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Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer

Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer

A number of molecularly targeted agents directed at
critical pathways involved in cell survival and cell proliferation have recently
entered clinical evaluation in children with cancer. These agents offer the
potential for more effective anticancer therapy while diminishing acute and
long-term toxic effects. Systematic evaluations of agents such as these are
essential if continuing improvements in outcome are to be achieved in children
with cancer. Brief summaries of the rationale for conducting studies of several
agents in children are provided below. Following these summaries is a listing of
phase I, phase I/II, phase II, and pilot studies of these agents in pediatric
populations.

Farnesyltransferase Inhibitors R115777 and SCH66336

Two farnesyltransferase inhibitors (FTIs) are in clinical evaluation in
children with cancer: R115777 (Janssen Pharmaceutica, Inc) and SCH66336
(Schering-Plough, Ltd). Although FTIs were initially developed to inhibit cancer
cell growth by blocking farnesylation of Ras and preventing its required
localization to the plasma membrane,[1,2] it is increasingly apparent that
inhibition of farnesylation of other proteins may contribute to the
growth-inhibitory effects of FTIs.[3,4] FTIs show in vitro activity against a
range of tumor cell lines.[2,4] The in vivo antitumor activity of FTIs
(including regression of some tumors) has been observed against a number of
tumor types, including Bcr-Abl-expressing leukemias,[5,6] glioma,[7]
pancreatic,[4,8] colorectal cancers,[4] and melanoma.[4]

R115777 is an orally administered FTI that has been studied in phase I trials
in adults and children.[9] Multiple schedules have been evaluated in adults, but
in children the primary schedule studied has been twice daily dosing for 21 days
every 4 weeks.[10] In the pediatric solid tumor phase I trial, the maximum
tolerated dose was 200 mg/m2, and dose-limiting toxicities at higher doses
included grade 4 neutropenia, grade 3/4 thrombocytopenia, grade 3 rash,
hypofibrinogenemia, vomiting, and diarrhea.[10]

R115777 was studied in a phase I trial in adults with refractory and relapsed
leukemia using the twice-daily-for-21-days schedule.[11] Dose-limiting toxicity
occurred at 1,200 mg bid with central neurotoxicity evidenced by ataxia,
confusion, and dysarthria. Clinical responses occurred in 10 (29%) of the 34
evaluable patients, including 2 complete remissions. R115777 also induced
responses in adult patients with chronic myelogenous leukemia (CML)[12] and
myelodysplastic syndrome.[13]

SCH66336 has been studied in phase I trials in adults using a variety of
schedules.[9] For continuous daily oral administration, the recommended phase II
dosage in adults is 200 mg bid,[14] with higher doses causing
myelosuppression and neurotoxicity (confusion and disorientation). For both
R115777 and SCH66336, inhibition of protein farnesylation has been demonstrated
at doses with tolerable toxicity.[10,11,15]

R115777 is under evaluation in children with juvenile myelomonocytic leukemia
(AAML0122). Aberrant regulation of the Ras pathway, either by Ras-activating
mutations[16] or by inactivating mutations of neurofibromin,[17] is
characteristic of some cases of juvenile myelomonocytic leukemia. Supporting
evaluation of an FTI against juvenile myelomonocytic leukemia is the observation
that cells of this disease cultured in vitro show greater sensitivity to
FTI-mediated growth inhibition than do normal myeloid precursor cells.[18] On
the other hand, an FTI produced no apparent antileukemic effect in a transgenic
murine model of juvenile myelomonocytic leukemia based on homozygous
neurofibromin deletion.[19] R115777 is also being evaluated in a phase I trial
in children with acute leukemias (1930/ADVL0116), based in part on its activity
in adults with acute leukemia.[11]

The Pediatric Brain Tumor Consortium is conducting a phase I evaluation of
SCH66336 in children with brain tumors (PBTC-003). The rationale for this study
includes the significant antiproliferative effects of FTIs against human
malignant glioma cells[20,21] and the in vivo antitumor activity of FTIs against
human glioma xenograft models.[7,21]

FTIs are of interest for patients with neurofibromatosis 1 because mutations
in neurofibromin lead to increased Ras signaling.[22,23] The potential
applications of FTIs in this patient population include treatment of plexiform
neurofibromas [24] and neurofibromatosis 1-associated malignancies.[25] A
trial of R115777 in children and adults with plexiform neurofibromas is ongoing
(T99-0090).

