Lars M. Wagner

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

Preclinical models show sequence‐dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion.

Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study

PURPOSE To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. RESULTS Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1). CONCLUSION MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.

Phase I Trial of Temozolomide and Protracted Irinotecan in Pediatric Patients with Refractory Solid Tumors

Purpose: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. Experimental Design: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m2/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m2/day (n = 6) or 15 mg/m2/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. Results: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m2/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing’s sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O6-methylguanine-DNA methyltransferase expression in tumor tissue. Conclusions: The MTD using this schedule was temozolomide (100 mg/m2/day) and irinotecan (10 mg/m2/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.

Phase II Study of Irinotecan and Temozolomide in Children With Relapsed or Refractory Neuroblastoma: A Children's Oncology Group Study

PURPOSE This phase II study was conducted to determine the response rate associated with use of irinotecan and temozolomide for children with relapsed/refractory neuroblastoma. PATIENTS AND METHODS Patients with relapsed/refractory neuroblastoma measurable by cross-sectional imaging (stratum 1) or assessable by bone marrow aspirate/biopsy or metaiodobenzylguanidine (MIBG) scan (stratum 2) received irinotecan (10 mg/m(2)/dose 5 days a week for 2 weeks) and temozolomide (100 mg/m(2)/dose for 5 days) every 3 weeks. Response was assessed after three and six courses using International Neuroblastoma Response Criteria. Of the first 25 evaluable patients on a given stratum, five or more patients with complete or partial responses were required to conclude that further study would be merited. RESULTS Fifty-five eligible patients were enrolled. The objective response rate was 15%. Fourteen patients (50%) on stratum 1 and 15 patients (56%) on stratum 2 had stable disease. Objective responses were observed in three of the first 25 evaluable patients on stratum 1 and five of the first 25 evaluable patients on stratum 2. Less than 6% of patients experienced ≥ grade 3 diarrhea. Although neutropenia was observed, less than 10% of patients developed evidence of infection while neutropenic. CONCLUSION The combination of irinotecan and temozolomide was well tolerated. The objective response rate of 19% in stratum 2 suggests that this combination may be effective for patients with neuroblastoma detectable by MIBG or marrow analysis. Although fewer objective responses were observed in patients with disease measurable by computed tomography/magnetic resonance imaging, patients in both strata seem to have derived clinical benefit from this therapy.

Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study

PURPOSE Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma. PATIENTS AND METHODS Patients received oral temozolomide on days 1 through 5 combined with oral irinotecan on days 1 through 5 and 8 through 12 in 3-week courses. Daily oral cefixime was used to reduce irinotecan-associated diarrhea. RESULTS Fourteen assessable patients received 75 courses. Because neutropenia and thrombocytopenia were initially dose-limiting, temozolomide was reduced from 100 to 75 mg/m(2)/d for subsequent patients. Irinotecan was then escalated from 30 to 60 mg/m2/d. First-course grade 3 diarrhea was dose-limiting in one of six patients treated at the irinotecan MTD of 60 mg/m2/d. Other toxicities were mild and reversible. The median SN-38 lactone area under the plasma concentration versus time curve at this dose was 72 ng . hr/mL. One patient with bulky soft tissue disease had a complete response through six courses. Six additional patients received a median of seven courses (range, three to 22 courses) before progression. CONCLUSION This all-oral regimen was feasible and well tolerated in heavily pretreated children with resistant neuroblastoma, and seven (50%) of 14 assessable patients had response or disease stabilization for three or more courses in this phase I trial. SN-38 lactone exposures were similar to those reported with protracted intravenous irinotecan. The dosages recommended for further study in this patient population are temozolomide 75 mg/m2/d plus irinotecan 60 mg/m2/d when given with cefixime.

New therapeutic targets for the treatment of high-risk neuroblastoma

High‐risk neuroblastoma remains a major problem in pediatric oncology, accounting for 15% of childhood cancer deaths. Although incremental improvements in outcome have been achieved with the intensification of conventional chemotherapy agents and the addition of 13‐cis‐retinoic acid, only one‐third of children with high‐risk disease are expected to be long‐term survivors when treated with current regimens. In addition, the cost of cure can be quite high, as surviving children remain at risk for additional health problems related to long‐term toxicities of treatment. Further advances in therapy will require the targeting of tumor cells in a more selective and efficient way so that survival can be improved without substantially increasing toxicity. In this review we summarize ongoing clinical trials and highlight new developments in our understanding of the molecular biology of neuroblastoma, emphasizing potential targets or pathways that may be exploitable therapeutically. J. Cell. Biochem. 107: 46–57, 2009.

Treatment of metastatic rhabdoid tumor of the kidney.

Metastatic rhabdoid tumor of the kidney (RTK) is a highly lethal malignancy; only one survivor with stage 4 disease has been reported. The authors reviewed the cases of two patients with metastatic RTK who had excellent responses to therapy. Both patients were treated with radiation therapy and alternating courses of ifosfamide, carboplatin, and etoposide (ICE) and vincristine, doxorubicin, and cyclophosphamide (VDC). The patients are without evidence of disease at 24 months and 12 months from the detection of metastasis. Alternating courses of ICE and VDC have activity against metastatic RTK. This combination of agents warrants prospective investigation in clinical trials.

Fractures in pediatric Ewing sarcoma

Purpose To determine the incidence, timing, and clinical significance of long-bone fractures in children with Ewing sarcoma family of tumors (ESFT). Patients and Methods We retrospectively reviewed 93 consecutive cases of ESFT of the long bones seen at a single institution over the course of a 37-year period. Results Fracture occurred in 14 (15%) of 93 patients with long-bone ESFT, most commonly in the femur. Approximately 30% of patients with tumors of the femur had fractures at some point in the course of their disease. The incidence of fracture was highest among patients with tumors of the proximal third of the femur (50%); these fractures were usually present at the time of initial diagnosis. Nine (64%) of the 14 fractures occurred after the start of radiotherapy, and three of these were associated with either local recurrence or second malignancy. Conclusions Patients with femoral ESFT are at high-risk for fracture. If fractures occur after the completion of therapy, recurrence or second malignancy should be suspected.

Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study.

In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three‐drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan‐associated diarrhea.

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

AIM Patients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS. PATIENTS AND METHODS Patients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility. RESULTS Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg). CONCLUSIONS ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma.