Michaele C. Christian, M.D., Associate Director

The Cancer Therapy Evaluation Program (CTEP) improves the lives of cancer patients by finding better ways to treat, control, and cure cancer. CTEP funds an extensive national program of cancer research and sponsors clinical trials to evaluate new anticancer agents, with an emphasis on translational research to elucidate molecular targets and drug-effect mechanisms. CTEP forges broad collaborations in the research community and works extensively with the pharmaceutical/biotechnology industry to develop new cancer treatments. CTEP also seeks to involve outside experts and patients or their advocates in formulating research priorities. In choosing clinical research for National Cancer Institute (NCI) sponsorship, CTEP attempts to fill critical gaps in the national cancer research effort and avoid duplicating private-sector efforts. Active new anticancer agents are made available to patients as rapidly and widely as possible.

GRANTS

Epithelial Ovarian Cancer Program Project
A grant at Memorial Sloan-Kettering Cancer Center funded one of two laboratories that cloned the cDNA that encodes the core peptide of CA125, a substance shed by cancer cells. Dr. Kenneth Lloyd's laboratory accomplished this work at the Sloan-Kettering Institute for Cancer Research (SKICR). For two decades, serum CA125 has been used to monitor the response to chemotherapy and recurrence of ovary cancer patients. Dr. Lloyd's group and Dr. Timothy O'Brien's group in Little Rock used different but complementary approaches to partially clone CA125. Dr. Lloyd used a rabbit polyclonal antiserum prepared against native CA125 to screen a cDNA library from human OVCAR-3 ovary cancer cells expressed in E. coli. The gene that encodes CA125 is MUC16. Northern blot analysis demonstrated that the level of MUC16 mRNA corresponded to CA125 expression in a panel of cell lines. Transfection of a partial MUC16 cDNA into CA125-negative ovary cancer cell lines showed CA125 synthesis by three different assays. Work of the Little Rock group confirmed and extended Dr. Lloyd's findings. Improved CA125 assays or novel therapies may extend these findings to the clinic.

Breast Cancer Stem-Cell Discovery May Lead to New Therapies
NCI-supported principal investigators at the University of Michigan Medical School--Drs. Michael Clarke, Sean Morrison, Muhammad Al-Hajj, and Max Wicha--have discovered the existence of cancer stem cells in human breast cancer tissue. Breast tumors comprise diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, Dr. Clarke's team found that only a minority of breast cancer cells could form new tumors. The researchers were able to distinguish tumorigenic (tumor initiating) from non-tumorigenic cancer cells based on cell-surface protein or marker expression. Fluorescent sorting identified tumorigenic cells. Dr. Clarke and colleagues called these tumorigenic cells cancer stem cells because they could self-replicate and differentiate into other phenotype populations and form tumors. The work was published in the Proceedings of the National Academy of Sciences in March 2003.

This finding is significant because cancer stem cells have never been found in solid tumors, although similar cells have been identified in human leukemia. Current drug therapies, developed to kill as many cells in the tumor as possible, may target the majority phenotype (non-tumorigenic cells). This may result in tumor regression but does not lead to complete cures. To be effective, new therapies must target the cancer stem-cell population. Identifying breast cancer stem cells should allow molecular characterization of these cells and elucidation of pathways that account for their tumorigenic potential and drug resistance. This could open a new frontier for targeted drug development, revolutionize breast cancer therapies, and bring new cures to thousands of cancer patients with tumorigenic metastases.

New Approaches to Surgical Oncology
Dr. Donald Morton and colleagues at the John Wayne Cancer Institute in Santa Monica, CA, completed accrual on a major phase III trial on selective lymphadenectomy. This is a clinical study of wide excision alone versus wide excision with intraoperative lymphatic mapping and selective lymph node dissection (sentinel node concept) in treating patients with cutaneous invasive melanoma. The multicenter selective lymphadenectomy trial (MSLT) enrolled 2001 patients and is the largest randomized surgical study of melanoma. Results from this trial should change clinical practice.

Management of patients with primary cutaneous melanoma and clinically normal regional lymph nodes has been controversial for more than 100 years, since Snow first advocated routine elective lymph node dissection in patients with primary melanoma. Such dissection is based on the concept that melanoma cells from the primary site spread first to nodes in the regional nodal basin, where they establish micrometastases that later metastasize to distant sites. By histopathological study, however, only 20% of patients have micrometastases in the regional nodes and could benefit from complete lymph node dissection. Thus, five radical lymphadenectomies would be required to potentially benefit one patient.

