Clara C. Chen

A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. Experimental Design: T cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.

Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor

PURPOSE T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. CONCLUSION This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.

Somatostatin Receptor Scintigraphy: Its Sensitivity Compared with That of Other Imaging Methods in Detecting Primary and Metastatic Gastrinomas: A Prospective Study

Studies have shown that many tumors, such as gastroenteropancreatic tumors (pancreatic endocrine tumors, carcinoid tumors), various lymphomas, and central nervous system tumors (meningiomas, astrocytomas), have a high density of somatostatin receptors and can be imaged in vivo by using somatostatin receptor scintigraphy with either [123I-Tyr3]octreotide or [111In-DTPA-DPhe1]octreotide [1-6]. Recently, [111In-DTPA-DPhe1]octreotide was approved for use in the United States for the imaging of primary and metastatic neuroendocrine tumors [6]. Many conventional imaging methods, including ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), selective arteriography, and selective intra-arterial secretin stimulation with venous sampling, already exist for the localization of gastroenteropancreatic tumors [7-10]. Although numerous studies have shown somatostatin receptor scintigraphy to be sensitive for the detection of neuroendocrine tumors, information on its sensitivity compared with that of other imaging techniques is limited; thus, it is difficult for the practitioner to define the potential role of somatostatin receptor scintigraphy in the evaluation of a patient with a gastroenteropancreatic syndrome. This is important because somatostatin receptor scintigraphy and the other imaging studies are expensive [1] and because accurate localization of the primary tumor is particularly important for the management of neuroendocrine tumors, which are often small and difficult to find [11-13]. Furthermore, accurate assessment of the extent of the tumor is essential for making decisions about resectability, tumoricidal therapy, disease progression, and liver transplantation [8, 14, 15]. Because neuroendocrine tumors are uncommon [8], many studies do not provide the data needed to define the role of somatostatin receptor scintigraphy in the management of these tumors. Several studies have compared the sensitivity of somatostatin receptor scintigraphy with that of ultrasonography or CT by assessing tumor detection on a lesion-by-lesion basis. However, few studies have compared somatostatin receptor scintigraphy with the most sensitive conventional imaging studies, particularly selective arteriography and MRI using STIR (short-time inversion-inversion recovery sequences) [8, 16, 17]. Thus, it is difficult to know the sensitivity and the role of somatostatin receptor scintigraphy in relation to these methods. Furthermore, only one study [18] has evaluated the possibility of conventional imaging combined with somatostatin receptor scintigraphy; therefore, it remains unclear whether additional localization studies are helpful when somatostatin receptor scintigraphy results are negative. Finally, most studies have not assessed the sensitivity of somatostatin receptor scintigraphy relative to other methods in different clinical situations. Patients with gastroenteropancreatic tumors are assessed for location of the primary tumor (to assist in possible tumor resection [7, 11-13]), for metastasis to the liver (for possible resectability [8, 14, 19, 20]), for the need for tumoricidal therapy [21], and for distant metastases (for possible specific tumoricidal therapies, such as local radiation to bone metastases [22]). Different localization methods are better for certain clinical situations [8, 9, 17], and somatostatin receptor scintigraphy needs to be compared with other methods in each of these clinical circumstances. Sixty percent to 90% of patients with the Zollinger-Ellison syndrome have malignant tumors, and their tumors thus resemble all pancreatic endocrine tumors with the exception of insulinomas [8, 23, 24]. The Zollinger-Ellison syndrome occurs more frequently than other malignant pancreatic endocrine tumors. Therefore, several groups, including ours, have a sufficient number of patients with this syndrome to be able to systematically address questions about localization in different clinical situations [8, 25, 26]. Gastrinomas resemble other, less common pancreatic endocrine tumors in that they are composed of amine precursor uptake and decarboxylation (APUD) cells and have similar growth patterns, locations, imaging properties, metastatic rates, immunohistochemistry, and rates of occurrence of somatostatin receptors [24, 27]. Gastrinomas are therefore an excellent model from which to obtain information that is also pertinent to the less common pancreatic endocrine tumors [25]. We prospectively compared the ability of somatostatin receptor scintigraphy with that of other conventional localization methodsultrasonography, CT, MRI, bone scanning, and selective angiographyin the localization of primary and metastatic gastrinoma in patients with the Zollinger-Ellison syndrome. Methods We prospectively studied 80 consecutive patients with the Zollinger-Ellison syndrome who were admitted to the National Institutes of Health (NIH) between June 1994 and May 1995. Our study is part of a prospective study of patients with the Zollinger-Ellison syndrome that has been ongoing at the NIH since 1974, as approved by the clinical research committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Thirty-one of the patients had no previous gastrinoma resection, and 49 had had noncurative resections of gastrinomas 0.25 years to 13 years before the study. The Zollinger-Ellison syndrome was diagnosed as described elsewhere [28]. Serum gastrin levels were determined by Bioscience Laboratories (New York, New York). The diagnostic criteria for the presence of multiple endocrine neoplasia type I in a patient with the Zollinger-Ellison syndrome have been described elsewhere [29]. Basal acid output and maximal acid output were determined for each patient by using methods described previously [30]. Doses of oral antisecretory drug were determined by establishing the dose required to reduce gastric acid output to less than 10 mEq per hour before the next dose of medication and to less than 5 mEq per hour for patients who had had gastric acid-reducing surgery or who had advanced esophageal disease [31]. Specific Protocol The localization and the extent of gastrinomas were evaluated in all patients as described elsewhere [17, 32] by using upper gastrointestinal endoscopy, CT, MRI, transabdominal ultrasonography [33], and bone scanning. With MRI, T1-weighted spin-echo sequences and STIR sequences were obtained with a repetition time of 400 to 600 ms and an echo time of 10 ms as described [16]. We did CT as described [16, 17] at 10-mm thickness with an oral contrast agent (diatrizoate sodium, Winthrop-Breon, Rensselaer, New York) with and without the rapid (2 mL/s) intravenous injection of the contrast agent iopamidol 300 (Winthrop-Breon). If surgical exploration was being considered or the extent of disease remained unclear, selective abdominal angiography was done with injection of the splenic, superior mesenteric, gastroduodenal, and hepatic arteries as described elsewhere [17, 34]. One radiologist evaluated the results of all conventional imaging studies. For somatostatin receptor scintigraphy studies, patients were hydrated before and after the intravenous injection of [111In-DTPA-DPhe1]octreotide and were given a laxative on the night of administration to avoid artifacts from radioactive accumulation in the intestines. Each patient received 6 mCi of [111In-DTPA-DPhe1]octreotide intravenously as recommended by the manufacturer for single-photon emission computed tomographic (SPECT) imaging (Mallinckrodt Diagnostic Imaging Service Radiopharmacy, Beltsville, Maryland). Images were obtained 4 and 24 hours after injection using a TRIONIX (Twinburg, Ohio) or ADAC (Milipitas, California) dual-headed camera with 20% windows at 173 and 247 keV. At 4 hours, a 30-minute whole-body scan was obtained; 10-minute planer spot views of the abdomen and other regions were obtained as needed. At 35 minutes and at 24 hours, SPECT images of the abdomen were obtained. Forty-second, 128 128 matrix SPECT images were acquired at 4-degree intervals over 360 degrees. The images were reconstructed with the manufacturers software using a standard filter back projection algorithm. A Hamming filter was used. Images were displayed as orthogonal (transverse, coronal, sagittal) sections and as reprojected views. Results of somatostatin receptor scintigraphy were obtained while the investigator was blinded to the results of the conventional imaging studies. Surgical exploration was done in all new patients and all patients who had a positive extrahepatic gastrinoma localized, had no liver metastases, had multiple endocrine neoplasia type I or a recent exploration (< 2 years), and had had exploratory laparotomy for possible gastrinoma resection (n = 15). All patients with possible liver metastases had percutaneous CT- or ultrasonography-guided biopsies (n = 24). Statistical Analysis The Fisher exact test was used to compare independent percentages, and the McNemar test was used to compare sensitivities in the same patients. Two-tailed P values and 95% CIs from the StatXact statistical package (Version 3.0, Cytel Software Corp., Cambridge, Massachusetts) are reported. P values less than 0.05 were considered statistically significant. Results The clinical and laboratory characteristics of the 80 study patients are shown in Table 1. These patients resemble patients in other large series [8, 35] with regard to sex, age, multiple endocrine neoplasia type I, basal acid output, maximal acid output, fasting serum gastrin concentration, and disease duration. Table 1. Clinical and Laboratory Characteristics of Patients with the Zollinger-Ellison Syndrome* Somatostatin receptor scintigraphy detected tumors either inside or outside of the liver in 56 of the 80 patients (70%); conventional imaging studies were significantly less sensitive (P < 0.001) (Figure 1). Angiography, CT, and MRI each detected tumors in 38% to 45% of patients; ultrasonograph

Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer

PURPOSE Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. METHODS Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. RESULTS After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. CONCLUSION In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.

A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.

PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

Superiority of Fluorodeoxyglucose Positron Emission Tomography to Other Functional Imaging Techniques in the Evaluation of Metastatic SDHB-Associated Pheochromocytoma and Paraganglioma

PURPOSE Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL. PATIENTS AND METHODS Sensitivities for the detection of metastases were compared between [18F]fluorodopamine ([18F]FDA) and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (123I) and iodine-131 (131I) -metaiodobenzylguanidine (MIBG), 111In-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference. RESULTS Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for 123I-MIBG and 88%/70% for [18F]FDA-PET. False-negative results on 123I-MIBG scintigraphy and/or [18F]FDA-PET were not predicted by genotype or biochemical phenotype. [18F]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or [18F]FDA-PET were detected by [18F]FDG-PET. In two patients, 111In-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or 131I-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of 123I-MIBG scintigraphy. CONCLUSION With a sensitivity approaching 100%, [18F]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL.

Comparison of 18F-Fluoro-L-DOPA, 18F-Fluoro-Deoxyglucose, and 18F-Fluorodopamine PET and 123I-MIBG Scintigraphy in the Localization of Pheochromocytoma and Paraganglioma

CONTEXT Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA). OBJECTIVE The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging. DESIGN This was a prospective observational study. INTERVENTION There were no interventions. PATIENTS Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype. MAIN OUTCOME MEASURES Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured. RESULTS Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%). CONCLUSIONS (18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.

Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.

BACKGROUND Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkins lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy. METHODS We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes. RESULTS The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up. CONCLUSIONS Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

6-[18F]Fluorodopamine Positron Emission Tomographic (PET) Scanning for Diagnostic Localization of Pheochromocytoma

The diagnosis and treatment of pheochromocytoma depend critically on effective means to localize the tumor. Computed tomography and magnetic resonance imaging have good sensitivity but poor specificity for detecting pheochromocytoma, and nuclear imaging approaches such as 131I-metaiodobenzylguanidine scintigraphy have limited sensitivity. Here we report initial results using 6-[18F]fluorodopamine positron emission tomography (PET) scanning in the diagnostic localization of pheochromocytoma. Twenty-eight patients with known or clinically suspected pheochromocytoma underwent PET scanning after intravenous injection of 6-[18F]fluorodopamine. Of the 28 patients, 9 had surgical confirmation of the tumor, 8 had previously diagnosed metastatic pheochromocytoma, and 11 had plasma levels of metanephrines that were within normal limits. All 9 patients with surgically proven pheochromocytoma had abnormal 6-[18F]fluorodopamine PET scans that identified the tumors. All 8 patients with metastatic pheochromocytoma had extra-adrenal sites of 6-[18F]fluorodopamine-derived activity. Of the 11 patients with normal plasma levels of metanephrines, 9 had negative 6-[18F]fluorodopamine PET scans, 1 had extra-adrenal foci of 6-[18F]fluorodopamine-derived activity, and 1 had symmetric uptake of 6-[18F]fluorodopamine in the region of the adrenal glands. In patients with known disease, 6-[18F]fluorodopamine PET scanning can detect and localize pheochromocytomas with high sensitivity. In patients in whom the diagnosis of pheochromocytoma is considered but excluded because of negative plasma metanephrine results, 6-[18F]fluorodopamine PET scans are consistently negative. These findings justify a clinical trial of 6-[18F]fluorodopamine PET scanning as a diagnostic tool.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.