Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer

A number of molecularly targeted agents directed atcritical pathways involved in cell survival and cell proliferation have recentlyentered clinical evaluation in children with cancer. These agents offer thepotential for more effective anticancer therapy while diminishing acute andlong-term toxic effects. Systematic evaluations of agents such as these areessential if continuing improvements in outcome are to be achieved in childrenwith cancer. Brief summaries of the rationale for conducting studies of severalagents in children are provided below. Following these summaries is a listing ofphase I, phase I/II, phase II, and pilot studies of these agents in pediatricpopulations.

Farnesyltransferase Inhibitors R115777 and SCH66336

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

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to current clinical trials of molecularly targeted agents for children with cancer.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at www.cancer.gov/cancer_information/pdq/, or contact the Cancer Information Service offices (1-800-4-CANCER).

R115777 is an orally administered FTI that has been studied in phase I trialsin adults and children.[9] Multiple schedules have been evaluated in adults, butin children the primary schedule studied has been twice daily dosing for 21 daysevery 4 weeks.[10] In the pediatric solid tumor phase I trial, the maximumtolerated dose was 200 mg/m2, and dose-limiting toxicities at higher dosesincluded 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 relapsedleukemia using the twice-daily-for-21-days schedule.[11] Dose-limiting toxicityoccurred at 1,200 mg bid with central neurotoxicity evidenced by ataxia,confusion, and dysarthria. Clinical responses occurred in 10 (29%) of the 34evaluable patients, including 2 complete remissions. R115777 also inducedresponses in adult patients with chronic myelogenous leukemia (CML)[12] andmyelodysplastic syndrome.[13]

SCH66336 has been studied in phase I trials in adults using a variety ofschedules.[9] For continuous daily oral administration, the recommended phase IIdosage in adults is 200 mg bid,[14] with higher doses causingmyelosuppression and neurotoxicity (confusion and disorientation). For bothR115777 and SCH66336, inhibition of protein farnesylation has been demonstratedat 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-activatingmutations[16] or by inactivating mutations of neurofibromin,[17] ischaracteristic of some cases of juvenile myelomonocytic leukemia. Supportingevaluation of an FTI against juvenile myelomonocytic leukemia is the observationthat cells of this disease cultured in vitro show greater sensitivity toFTI-mediated growth inhibition than do normal myeloid precursor cells.[18] Onthe other hand, an FTI produced no apparent antileukemic effect in a transgenicmurine model of juvenile myelomonocytic leukemia based on homozygousneurofibromin deletion.[19] R115777 is also being evaluated in a phase I trialin children with acute leukemias (1930/ADVL0116), based in part on its activityin adults with acute leukemia.[11]

The Pediatric Brain Tumor Consortium is conducting a phase I evaluation ofSCH66336 in children with brain tumors (PBTC-003). The rationale for this studyincludes the significant antiproliferative effects of FTIs against humanmalignant glioma cells[20,21] and the in vivo antitumor activity of FTIs againsthuman glioma xenograft models.[7,21]

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

Imatinib Mesylate (Gleevec)

Imatinib mesylate (STI571, Gleevec [Novartis]) is the first rationallydesigned molecularly targeted agent approved for a cancer indication. The drugpotently inhibits several tyrosine kinases, including c-Abl, c-Kit,platelet-derived growth factor (PDGF) receptor, and the p210^Bcr-Abl andP190^Bcr-Abl
fusion proteins associated with Philadelphia chromosome (Ph)-positiveleukemias.[26,27] Imatinib inhibits the growth of cells expressing the
Bcr-Abl fusion protein[26] and induces apoptosis of Bcr-Abl-positivecells,[26] showing activity both in vitro[26,28,29] and in vivo.[26,30]

These preclinical observations have been replicated clinically, with highlevels of antitumor activity observed for patients with chronic phase CMLrefractory to or intolerant of interferon-alpha.[31] Single-agent activity wasalso observed against Ph-positive acute lymphocytic leukemia (ALL) andPh-positive CML in blast crisis, although the response rates were lower and theduration of response relatively short compared to those achieved againstchronic-phase CML.[32] Imatinib is very active against the gastrointestinalstromal tumor, which is associated with activating mutations of the c-Kitreceptor.[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 poorsurvival rate of patients with Ph-positive leukemia treated with conventionalchemotherapy agents. Inhibition of Bcr-Abl can reverse drug resistance,[40] andimatinib has been shown to potentiate the activity of cytotoxic agents againstBcr-Abl-expressing cells.[41,42] The concept of combining imatinib with knownactive agents is an important one, because resistance to imatinib as a singleagent can develop by multiple mechanisms, including overexpression of theBcr-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 antileukemicactivity in children was similar to that seen in adults. Building upon thisphase I experience, a phase II trial of imatinib in children with CML who arerefractory to or intolerant of interferon-alpha is being conducted (AAML0123).Given the relatively poor prognosis of children with Ph-positive ALL, a highpriority of research in childhood ALL is to define ways in which imatinib canpotentiate the effect of conventional chemotherapy. The AALL0031 pilot studycombines imatinib in 14-day treatment courses with the different chemotherapyblocks used to treat childhood ALL. Recent results from studies in adults withPh-positive ALL support the feasibility of combining imatinib with the intensivechemotherapy regimens used to treat Ph-positive ALL.[47]