Dr. Morton and colleagues decided to develop methods to determine which patients had metastases in the regional nodes and perform complete lymph node dissection only in those patients. This approach would expose only patients with micrometastases in their regional nodes to a surgical procedure with postoperative complications such as nerve dysfunction, pain, and limb swelling. Dr. Morton hypothesized that lymphatic metastasis is an orderly sequential process in which lymph from the cutaneous site of a primary melanoma drains first to one or two nodes (sentinel nodes) in the regional lymphatic basin. Because metastasis should reach the sentinel nodes before reaching other nodes in the lymphatic basin, the pathologic status of the sentinel node should predict the status of the entire lymphatic basin.

Preoperative identification of the regional lymphatic drainage basin by cutaneous lymphoscintigraphy and intraoperative identification of sentinel nodes in that basin by injecting blue dye, alone or with a radiocolloid, allowed Dr. Morton to devise a minimally invasive operation for determining the tumor status of clinically normal regional lymph nodes. The phase III clinical trial mentioned above tests this concept of sentinel nodes as predicting pathologic status of the lymphatic basin. Although the trial has finished accrual, survival data has not been unblinded to the investigators. The only data available pertains to the accuracy of the sentinel node detection technique, which was comparable to the accuracy of the technique performed by surgeons at other cancer centers. This indicates that the technique can be disseminated to the surgical community.

The sentinel node concept is being tested in clinical trials in other solid tumors and organ sites, including skin, breast, oral pharynx, lung, stomach, pancreas, colon, thyroid, and vulva. The impact on patient care in the U.S. potentially will be great. For the 53,600 cases per year of melanoma, 60%-80% will be sentinel node negative, sparing about 34,000 patients with intermediate-thickness melanoma from lymph node dissection. For the 203,500 cases per year of breast cancer, 63% will be sentinel node negative, sparing 128,000 patients from lymph node dissection. For the 148,300 cases per year of colorectal cancer, 14% will have a change in their operative plans and 10%-20% will have improved lymphatic staging sensitivity.

Chronic Lymphocytic Leukemia (CLL)
The CLL Research Consortium is making progress in the genetics, biochemistry, immunobiology, pharmacology, and clinical studies of this disease. Several new proto-oncogenes overexpressed in CLL have been identified. One of these genes, Tcl1, was placed under the control of a B cell promoter/enhancer in transgenic mice. The mice developed oligoclonal and then monoclonal expansions of CD5 B cells that share biologic, immunologic, and pathophysiologic characteristics with CLL in humans. The mouse CLL model may allow investigators to study disease pathogenesis and perform preclinical evaluation of novel therapeutics in vivo.

Studies of biochemical mechanisms that lead to drug resistance of leukemia cells to apoptosis have resulted in the identification of targets for novel therapeutic approaches. The compound 2-cyano-3, 12, dioxoolean1,9-dien-28-oic acid (CDDO) sensitizes CLL B cells to apoptosis. Several novel histone deacetylase inhibitors have been identified that activate expression of genes encoding anti-apoptotic proteins. Tubulin undergoes rapid turnover in leukemic cells. Interference with this turnover by agents can induce the release of several newly identified proteins that turn on apoptotic pathways in the leukemia cell. While this may explain the clinical activity of such agents as vincristine, it also permits identification of novel compounds such as indanocine that should have a higher therapeutic index in treating CLL patients.

Nurse-like cells that protect leukemia cells from spontaneous or drug-induced apoptosis in vitro have been isolated. These cells differentiate from hematopoietic cells when in contact with CLL cells and are present at increased numbers in CLL patients. This may account for CLL-cell resistance to drugs or biologics in vivo. A recent finding suggests that anti-CD20 mAb rituximab has synergistic activity with glucocorticoids in inducing CLL cell apoptosis only in the presence of these nurse-like cells. This interaction thus represents a novel target for therapeutic intervention. Preliminary data indicate the important role of chemokine stromal-derived factor-1 and alpha-4 integrins in this interaction.

Inhibitors of integrin interaction or stromal-derived factor-1 or its receptor CXCR4 impair the ability of nurse-like cells to sustain CLL viability in vitro. New combination therapy with drugs (nelarabine, fludarabine) and biologics (rituximab, Hu1D10) are under development.

PARTNERSHIPS AND COLLABORATIONS

Connecting for Health, a public-private collaboration supported by the Markle Foundation, partnered with governmental and non-governmental agencies to develop standards for electronically communicating medical information. As part of this group, the Clinical Investigations Branch staff championed the Common Data Elements (CDE) model developed with the Center for Bioinformatics, and the Foundation adopted this format.

