A Phase I Study of the Combination of Temsirolimus with Irinotecan for Metastatic Sarcoma

Verschraegen, Claire F.; Movva, Sujana; Ji, Yongli; Schmit, Berndt P.; Quinn, Robert H.; Liem, Ben; Bocklage, Thèrése; Shaheen, Monte

doi:10.3390/cancers5020418

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities . Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ) .…”

Section: Discussionmentioning

confidence: 99%

“…12 Although temsirolimus is well tolerated as a single agent, phase I combination studies including temsirolimus have frequently been found to have significant toxicities. [16][17][18][19][20][21][22] Oral mucositis was the predominant toxicity in a pediatric phase I combination of temsirolimus with cixutumumab, resulting in two grade 3 mucositis DLTs and required two dose deescalations to achieve a RP2D (temsirolimus 8 mg/m 2 ). 19 Significant oral mucositis and hypertriglyceridemia, accounting for four DLTS, occurred in a pediatric study of temsirolimus (15 mg/m 2 weekly) with vinorelbine and cyclophosphamide for rhabdomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

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Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Deyell

Rassekh

et al. 2018

Pediatric Blood & Cancer

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Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2) and temsirolimus (15 mg/m2) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8–18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose‐limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level −2 (temsirolimus 10 mg/m2, vinblastine 4 mg/m2) with no protocol‐related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred—an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)—unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1–8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2) and vinblastine (4 mg/m2) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Deyell

Rassekh

et al. 2018

Pediatric Blood & Cancer

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“…The regimen irinotecan + temsirolimus was evaluated in adult patients with metastatic sarcoma, with disease stabilization observed in some patients (11%) [ 57 ]. DLTs included neutropenia, muscle weakness, platelet count decrease, and the recommended phase 2 dose (RP2D) was irinotecan 80 mg/m 2 + temsirolimus 20 mg on a weekly basis for 3 out of 4 weeks [ 57 ].…”

Section: Clinical Experience With Topoisomerase I Inhibitors In Sarcomasmentioning

confidence: 99%

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Schöffski,

Wang,

Schöffski

et al. 2023

Oncol Res Treat

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Background: Topoisomerase I is an enzyme that plays a crucial part in DNA replication and transcription by the relaxation of supercoiled double-stranded DNA. Topoisomerase I inhibitors bind to the topoisomerase I cleavage complex, thereby stabilizing it and preventing the religation of the DNA strands, leading to DNA damage, cell cycle arrest, and apoptosis. Various topoisomerase I inhibitors have been evaluated in solid tumors, and irinotecan and topotecan have been approved for the treatment of epithelial malignancies. None of them have been approved for sarcoma, a diverse group of rare solid tumors with an unmet need for effective treatments. Summary: Topoisomerase I inhibitors have been evaluated in preclinical studies as single agents or in combination in solid tumors, some of which have included sarcomas where activity was observed. Clinical trials evaluating topoisomerase I inhibitors for the treatment of sarcoma have shown limited efficacy as monotherapy. In combination with other cytotoxic agents, topoisomerase I inhibitors have become part of clinical routine in selected sarcoma subtypes. Regimens such as irinotecan/vincristine/temozolomide are used in relapsed rhabdomyosarcoma, irinotecan/temozolomide and vincristine/topotecan/cyclophosphamide are commonly given in refractory Ewing sarcoma, and topotecan/carboplatin showed some activity in advanced soft tissue sarcoma. This review provides an overview of key studies with topoisomerase I inhibitors for the treatment of sarcoma. Topoisomerase I inhibitors are currently also being assessed as “payloads” for antibody-drug conjugates (ADCs), allowing for the targeting of specific antigen-expressing tumor cells and the delivery of the inhibitor directly to the tumor cells with the potential of enhancing therapeutic efficacy while minimizing systemic toxicity. Here, we also provide a brief overview on topoisomerase I-ADCs. Key Message: Topoisomerase I inhibitors are an important component of some systemic therapies for selected sarcomas and have potent cytotoxic properties and pharmacological characteristics that make them relevant candidates as payloads for the development of sarcoma-specific ADCs. ADCs are antibody-based targeted agents allowing for efficient and specific delivery of a given drug to the tumor cell. Topoisomerase I-ADCs are a novel targeted delivery approach which may have the potential to improve the therapeutic index of topoisomerase I inhibitors in the treatment of sarcoma and warrants investigation in a broad variety of mesenchymal malignancies.

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“…Combination mTOR clinical trials have been or are being performed with multiple therapeutic partners. Regarding cytotoxics, liposomal doxorubicin , cyclophosphamide , irinotecan have all been attempted with modest results. In addition, there is an ongoing study with gemcitabine (NCT01684449).…”

Section: Targeting Cell Cyclementioning

confidence: 99%

Targeted therapy in sarcomas other than GIST tumors

Sborov

Chen

2014

Journal of Surgical Oncology

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Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials.

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A Phase I Study of the Combination of Temsirolimus with Irinotecan for Metastatic Sarcoma

Cited by 9 publications

References 37 publications

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma-Specific Antibody-Drug Conjugates

Targeted therapy in sarcomas other than GIST tumors

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