Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group

Vassal, Gilles; Couanet, D.; Stockdale, Elizabeth; Geoffray, A.; Geoerger, Birgit; Orbach, Daniel; Pichon, F.; Gentet, Jean Claude; Picton, Susan; Bergeron, Christophe; Cisar, Laura A.; Assadourian, Sylvie; Morland, Bruce

doi:10.1200/jco.2006.06.1960

Cited by 57 publications

(44 citation statements)

References 22 publications

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“…[23][24][25][26][27] These studies established an administration schedule of irinotecan 20 mg/m 2 /d, 5 days/wk for 2 consecutive weeks, every 3 weeks. 27 Diarrhea and abdominal cramps were the predominant toxicities.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

Trippett

Herzog

Whitlock

et al. 2009

JCO

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A B S T R A C T PurposeTo determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and MethodsThis open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m 2 ) in a 3 ϩ 3 design, plus irinotecan (16 or 20 mg/m 2 /d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. ResultsTwenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m 2 weekly plus irinotecan 16 mg/m 2 /d (pediatric) or 20 mg/m 2 /d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). ConclusionThe cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

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Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

Trippett

Herzog

Whitlock

et al. 2009

JCO

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“…The experience with neuroblastoma has been somewhat similar to that seen with rhabdomyosarcoma: encouraging preclinical activity [6,8] later followed by at least one response in several single-agent Phase I trials which have included neuroblastoma patients [19,20,[26][27][28]. However, in larger Phase II trials using a q3 week [25] or dx5 schedule [21], response rates were <10%.…”

Section: Neuroblastomamentioning

confidence: 81%

“…Both partial and complete responses have been seen in rhabdomyosarcoma patients treated on early clinical trials [17][18][19], although response rates in Phase II trials for relapsed patients using a q 3 week [20], dx5 [21], or dx5x2 schedule [22] are relatively modest at 6-16%. To better assess activity in newly-diagnosed patients, the Children's Oncology Group (COG) administered two courses of irinotecan on the dx5x2 schedule as initial therapy to patients with metastatic rhabdomyosarcoma, using the so-called "upfront window" approach prior to incorporating more traditional agents.…”

Section: Rhabdomyosarcomamentioning

confidence: 97%

Irinotecan for Treatment of Childhood Cancers: A Promising Therapeutic Partner

Wagner

2010

CCTR

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Irinotecan has been increasingly used for treatment of pediatric cancers over the past decade. Irinotecan has modest single-agent activity against common childhood solid tumors, and the low incidence of myelosuppression seen with protracted administration makes it well-suited for combination chemotherapy regimens. Data from mouse xenograft models and clinical trials suggest the activity of irinotecan can be improved by the addition of temozolomide, vincristine, or bevacizumab. These observations have led to focused investigation in at least seven different types of childhood cancer. This report summarizes the progress made in understanding the spectrum of activity, pharmacokinetics, pharmacogenetics, toxicity profile, and mechanisms of resistance of this agent. Also reviewed are the different schedules and routes of administration that have been investigated in pediatric clinical trials. Finally, potential applications for future use are discussed, including novel combinations with targeted therapies.Irinotecan (CPT-11; Camptosar) has become an important chemotherapeutic agent for the treatment of pediatric solid tumors. Its parent compound, camptothecin, is an alkaloid which was first isolated from the Chinese tree Camptotheca acuminata in 1966 [1]. Although camptothecin showed significant in vivo activity in animal models [2], clinical use was limited by severe toxicity, including myelosuppression, diarrhea, and hemorrhagic cystitis [3]. Irinotecan is a camptothecin derivative created through substitution of a piperidine lateral chain (Fig. 1), making it more watersoluble and less toxic. Irinotecan functions primarily as a prodrug which is converted by endogenous carboxylesterases to the active metabolite SN-38. Like other camptothecins, SN-38 mediates cytotoxicity by stabilizing the DNAtopoisomerase I covalent complex created during DNA replication. This stabilization process prevents religation of DNA, thus "poisoning" the activity of the topoisomerase I enzyme [4]. The collision of advancing DNA replication forks with the drug-enzyme-DNA complex produces an irreversible double-strand break in DNA that results in cell cycle arrest and apoptotic cell death. A schema of irinotecan metabolism, action, and resistance is depicted in Fig. (2). Early adult clinical trials of irinotecan showed benefit for patients with colorectal cancer [5], leading to accelerated approval by the US FDA in 1996 for treatment of this tumor type. During the 1990s there were also encouraging results from preclinical experiments using a wide variety of pediatric tumor models, including neuroblastoma [6], rhabdomyosarcoma [7], Ewing sarcoma [8], medulloblastoma [9], and glioblstoma [10]. Importantly, some xenograft models responding to irinotecan were resistant to alkylating agents, vincristine, and topotecan [7]. These findings suggest that irinotecan may be non-cross-resistant with many commonly used chemotherapeutics, and that resistance patterns are not uniform even among camptothecins. Proposed mechanisms of resistance for irinotecan...

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“…13 Irinotecan is also active toward RMS xenografts 10 and as a single agent was active in phase I and II trials for RMS. [14][15][16][17][18] In the phase II setting, the combination of vincristine and irinotecan demonstrated an overall response rate from 25% to 37%. 19 Administered in an upfront window format for newly diagnosed RMS, VI had a 70% response rate and is now being evaluated in ongoing phase III trials.…”

Section: Discussionmentioning

confidence: 98%

Vincristine, Irinotecan, and Temozolomide for Treatment of Relapsed Alveolar Rhabdomyosarcoma

Mixon

Eckrich

Lowas³

et al. 2013

Journal of Pediatric Hematology/Oncology

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Event-free survival for recurrent alveolar rhabdomyosarcoma (ARMS) is poor, and a consensus approach to treatment in the relapse setting has not been established. Recent studies suggest that a combination regimen of vincristine, irinotecan, and temozolomide (VITA) is active against recurrent sarcomas. We present our single-institution experience with this regimen for relapsed ARMS in heavily pretreated patients, including those with prior exposure to a combination regimen of vincristine and irinotecan. We observed a complete radiographic response in 1 of 4 patients who received VITA as a fifth attempted salvage regimen. Radiographic remission for the responsive patient was sustained for 27 weeks before disease recurrence. All therapies were administered in the outpatient setting and no grade III or grade IV toxicities were observed. These findings suggest that for patients with refractory ARMS, VITA in combination should be among the treatment options considered. They also reinforce the need for biological correlates to prospectively identify patients who may benefit from this treatment.

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Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group

Abstract: In heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2 every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.

Cited by 57 publications

References 22 publications

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

Irinotecan for Treatment of Childhood Cancers: A Promising Therapeutic Partner

Vincristine, Irinotecan, and Temozolomide for Treatment of Relapsed Alveolar Rhabdomyosarcoma

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