CTEP is working with the Cancer Diagnosis Program (CDP) on tissue banking support and policies to promote integration of biomarker evaluation, molecular profiling, and translational research in the clinical protocols of the Cooperative Groups, and integrating Director's Challenge projects with other Cooperative Groups projects. Also with CDP, CTEP is working with the Program for the Assessment of Clinical Cancer Tests (PACCT) Strategy projects, including a joint initiative to develop a prospective, large clinical trial to test new biomarkers as prognostic indicators of the value of adjuvant chemotherapy for women with node-negative, hormone-receptor-positive breast cancer.

CTEP developed a partnership with staff from the Center for Cancer Research, the Children's Oncology Group (COG) Phase I Consortium, and the COG Biopathology and Translational Research Committee to develop tissue and cell arrays and protein arrays of a panel of childhood cancer xenografts representing the most common childhood cancers. Arrays from the project, the Pediatric Oncology Preclinical Protein-Tissue Array Project (POPP-TAP) will provide a resource for studying molecular targets and cell signaling profiles to facilitate pediatric cancer drug development. More than 90 xenograft lines developed by childhood cancer researchers have been identified, and these will be processed into tissue and protein arrays in the laboratory of Stephen Hewitt, M.D., PhD., of the Tissue Array Research Program, a collaboration between NCI and the National Human Genome Research Institute. Arrays will be available to qualified intra- and extramural investigators who will work to identify the presence and activation status of cancer-related molecular targets and signaling pathways. Gene expression analyses will be performed for the POPP-TAP xenografts in the laboratories of Javed Kahn, M.D., (Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research) and Timothy Triche, M.D. (COG Biopathology and Translational Research Committee).

CTEP fostered the development of a collaboration between GOG and MRC on GOG 182/ ICON 5. Trial is now open at 35 sites in UK, as well as GOG, SWOG, and CTSU sites in US, Canada, and Australia. Accrual to date: 2000 of planned 4000.

CRADA and CTA: CTEP maintains agreements for the performance of non-clinical and clinical research with more than 80 pharmaceutical collaborators partners. This year, CTEP signed 34 new Clinical Trials Agreements (CTA) and 4 new Cooperative Research and Development Agreements (CRADA); currently CTEP maintains CRADAs/CTAs with 76 collaborators. Regular (usually quarterly) meetings are held between CTEP staff, pharmaceutical collaborators, and academic investigators. These meetings: 1) ensure that complementary development plans are made to hasten the availability of effective treatments to patients with many different types of cancer, 2) provide an opportunity to discuss progress on both industry and CTEP sponsored trials, and 3) provide an opportunity to review non-clinical advances and plan their appropriate implementation in clinical trials.

CLINICAL TRIALS RESULTS

Breast cancer

A U.S. Intergroup trial used a 2x2 factorial design to assess the relation of two factors of dose density and sequence of agents and the potential interaction between the two factors with disease-free survival (DFS) and overall survival. Two thousand and five female volunteers with auxiliary node-positive adenocarcinoma of the breast were randomized postoperatively in a 2x2 factorial design to one of four treatment regimens: (I) sequential A x 4_T x 4_C x 4 with doses every three weeks, (II) sequential A x 4_T x 4_C x 4 every two weeks, (III) concurrent AC x 4_T x 4 every three weeks, and (IV) concurrent AC x 4_T x 4 every two weeks. Filgrastim was given to permit retreatment on schedule in dose-dense regimens (II, IV). The three-year overall survival was 92% for dose-dense regimens versus 90% for every-three-weeks regimens; four-year DFS was 82% for dose-dense regimens and 75% for every-three-weeks regimens. With approximately 70,000 women in the U.S. diagnosed annually with node-positive breast cancer, application of dose-dense therapy could mean that 1400 more women a year might be alive three years after diagnosis, and 5000 more a year might be free of disease four years after diagnosis.

Reference 1. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. Journal of Clinical Oncology 2003;21:1431-9.

A U.S. Intergroup trial randomized 1477 postmenopausal, receptor-positive, node-positive women to either tamoxifen (T) for five years (361 patients), oral cyclophosphamide Adriamycin (CAF) plus T for five years started concurrently with CAF (CAFT) (563 patients), or (CAF) plus T for five years (CAF-T) (550 patients) started after the completion of all chemotherapy. The absolute improvement in disease-free survival from CAFT at five years was 9% (76% vs. 67%). After the first four years of follow up, survival curves diverged, with CAFT superior to T. The adjusted T/CAFT hazard was 1.29 (1.04-1.59). At five years, there was a 5% absolute survival benefit from CAFT (84% vs. 79%) that persisted at eight years. Eight-year disease-free survival estimates were 67% for CAF-T, 62% for CAFT, and 55% for T alone. CAF-T was superior to CAFT for disease-free survival but not for survival, with a median follow up of eight and a half years. Administration of tamoxifen following adjuvant chemotherapy should result in about 3500 more women free of disease eight years postdiagnosis annually.

