Frank M. Balis

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.

Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.

Abstract Background. 2′,3′-Dideoxyinosine (ddI) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddI showed evidence of antiretroviral activity with little hematologic toxicity. Methods. We conducted a phase I–II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddI was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddI: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. Results. After oral administration, ddI was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddI at each of the two highest doses. The median CD...

Trimetrexate for the Treatment of Pneumocystis carinii Pneumonia in Patients with the Acquired Immunodeficiency Syndrome

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.

Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas

PURPOSE This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) -related plexiform neurofibromas. PATIENTS AND METHODS Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. RESULTS Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. CONCLUSION Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.

Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

PURPOSE Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. PATIENTS AND METHODS A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. RESULTS The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. CONCLUSIONS The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

NF1 plexiform neurofibroma growth rate by volumetric MRI Relationship to age and body weight

Objective: To longitudinally analyze changes in plexiform neurofibroma (PN) volume in relation to age and body growth in children and young adults with neurofibromatosis type 1 and inoperable, symptomatic, or progressive PNs, using a sensitive, automated method of volumetric MRI analysis. Methods: We included patients 25 years of age and younger with PNs entered in a natural history study or in treatment trials who had volumetric MRI over ≥16 months. Results: We studied 49 patients (median age 8.3 years) with 61 PNs and a median evaluation period of 34 months (range 18 to 70). The PN growth rates varied among patients, but were constant within patients. Thirty-four patients (69%) experienced ≥20% increase in PN volume during the observation period. PN volume increased more rapidly than body weight over time (p = 0.026). Younger patients had the most rapid PN growth rate. Conclusions: Volume increase of plexiform neurofibromas is a realistic and meaningful trial endpoint. In most patients plexiform neurofibroma growth rate exceeded body growth rate. The youngest patients had the fastest plexiform neurofibroma growth rate, and clinical drug development should be directed toward this population. Age stratification for clinical trials for plexiform neurofibromas should be considered.

Effect of continuous-infusion zidovudine therapy on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection

Neuropsychologic function was assessed in 13 children with symptomatic human immunodeficiency virus disease (Centers for Disease Control Class P2), ranging in age from 14 months to 12 years. Before the initiation of treatment, eight patients were classified as having encephalopathy. Psychologic tests were administered both before and after 6 and 12 months of continuous-infusion azidothymidine (AZT; zidovudine) treatment. After 6 months of treatment a significant increase of 15.5 (+/- 3.3) IQ points was demonstrated in general cognitive functioning (p less than 0.001). Follow-up for 10 of these patients indicated that after 12 months of AZT therapy, they had maintained their gains in IQ points. Improvements in adaptive behavior after 6 months of therapy, assessed with a standardized interview, paralleled the findings on the IQ data. No significant differences in the amount of change was observed for the different subgroups. The magnitude of these improvements could not be explained by practice effects, environmental changes, or general improvement in physical state. We conclude that neuropsychologic function was significantly improved with continuous infusion AZT treatment.

Remission induction of meningeal leukemia with high-dose intravenous methotrexate.

Twenty children with acute lymphoblastic leukemia who developed meningeal disease were treated with a high-dose intravenous methotrexate regimen that was designed to achieve and maintain CSF methotrexate concentrations of 10(-5) mol/L without the need for concomitant intrathecal dosing. The methotrexate was administered as a loading dose of 6,000 mg/m2 for a period of one hour followed by an infusion of 1,200 mg/m2/h for 23 hours. Leucovorin rescue was initiated 12 hours after the end of the infusion with a loading dose of 200 mg/m2 followed by 12 mg/m2 every three hours for six doses and then every six hours until the plasma methotrexate level decreased to less than 1 X 10(-7) mol/L. The mean steady-state plasma and CSF methotrexate concentrations achieved were 1.1 X 10(-3) mol/L and 3.6 X 10(-5) mol/L, respectively. All 20 patients responded to this regimen, 16/20 (80%) achieved a complete remission, and 20% obtained a partial remission. The most common toxicities encountered were transient serum transaminase and bilirubin elevations, neutropenia, and mucositis. One patient had focal seizures and transient hemiparesis but recovered completely. High-dose intravenous methotrexate is an effective treatment for the induction of remission after meningeal relapse in acute lymphoblastic leukemia.

Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma

Purpose: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. Experimental Design: We conducted a phase I/II trial of vandetanib for children (5–12 years) and adolescents (13–18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m2/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit. Results: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2–52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%–75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects. Conclusion: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC. Clin Cancer Res; 19(15); 4239–48. ©2013 AACR.