher dose levels (88 and 116 mg/m2
/d). The exact antitumor mechanism of action is unknown, although potential mechanisms have been identified, including induction of apoptotic signals27
and inhibition of angiogenesis.
In summary, lenalidomide is relatively well tolerated in pediatric patients with recurrent, refractory, and progressive CNS tumors at doses up to 116 mg/m2/d, particularly in the acute setting, although long-term toxicity may be limiting. No MTD was defined. As in adult studies, the primary toxicity was myelosuppression. Lenalidomide seems to have activity in this patient population. It is unclear whether toxicity and antitumor activity are dose related. Further trials of lenalidomide in the pediatric brain tumor population are planned.