Reference Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100 (SWOG-8814). Proceedings of the American Society of Clinical Oncology 2002;21(Suppl 1):37a (Abstract 143).

In a U.S. Intergroup trial, 3170 patients were randomized in a 3 x 2 factorial design ito C (600 mg/m2 ) plus A (60, 75, or 90 mg/m2 ) plus G-CSF q 3 wks x 4 followed by no T (AC) or by T (175 mg/m2 ) q 3 wks x 4 (AC + T). Tamoxifen 20 mg daily for 5 yrs was then offered to patients with ER positive tumors. While the dose escalation of doxorubicin results in no additional benefit, the addition of paclitaxel for four cycles improved DFS and S. With approximately 70,000 women diagnosed annually with node-positive breast cancer in the U.S., the addition of paclitaxel should result in about 1500 more women alive five years after diagnosis each year.

Reference Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology 2003;21(6):976-83.

Colorectal carcinoma

Investigators from the North Central Cancer Treatment Group (NCCTG), led by Drs. Richard Goldberg and Daniel Sargeant, and supported by Percy Ivy, M.D., of CTEP's Investigational Drug Branch and Richard Kaplan, M.D., of the Clinical Investigations Branch, developed a treatment protocol for advanced and metastatic colorectal cancer (CRC). The study was designed to examine six promising early clinical phase II trial results in which limited clinical experience and toxicity data were available. An early warning system was implemented by the NCCTG coordinating group to detect excessive adverse events or early death within 60 days of initiating therapy. Despite much doubt in the cooperative group community that such a complex trial could be successful, the study was stopped early by the data safety monitoring board in April 2002 because one arm was significantly advantageous. This trial established the role of FOLFOX4 combination (oxaliplatin + fluorouracil and leucovorin) in first line therapy of advanced colorectal cancer, adding about four and a half months of survival for more than 60,000 patients a year compared to the prior standard therapy. Time to progression, response rate, and adverse events profiles were improved. The study was an intergroup trial involving accrual from NCCTG, the Cancer and Leukemia Group B (CALGB), the Southwest Oncology Group, the Eastern Cooperative Oncology Group, and the National Cancer Institute of Canada, with agent and expert consultation from CTEP, Sanofi-Synthelabo, and Pharmacia. Immediately following the announcement of the results of this trial, CTEP made oxaliplatin available to the public throughout the U.S. via a Treatment Referral Center trial until the agent was approved by the Food and Drug Administration (FDA). The FDA approved oxaliplatin for second-line use in 2002, making it widely available in the U.S. Sanofi-Synthelabo's application for approval for first-line use is under fast-track FDA review.

Gastrointestinal tumors (GIST)

Investigators in the cooperative groups, led by Dr. George Demetri, in collaboration with Drs. Anthony Murgo and Scott Saxman in CTEP, prepared, activated and completed accrual of more than 700 patients completing accrual in September 2001, to a trial of imatinib mesylate in patients with advanced GIST, a disease for which there has previously been no useful therapy. In Feb. 2002, the FDA granted accelerated approval for Gleevec (imatinib; STI571) in the treatment of patients with metastatic or unresectable GIST based on an objective tumor shrinkage rate of about 50%, substantially higher than the less than five percent rate achievable with available standard chemotherapy in a small phase II trial. The large cooperative group trial comparing treatment with 400 and 800 mg daily of imatinib represents the phase IV requirement for this accelerated approval by the FDA, and represents acollaboration between the cooperative group investigators, CTEP, and Novartis Pharmaceuticals. Gleevec's antitumor activity against GIST is attributed to its ability to inhibit kit, the molecular abnormality responsible for the growth of this relatively rare sarcoma. Tumors with mutations of c-kit are more likely to respond than those without such mutations. Gleevec is the first molecularly targeted drug to be approved by the FDA for the treatment of GIST or any other type of sarcoma. Preliminary results of this trial were presented at the American Society of Clinical Oncology annual meeting in May 2003. These results suggest that the response rates and event-free survival rates for the lower dose of Gleevec are as effective as the higher dose.

Reference Benjamin RS, Rankin C, Fletcher C, Blanke C, von Mehren M, Maki R, et al. Phase III dose-randomized study of imatinib mesylate (ST1571) for GIST: Intergroup S0033 early results. Proc. Amer. Soc Clin Oncol 22, Abstr#3271, 2003.