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

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

Proteasome Inhibitor PS-341

PS-341 (also known as LDP-341 or MLN-341), a dipeptidyl boronic acid derivative, is apotent proteasome inhibitor.[61,62] PS-341 induces apoptosis in vitro atnanomolar concentrations in a variety of cancer types, including some leukemiacell lines[63,64] and multiple myeloma cells.[65] It is active in vivo as asingle agent against multiple myeloma, prostate, and lung cancer xenograftmodels and is also active against murine squamous cell carcinoma models.[66,67]It enhances the cytotoxic activity of conventional anticancer agents[68-71]and radiation.[68,72] The basis of the antitumor activity of PS-341 and of itsability to enhance the activity of other anticancer treatments may result fromits ability to inhibit nuclear factor (NF)-kappaB activation.[67,69] Otherpotentially relevant biological activities include stabilization of p53, p21^WAF/CIP-1, andp27^KIP1, inhibition of angiogenesis, and overcoming bcl-2protective functions.[63,67,73-76]

PS-341 has been evaluated in several different schedules, including twiceweekly dosing for 2 weeks (with 1 week’s rest), twice weekly dosing for 4weeks (2 weeks’ rest), twice weekly dosing every other week, and weekly dosingfor 4 weeks (2 weeks’ rest). The recommended phase II dose for these scheduleshas ranged from 1.3 to 1.7 mg/m2.[77] Toxicities that limited dose escalationincluded painful neurosensory toxicity, diarrhea, and fatigue.[77] In phase Istudies, antitumor activity was observed against multiple myeloma, prostatecancer, non-small cell lung cancer, and non-Hodgkin lymphoma.[77-79] A phase IItrial of PS-341 (1.3 mg/m2 per dose twice weekly ´ 2 weeks every 3 weeks) inpatients with multiple myeloma produced high response rates (approximately 50%)in a heavily pretreated population.[80]

A pediatric phase I trial of PS-341 in children with solid tumors is ongoing(ADVL0015). The rationale for evaluating PS-341 in children primarily rests ondata from experiments using other proteasome inhibitors against pediatric tumorsand on data concerning the expression of the NF-kappaB pathway in pediatriccancers. The proteasome inhibitor lactacystin induced differentiation of amurine neuroblastoma cell line (Neu 2A),[81] blocked cell-cycle progression ofhuman osteosarcoma cells in vitro,[81] and induced apoptosis in a Ewing’sSarcoma cell line.[82] A peptidyl aldehyde proteasome inhibitor administered asa single dose induced tumor regression in a murine model of human Burkitt’sLymphoma.[83] The NF-kappaB pathway is activated in leukemia cells from childrenwith ALL[84] and in Reed-Sternberg cells from patients with Hodgkin disease.[85]in the latter setting, NF-kappaB inhibition is sufficient to induceapoptosis.[85,86]

Phase II

Title: Phase II Study of R115777, Isotretinoin, Cytarabine, andFludarabine Followed by Allogeneic Bone Marrow or Umbilical Cord BloodTransplantation in Children With Newly Diagnosed Juvenile MyelomonocyticLeukemia
Protocol Number: COG-AAML0122
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Imatinib Mesylate in Patients WithPhiladelphia Chromosome Positive Chronic Phase Chronic Myelogenous Leukemia
Protocol Number: COG-AAML0123
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Imatinib Mesylate in Patients With Relapsedor Refractory Pediatric Solid Tumors
Protocol Number: COG-ADVL0122
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Randomized Study of R115777 in Pediatric Patients WithNeurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Protocol Number: NCI-01-C-0222A, NCI-T99-0090
Participating Institutions: National Cancer Institute Pediatric OncologyBranch
Contact: Brigitte C. Widemann, (301) 496-7387; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Phase I/II

Title: A Phase I/II Trial of STI571 in Children With Newly Diagnosed PoorPrognosis Brainstem Gliomas and Recurrent Intracranial Malignant Gliomas
Protocol Number: PBTC-006
Participating Institutions: Pediatric Brain Tumor Consortium
Contact: Ian F. Pollack, (412) 692-5881

Phase I

Title: Phase I Study of R115777 in Pediatric Patients With RefractoryLeukemia
Protocol Number: COG-ADVL0116, NCI-01-C-0196, NCI-1930
Participating Institutions: National Cancer Institute Pediatric OncologyBranch, Children’s Oncology Group
Contact: Brigitte C. Widemann, (301) 496-7387; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I Study of PS-341 in Pediatric Patients With AdvancedSolid Tumors
Protocol Number: COG-ADVL0015
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I Study of SCH 66336 in Children With Recurrent orProgressive Brain Tumors
Protocol Number: PBTC-003
Participating Institutions: Pediatric Brain Tumor Consortium
Contact: Mark W. Kieran, (617) 632-4907; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Pilot Studies

Title: Phase II Pilot Study of Intensified Chemotherapy With orWithout Allogeneic Hematopoietic Stem Cell Transplantation in Children With VeryHigh-Risk Acute Lymphoblastic Leukemia
Protocol Number: COG-AALL0031
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:http://www.cancer.gov/clinical_trials/

Title: Intensive Induction Therapy for Children With Acute LymphoblasticLeukemia Who Experience a Bone Marrow Relapse
Protocol Number: AALL01P2
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116

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