A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

Siegel-Lakhai, Wandena S.; Zandvliet, Anthe S.; Huitema, Alwin D. R.; Tibben, Matthijs M.; Milano, Gérard; Girre, V.; Dièras, Véronique; King, Arlene; Richmond, Elaine; Wanders, J.; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1038/sj.bjc.6604300

Cited by 16 publications

(9 citation statements)

References 27 publications

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“…Grade 3 and 4 events were mostly reversible electrolyte abnormalities. Handfoot syndrome and stomatitis were reported in a phase I trial that combined indisulam and capecitabine, 8 but these AEs were not encountered in our trial. The likely explanation for this better toxicity profile is that the doses of idarubicin and cytarabine received in the current study were lower than the usual 12 mg/m 2 and 1.5 g/m 2 doses, respectively, used as induction regimen at our institution.…”

Section: Discussioncontrasting

confidence: 59%

“…Despite substantial research efforts over 2 decades, until recently, the precise molecular target of indisulam was yet to be elucidated. Preclinical and clinical studies have established the synergy of indisulam with nucleoside analogs as well as topoisomerase inhibitors . In a phase 2 study combining indisulam with chemotherapy in colorectal cancer, indisulam was used at the recommended dose of 400 mg/m 2 on days 1 and 8 of a 21‐day cycle .…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical and clinical studies have established the synergy of indisulam with nucleoside analogs as well as topoisomerase inhibitors. 6,8,9 In a phase 2 study combining indisulam with chemotherapy in colorectal cancer, indisulam was used at the recommended dose of 400 mg/m 2 on days 1 and 8 of a 21-day cycle. 10 The combination was tolerated with acceptable toxicities, including diarrhea, vomiting, and myelosuppression.…”

Section: Introductionmentioning

confidence: 99%

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Final results of a phase 2, open‐label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Assi

Kantarjian

Kadia

et al. 2018

Cancer

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The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4-associated factor 15) as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker-driven trial or in patients who have splicing factor mutations. Cancer 2018;124:2758-65. © 2018 American Cancer Society. Cancer 2018;124:2758-2765. © 2018 American Cancer Society.

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Section: Discussioncontrasting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Final results of a phase 2, open‐label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Assi

Kantarjian

Kadia

et al. 2018

Cancer

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“…Eisai, Inc.’s indisulam/E7070, another CAIX inhibitor, continues to be tested in numerous clinical trials. In Phase I trials, the combination of indisulam and carboplatin or capecitabine was generally well tolerated [88,89]. In a Phase I trial in patients with advanced solid tumors, combination treatment with indisulam and capecitabine resulted in a PR in one patient with colon cancer and another PR in a patient with pancreatic adenocarcinoma; SD was documented in 17 patients after one cycle of treatment.…”

Section: Cell Metabolism Pathwaysmentioning

confidence: 99%

Investigational cancer drugs targeting cell metabolism in clinical development

Sborov¹,

Haverkos²,

Harris³

2014

Expert Opinion on Investigational Drugs

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Introduction Malignant cell transformation and tumor progression are associated with alterations in glycolysis, fatty acid synthesis, amino acid delivery and production of reactive oxygen species. With increased understanding of the role of metabolism in tumors, there has been interest in developing agents that target tumor specific metabolic pathways. Numerous promising agents targeting altered metabolic pathways are currently in Phase I – III clinical trials. Areas covered This paper reviews the early phase clinical trial development of these agents and provides perspective on the future direction of this emerging field. Specifically, the authors describe novel and repurposed therapies, focusing on the effects of each agent on tumor metabolism and results from relevant Phase I and II clinical trials. Expert opinion Metabolism modulating agents, alone and in combinations with other classes of agents, have shown efficacy in the treatment of neoplasm, which, the authors believe, will bear positive results in future studies. Because of the significant crosstalk between metabolic pathways and oncogenic signaling pathways, the authors also believe that combining metabolic modifiers with targeted agents will be an important strategy. An increased understanding of cancer metabolism, in addition to the continued study of metabolic modulators, should lead to further advances in this nascent therapeutic field in the future.

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“…The best response was 2 prs. Toxicities included myelosuppression, stomatitis, and hand-foot syndrome 56 .…”

Section: Indisulammentioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

196

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

Cited by 16 publications

References 27 publications

Final results of a phase 2, open‐label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Final results of a phase 2, open‐label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Investigational cancer drugs targeting cell metabolism in clinical development

Development of Cell-Cycle Inhibitors for Cancer Therapy

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