Myelodysplastic syndrome

Lewis Silverman, M.D., and colleagues developed a CTEP-sponsored phase III trial of the investigational agent 5-azacytidine in patients with myelodysplastic syndrome (MDS). This agent is a nucleoside analog in clinical development by the NCI/Division of Cancer Treatment and Diagnosis. MDS is a heterogeneous disorder of blood-forming cells. MDS patients are at risk of developing anemia and requiring transfusions, bleeding due to low platelet counts, and contracting serious infections due to abnormal production of white blood cells. In some patients, MDS transforms to acute leukemia. The study randomly assigned 191 MDS patients to receive either subcutaneous injections of 5-azacytidine or standard supportive care alone. Treatment with 5-azacytidine resulted in significantly higher rates of improved blood counts and quality of life, and reduced risk of transformation to acute leukemia. The CTEP staff, led by Anthony Murgo, M.D., of the Investigational Drug Branch, has ensured the availability of this investigational agent to patients via a compassionate-release program. The FDA is reviewing patient outcomes as part of an assessment of the new drug application for this agent.

References 1. Kornblith AB, Herndon JE II, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: A Cancer and Leukemia Group B study. Journal of Clinical Oncology 2002;18(12):2441-52. 2. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. Journal of Clinical Oncology 2002;18(12):2429-40. 3. Kantarjian HM. Treatment of myelodysplastic syndrome: Questions raised by the azacitidine experience. Journal of Clinical Oncology. 2002;18(12):2415-6.

Non-small-cell lung cancer

A Radiation Therapy Oncology Group trial demonstrated that concurrent chemoradiotherapy is superior to the same therapy given sequentially for patients with locally advanced non-small-cell lung cancer. These results have implications for such patients and for the design of future clinical trials investigating new therapeutic agents given in conjunction with radiation therapy.

Combination chemotherapy has become the standard of care for patients with advanced non-small cell lung cancer and has been shown in multiple trials to improve survival. However, there is still controversy about whether combination chemotherapy is superior to a single agent. To study this, the CALGB conducted a phase III randomized trial of carboplatin and paclitaxel vs. paclitaxel alone in patients with selected advanced non-small-cell lung cancer. This trial demonstrated that the combination was superior. The study provided confirmatory evidence that combination chemotherapy significantly improves survival compared to single-agent therapy, and showed that elderly and poor-performance-status patients have greater benefit with combination therapy. Future studies will incorporate molecularly targeted therapy into combination chemotherapy regimens.

Elderly patients with non-small-cell lung cancer are often judged ineligible for aggressive chemotherapy because they are perceived as having worse toxicity and inferior survival than younger patients. EGOC conducted an analysis of the effect of age on toxicity and survival that demonstrated that response, toxicity, and survival are similar in young and elderly patients with good performance status. The investigators determined that advanced age alone should not preclude patients from receiving appropriate therapy or from participating in clinical trials.

Pediatric cancers

Children with standard-risk acute lymphoblastic leukemia (ALL) have overall favorable outcomes, with five-year event-free survival rates of 75%-80%. Intrathecal and maintenance therapy are key components of successful therapy. Researchers from the Children's Cancer Group, now part of COG, conducted a study that used a factorial design to ask two important therapeutic questions about these therapy components. The study compared intrathecal methotrexate (ITM) to intrathecal triples therapy (ITT = methotrexate, hydrocortisone, and cytarabine), and oral 6-mercaptopurine (6MP) to oral thioguanine (TG). The study determined that the five-year event-free survival rate was 85% for TG and 77% for MP, and that bone marrow (BM) isolated CNS, and testicular relapses were significantly reduced with TG. However, patients receiving TG had higher rates of VOD toxicities and portal hypertension, which complicates the incorporation of TG into standard ALL therapy. Further studies are needed to identify how to safely add TG for improved outcome. For the intrathecal therapy comparison, the incidence of isolated central nervous system relapse was significantly lower for ITT than for ITM. BM relapses occurred significantly more often with ITT than with ITM, however, and event-free survival was similar at five years. For the intrathecal therapy question, the exchange of fewer isolated central nervous system relapses for more frequent BM relapses with ITT supports the concept that isolated central nervous system relapses does not occur in isolation. An intervention like ITT, directed only at the central nervous system, may prevent such relapse without affecting ultimate event-free survival.

References 1. Lindemulder S, Sather H, Gaynon PS, La M, Yanofsky R, et al. Isolated central nervous system (CNS) relapse in children with standard risk (SR) ALL: Results CCG-1952. Blood 100 [11],36a.2002. 2. Stork LC, Sather H, Hutchinson RJ, Broxson EH, Matloub Y, Yanofsky R, et al. Comparison of Mercaptopurine (MP) with Thioguanine (TG) and IT Methotrexate (ITM) with IT "Triples" (ITT) in children with SR-ALL. Results of CCG-1952. Blood 100[11]156a, 2002.