Imatinib Mesylate (Gleevec)

Imatinib mesylate (STI571, Gleevec [Novartis]) is the first rationally
designed molecularly targeted agent approved for a cancer indication. The drug
potently inhibits several tyrosine kinases, including c-Abl, c-Kit,
platelet-derived growth factor (PDGF) receptor, and the p210Bcr-Abl and
P190Bcr-Abl
fusion proteins associated with Philadelphia chromosome (Ph)-positive
leukemias.[26,27] Imatinib inhibits the growth of cells expressing the
Bcr-Abl fusion protein[26] and induces apoptosis of Bcr-Abl-positive
cells,[26] showing activity both in vitro[26,28,29] and in vivo.[26,30]

These preclinical observations have been replicated clinically, with high
levels of antitumor activity observed for patients with chronic phase CML
refractory to or intolerant of interferon-alpha.[31] Single-agent activity was
also observed against Ph-positive acute lymphocytic leukemia (ALL) and
Ph-positive CML in blast crisis, although the response rates were lower and the
duration of response relatively short compared to those achieved against
chronic-phase CML.[32] Imatinib is very active against the gastrointestinal
stromal tumor, which is associated with activating mutations of the c-Kit
receptor.[33,34]

Bcr-Abl expression inhibits the apoptosis induced by cytotoxic agents,[35-39]
and this Bcr-Abl-driven chemoresistance is likely a major cause of the poor
survival rate of patients with Ph-positive leukemia treated with conventional
chemotherapy agents. Inhibition of Bcr-Abl can reverse drug resistance,[40] and
imatinib has been shown to potentiate the activity of cytotoxic agents against
Bcr-Abl-expressing cells.[41,42] The concept of combining imatinib with known
active agents is an important one, because resistance to imatinib as a single
agent can develop by multiple mechanisms, including overexpression of the
Bcr-Abl fusion protein and mutation of the Bcr-Abl gene.[43-45]

A pediatric phase I study of imatinib in children with Ph-positive leukemia
(P9973) has been reported.[46] Imatinib was well tolerated, and its antileukemic
activity in children was similar to that seen in adults. Building upon this
phase I experience, a phase II trial of imatinib in children with CML who are
refractory to or intolerant of interferon-alpha is being conducted (AAML0123).
Given the relatively poor prognosis of children with Ph-positive ALL, a high
priority of research in childhood ALL is to define ways in which imatinib can
potentiate the effect of conventional chemotherapy. The AALL0031 pilot study
combines imatinib in 14-day treatment courses with the different chemotherapy
blocks used to treat childhood ALL. Recent results from studies in adults with
Ph-positive ALL support the feasibility of combining imatinib with the intensive
chemotherapy regimens used to treat Ph-positive ALL.[47]

Imatinib is also being evaluated in a phase II study in children with
selected solid tumors (ADVL0122), based on its ability to inhibit the stem cell
factor/c-Kit pathway and the PDGF/PDGF-receptor pathway. For example, the PDGF
ligand and receptor have been detected in various pediatric cancers including
osteosarcoma,[48,49] desmoplastic small round-cell tumor,[50, 51] and synovial
cell sarcoma.[52] PDGF-C, which also binds to the PDGF-alpha and -beta
receptors,[53] has recently been described as a downstream target of
deregulation in EWS-FLI1 transformed cells.[54] c-Kit expression has been noted
in Ewing’s Sarcoma,[55] neuroblastoma,[56] and synovial cell sarcoma.[57]

The Pediatric Brain Tumor Consortium is conducting a phase I study of
imatinib in children with high-grade gliomas (PBTC-006). The rationale
supporting this study includes the in vivo activity of the drug against
intracranially implanted brain tumor xenograft models,[58] the expression of the
PDGF receptor in a substantial proportion of high-grade gliomas,[59] and the
ability of imatinib to inhibit PDGF-receptor activation in brain tissue in
preclinical models.[60]

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