Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer, Part 2

Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer, Part 2

A number of molecularly targeted agents directed at
critical cell survival and cell proliferation pathways have recently entered
clinical evaluation in children with cancer. These agents offer the potential
for more effective anticancer therapy while simultaneously diminishing acute and
long-term toxic effects. Systematic evaluations of targeted agents are essential
to achieving continued improvements in outcome for 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 and other agents in pediatric


G3139 (bcl-2 antisense, Genasense) is an 18-mer phosphorothioate
oligonucleotide antisense molecule that binds to the first six codons of human
bcl-2 mRNA and reduces expression of the bcl-2 gene by preventing translation
and production of the encoded protein.[1] By reducing levels of bcl-2 protein,
G3139 increases the activation of the apoptotic pathway in response to various
stimuli such as chemotherapy, irradiation, or other DNA-damaging events. Tumor
xenograft models have demonstrated single-agent activity of G3139 against
follicular lymphoma cell lines[1] and against a neuroendocrine malignancy (ie,
Merkel cell carcinoma).[2] In xenograft models in which G3139 was tested in
combination with chemotherapy, enhanced antitumor activity was observed for
cyclophosphamide (Cytoxan, Neosar) against non-Hodgkin lymphoma,[3] for
dacarabazine (DTIC-Dome) against melanoma,[4] and for cisplatin against gastric

G3139 has been studied in adults with cancer, both as a single agent[6] and
in combination with chemotherapy.[7,8] Because antisense-mediated
down-regulation of bcl-2 levels requires several days, G3139 is administered
intravenously as a single agent for 4 to 7 days prior to the initiation of

G3139 has been generally well tolerated, and serum levels in excess of those
associated with bcl-2 down-regulation and potentiation of chemotherapy have been
achieved. Combinations of G3139 with chemotherapy have not produced substantial
increases in toxicity compared to those expected for chemotherapy alone.
Down-regulation of bcl-2 in peripheral blood mononuclear cells and in tumor
cells has been observed in adult studies.[6,8]

G3139 may eventually have utility against several pediatric cancers in which
bcl-2 may be associated with treatment resistance, including
neuroblastoma,[9,10] synovial sarcoma,[11,12] acute lymphoblastic
leukemia,[13,14] and acute myeloid leukemia.[15,16] G3139 is being evaluated in
combination with doxorubicin and cyclophosphamide in a pediatric solid tumor
phase I study (ADVL0211) that should begin enrollment in the first quarter of


ZD1839 (Iressa) is an orally available agent that selectively inhibits the
tyrosine kinase activity of the epidermal growth factor receptor (EGFr).[17]
ZD1839 inhibits ligand-induced EGFr autophosphorylation, leading generally to a
cytostatic effect.[17] In preclinical models, oral dosing occasionally causes
tumor regression but more generally causes growth inhibition of EGFr-expressing
tumor xenografts.[18,19] The antitumor activity of a variety of conventional
chemotherapeutic agents can be potentiated when combined with ZD1839.[18,19]

Phase I trials of ZD1839 demonstrated that the agent is well tolerated at
doses that suppress EGFr phosphorylation in surrogate tissues.[20] When ZD1839
is administered daily, the most common toxicities observed are grade 1/2
diarrhea and a distinctive acneiform skin rash.[17] The pharmacokinetics of
ZD1839 justify administration on a once-daily schedule. ZD1839 has induced
responses in patients with colorectal, ovarian, non-small-cell lung cancer,
head and neck, renal, and hormone-resistant prostate cancers.[17,21,22] It has
been safely combined with several conventional chemotherapy agents, including
cisplatin/gemcitabine (Gemzar)[23] and fluorouracil/leucovorin.[24] Another EGFr
inhibitor, cetuximab (IMC-C225, Erbitux) has been safely administered in
combination with cisplatin,[25,26] irinotecan (CPT-11, Camptosar),[27] and
radiation therapy,[28] further supporting the feasibility of combining this
class of agent with conventional anticancer treatments.

The expression of EGFr in neuroblastoma,[29,30] rhabdomyosarcoma,[29,31]
osteosarcoma,[32] and glioma[33] provides the rationale for studying ZD1839 in
children. A pediatric phase I trial of ZD1839 (ADVL0016) in children with solid
tumors is scheduled to begin in the first quarter of 2002. For children with
high-grade gliomas (either supratentorial or brainstem), the Pediatric Brain
Tumor Consortium is conducting a phase I study of ZD1839 in combination with
radiation therapy (PBTC-007).


Rituximab (Rituxan) is a mouse/human chimeric antibody that targets the CD20
antigen, which is present exclusively on B cells (pre-B and mature B
lymphocytes) and on most B-cell lymphomas.[34,35] Rituximab kills cells via
several mechanisms, including antibody-dependent cellular toxicity, activation
of the complement cascade,[36,37] and modulation of signaling pathways leading
to apoptosis.[38,39] In preclinical models, rituximab enhances the activity of
chemotherapy agents.[40-43]

Rituximab was first shown to be active against low-grade or follicular
non-Hodgkin lymphoma[44] and was subsequently found to be active against diffuse
large-cell lymphoma.[45] Toxicities attributed to rituximab are generally mild
and most often associated with the first infusion. An acute tumor lysis
syndrome, likely related to cytokine release, has occurred in patients with high
circulating lymphocyte count or large tumor burden.[46-48] Rituximab has been
safely combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicin
HCl, vincristine [Oncovin], prednisone),[49,50] with no substantial increase in
toxicity above that associated with the CHOP regimen alone.

A randomized trial in elderly adults with diffuse large-cell lymphoma
comparing CHOP to CHOP plus rituximab demonstrated significantly higher
event-free survival and survival rates in patients receiving rituximab plus
chemotherapy.[51] Rituximab has also be been safely combined with an intensive
chemotherapy regimen used to treat Burkitt lymphoma.[52]

Among the lymphomas that occur in children, diffuse large-cell lymphoma and
Burkitt lymphoma both express high levels of CD20.[53-57] Rituximab induces
apoptosis in Burkitt lymphoma cell lines,[38,39] and anti-CD20 monoclonal
antibodies are active in a Burkitt lymphoma xenograft model.[58] There are
anecdotal reports of children with recurrent Burkitt lymphoma[59] and children
with post-transplant lymphoproliferative disease responding to rituximab.[60]

A Children’s Oncology Group pilot study (ANHL01P1) combining rituximab with
standard chemotherapy agents in children with newly diagnosed Burkitt lymphoma
and diffuse large-cell lymphoma should begin accrual in the second quarter of
2002. A second Children’s Oncology Group study (ANHL0121) will combine
rituximab with ICE (ifosfamide [Ifex], carboplatin [Paraplatin], etoposide) in
children with recurrent Burkitt lymphoma and diffuse large-cell lymphoma.
Rituximab plus ICE chemotherapy has shown substantial activity in adults with
recurrent high-grade B-cell lymphomas.[61] The ANHL0121 study should open in the
third quarter of 2002.


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