Renal cancer

More than half of renal cell carcinoma (RCC) patients have a mutation in the Von hippel-Lindau gene that causes overproduction of VEGF, a growth factor for cancer. This makes VEGF overproduction in such patients potential targets for novel agents that inhibit the ability of VEGF to support tumor growth. James Yang, M.D., in the NCI intramural program, in collaboration with CTEP and Genentech, Inc. (South San Francisco, CA) initiated a trial to examine the efficacy of an anti-angiogenic strategy (anti-VEGF monoclonal antibody, bevacizumab) in metastatic RCC. The double-blinded placebo-controlled study randomized 116 patients to three arms: high-dose bevacizumab, low-dose bevacizumab, and placebo. The results indicated that high-dose bevacizumab significantly prolonged the time to disease progression. Tumor shrinkage was also observed in 10% of patients on the high-dose arm. Because the study was not designed to detect survival benefit and most patients on the placebo arm crossed over to bevacizumab upon disease progression, difference in overall survival was not observed.

CLINICAL TRIALS DEVELOPED

Gastrointestinal tumors (GIST)

Based on promising phase II data with Gleevec in GIST, an investigator meeting was organized to develop a phase III study in this patient population. The study was designed to answer an important scientific dose-related question and will insure that patients with this otherwise untreatable disease can receive the drug prior to FDA approval.

Pediatric cancers

Three pediatric evaluations were initiated with the molecularly targeted agent Gleevec, which has been shown to effectively treat adults with chronic myeloid leukemia (CML) and GIST. One study is the first evaluation of Gleevec for children with newly diagnosed Philadelphia chromosome-positive (Ph+) ALL. Ph+ ALL is one of the most difficult types of ALL to treat. This study combines Gleevec with standard chemotherapy agents used to treat ALL, and builds on promising laboratory studies showing that Gleevec enhances the antileukemic activity of these standard agents. A second study is evaluating Gleevec in children with CML. Gleevec has been shown to be superior to previously used agents for treating adults with CML. This study will determine whether Gleevec is well tolerated and has high activity for children with CML. Gleevec is being tested in a third study to determine whether its preclinical activity against several solid tumors can be translated to the clinic. Targeted tumors include Ewing's sarcoma, osteosarcoma, and neuroblastoma.

A study for children with acute myelogenous leukemia (AML) evaluates the monoclonal antibody Mylotarg™ (gemtuzumab ozogamicin), which recognizes and delivers a toxin to leukemia cells. It has been approved for treating adults with recurrent AML. The study will determine whether Mylotarg can be combined with standard chemotherapy agents used to treat childhood AML. If so, Mylotarg will be tested in newly diagnosed children to determine whether it increases survival rates.

A randomized clinical trial is determining how best to administer the chemotherapy drug irinotecan to children with rhabdomyosarcoma. Irinotecan is one of the most active agents in mouse models of rhabdomyosarcoma. Identifying the best way to administer this agent for the treatment of rhabdomyosarcoma may lead to improved outcomes for children with this cancer.

The COG Phase 1/Pilot Consortium includes a subset of COG institutions that are responsible for expeditiously developing and implementing pediatric phase I and pilot studies to facilitate the integration into childhood cancer treatment of advances in cancer biology and therapy. After the Consortium evaluates the safety of the new agents, they will be studied in the larger group of COG institutions to determine their role in treating specific childhood cancers. In 2002, the Consortium opened the first studies for five new agents that target novel cancer cell components. Clinical trials were initiated by the COG Phase 1/Pilot Consortium for the following new agents: Genasense™, an antisense drug that decreases the activity of the cancer-protecting Bcl-2 protein; depsipeptide, an inhibitor of histone deacetylase, an enzyme that helps control gene expression; decitabine, an inhibitor of DNA methylation that can activate genes repressed in cancer cells; Zevalin™, a monoclonal antibody that targets radiation to lymphoma cells; and Iressa™, an inhibitor of the epidermal growth factor receptor.

The Pediatric Brain Tumor Consortium (PBTC) conducts phase I and II clinical evaluations of new therapeutic drugs, intrathecal (injected into the spine) agents, delivery technologies, biological therapies, and radiation treatment strategies in children with brain tumors. The PBTC includes 10 leading academic institutions with extensive experience in designing and conducting childhood cancer clinical trials for children with brain tumors. New treatment approaches evaluated by the PBTC can be studied by COG in definitive clinical trials designed to show whether the treatments are beneficial. The PBTC initiated accrual to five new studies in 2002, including: The first pediatric study of convection-enhanced delivery in malignant glial tumors using the novel biological IL13/pseudomonas exotoxin conjugate. The first pediatric study using local BCNU delivery (Gliadel®) in combination with systemically administered O6BG to reverse O6-alkylguanine-DNA alkyltransferase-mediated nitrosourea resistance. An evaluation of Iressa as an antitumor agent and a putative radiosensitizing agent for children with newly diagnosed brain stem glioma and supratentorial malignant gliomas. An evaluation of O6-benzylguanine (O6BG) as a biomodulator of O6-alkylating-agent resistance. In this study, oral temozolomide is administered with continuous infusion O6BG in children with recurrent central nervous system tumors. A phase II evaluation of oxaliplatin, an agent that may be active against childhood brain tumors and causes less hearing loss than currently used agents.

Renal cancer

New Approaches to Neuroblastoma Therapy (NANT) is a consortium of university and children's hospitals funded by the NCI to test promising new therapies for neuroblastoma. NANT members are a group of closely collaborating investigators linked with laboratory programs that are developing novel therapies for high-risk neuroblastoma. In late 2002 and early 2003, the NANT consortium initiated a phase I study of high-dose pyrazoloacridine supported with autologous hematopoietic stem cell rescue in children with recurrent or resistant neuroblastoma, and a phase I study of IL-12 with pulse IL-2 in the same high-risk neuroblastoma population.

Following up on data with non-myeloablative transplantation in patients with metastatic RCC generated by Richard Childs, M.D., National Heart Lung and Blood Institute (NHLBI), a group of investigators was convened to develop a collaborative intergroup study that will further define the toxicity and benefit of this approach for patients. This meeting resulted in the development of an Intergroup study that was activated in October 2001.

Based on this promising results for the metastatic RCC trial conducted by NCI and Genentech (mentioned above), CTEP has planned a large phase III study collaboration with investigators from the CALGB, the National Cancer Institute of Canada, and the phase II N01 CTEP contract to test the survival benefit of bevacizumab as a single agent or in combination with standard therapy with interferon alpha for metastatic RCC. This study will open to accrual in the third quarter of calendar year 2003.

Renal or hepatic injury

Percy Ivy, M.D. and collaborators developed an efficient mechanism for establishing the dose and safety of novel agents in patients who have renal or hepatic injury. The effort, a collaboration among investigators supported by CTEP, the FDA, Theradex Systems, Inc. (Princeton, NJ), and industry sponsors that include Sanofi-Synthelabo, Inc. (Malvern, PA), Millennium Pharmaceuticals, Inc. (Cambridge, MA), has permitted us to identify safe and effective doses of novel agents for this rare group of patients, for whom treatment recommendations often have not been available until long after agents were FDA approved.

Cancer cell pathways

Development of novel therapeutics addressing specific pathways in the cancer cell and its surrounding stroma has made the early evaluation of novel agent combinations critical to the efficient introduction of new potential treatments. Many of these agents alone can only slow tumor growth, whereas in the laboratory combinations may actually halt tumor growth or produce shrinkage in tumor models. Some agents now being evaluated are critical modulators of drug action and will have little, if any, activity on their own. Traditionally, pharmaceutical companies have been reluctant to combine investigational agents, avoiding the risk of confusing toxicities and complex intellectual property issues. Sherry Ansher, Ph.D., and Dale Shoemaker, Ph.D., in the Regulatory Affairs Branch, developed language included in CTEP's clinical trials agreements that so far has been acceptable to 10 corporate sponsors, facilitating the evaluation of agent combinations in eight trials to date. Although there are no final outcomes yet from the trials, this substantially improves the ability of investigators to evaluate novel combinations in the laboratory and the clinic.

TARGETED INITIATIVES

Blood and Marrow Transplant Clinical Trials Network (BMTCTN)
The BMTCTN, cofunded by NCI and NHLBI, was established in October 2001 to conduct large multi-institutional clinical trials. Their first phase III clinical trial is a randomized double-blind trial of fluconazole vs. voriconazole for preventing invasive fungal infections in allogeneic blood and marrow transplant patients. The protocol development team involved the staff of NCI, NHLBI, and National Institute of Allergy and Infectious Diseases (NIAID), principal investigators from 16 Network clinical centers, staff from the Network's central operations office (composed of the International Bone Marrow Transplant Registry/Autologous Bone and Marrow Transplant Registry, the National Marrow Donor Program, and the EMMES Corp.), a patient advocate, and a representative of transplant investigators at large. This trial will determine which of the two Pfizer drugs is more efficacious and will use a recently approved clinical assay for aspergillus (galactomannan assay) developed by BioRad Laboratories, Inc. (Hercules, CA). A total of 600 patients will be accrued (300 in each arm) over three years. The objective is to compare the study arms' fungal-free survival rates. Secondary objectives will be to compare the frequency of invasive fungal infection, time to invasive fungal infection, survival rate, duration of amphotericin B therapy for possible invasive fungal infection, time to neutrophil and platelet engraftment, time to and severity of acute and chronic graft-versus host disease, and the galactomannan assay's utility in detecting aspergillus. The relative safety of the two antifungals will also be assessed by collecting adverse events and routinely monitoring laboratories. The trial's multidisciplinary nature demonstrates the collaborative nature of the study and the coordination required to manage the Network.

A second phase III trial comparing nonmyeloablative allogeneic transplant to autologous transplant in multiple myeloma patients is being reviewed by the NHLBI Protocol Review Committee and the NHLBI Data and Safety Monitoring Board. The trial should be activated in 2003. Several NCI-funded clinical trials cooperative groups have expressed interest in joining this trial.

WORKSHOPS/MEETINGS

Common Data Elements (CDE)
CTEP organized meetings in 2002 with COG investigators to develop CDE for pediatric cancers. This effort complements ongoing efforts by CTEP to establish CDE for adult cancers and is an essential activity for facilitating protocol development and data sharing by different clinical trials groups. Pediatric CDE for neuroblastoma, acute lymphoblastic leukemia, acute myeloid leukemia, and Wilms' tumor have been developed. For tumors that occur in adults and children (e.g., brain tumors, sarcomas, and lymphomas), pediatric representation was included in the panels created to develop CDE for these diagnoses that will apply to pediatric and adult clinical trials.

Pediatric Preclinical Testing Program (PPTP)
CTEP, in collaboration with the Developmental Therapeutics Program and COG, is establishing the PPTP to develop data in pediatric preclinical models on the activity of new anticancer agents to help clinical researchers select new agents that are most likely to be effective for specific types of childhood cancers. As an initial step, CTEP organized a meeting of experts in preclinical drug testing to identify essential characteristics of a drug-testing program for pediatric preclinical models. This June 2002 meeting culminated in a published meeting report [1]. Building on the findings of that meeting, CTEP staff developed a concept proposal for the PPTP that was presented in 2002 to the NCI Board of Scientific Advisors, which approved the program. The PPTP will be responsive to the Best Pharmaceuticals for Children Act, enacted by Congress in January 2002.

References 1. Houghton PJ, Adamson PC, Blaney S, et al. Testing of new agents in childhood Cancer preclinical models (meeting summary). Clinical Cancer Research 2002;8:3646-57.

Intellectual Property
CTEP and the Technology Transfer Branch, in collaboration with COG, several pharmaceutical sponsors, and university technology transfer representatives, have addressed challenging intellectual property issues that limit early access by pediatric investigators to new anticancer agents for preclinical evaluation in pediatric tumor models. CTEP organized a meeting in May 2002 to examine industry and academic perspectives of this issue. As a result of the meeting and subsequent communications by participants, model materials transfer agreements have been developed that will be used to facilitate timely preclinical investigation of new agents, while maintaining and enhancing the drug development plans of pharmaceutical sponsors.

State of the Science
Information about recent and upcoming State of the Science (SOTS) meetings in gastric cancer, myelodysplastic syndromes, screening-detected lung cancer, myeloproliferative disorders and mastocytosis, sarcomas, prostate and bladder cancer (with the Society of Urologic Oncology), melanoma, and acute leukemia is available at http://www.webtie.org/SOTS/index.htm.

Osteosarcoma Basic Biology
A multidisciplinary meeting in November 2001 of laboratory, veterinary, and pediatric researchers specializing in osteosarcoma focused on the basic biology of osteosarcoma, preclinical models for understanding the disease, and new approaches to treatment under evaluation in the laboratory and clinic. This meeting led to the creation of the Clinical Oncology Group Comparative Models Subcommittee, which gives investigators access to cell lines and animal models of bone cancers for biological studies and evaluation of novel treatment approaches. New collaborations among basic scientists and veterinary researchers have been established to elucidate the potential role of immunotherapy in treating osteosarcoma.

Breast Cancer Groups Meeting
A meeting in May 2002 brought together all CTEP-supported breast cancer treatment groups in the U.S., Canada, and Europe to discuss new trial plans and seek collaborations. International collaboration on three premenopausal breast cancer adjuvant trials defining the roles of chemotherapy and hormonal therapy resulted from the meeting.