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  • American Society of Clinical Oncology (ASCO)  (2)
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  • American Society of Clinical Oncology (ASCO)  (2)
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  • 1
    Online Resource
    Online Resource
    Evaluation of the first-in-class antimitochondrial metabolism agent CPI-613 in hematologic malignancies.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 6524-6524
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6524-6524
    Abstract: 6524^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. Most tumor cells use glycolysis even under aerobic conditions (the Warburg effect). This altered metabolism is a possible therapeutic target. The novel lipoate derivative CPI-613 is a first-in-class agent that targets a key mitochondrial enzyme, pyruvate dehydrogenase complex (PDH). Methods: CPI-613 was tested against leukemia cell lines in vitro and in vivo. It is also the subject of a phase I clinical trial for patients with hematologic malignancies. Results: CPI-613 was active against HL60, Jurkat, and K562 cells, with an average IC50 value of 14 μM (range 12.2 – 16.4). CPI-613 was synergistic with doxorubicin, with Combinatorial Index (CI) values of 0.478 to 0.765. CPI-613 sensitivity increased with knockdown of p53 or MN1 expression, despite their increased resistance to standard therapy. CPI-613 was synergistic with nilotinib against BCR-ABL-expressing cells and with sorafenib against Flt3 ITD-expressing cells. CI values for nilotinib + CPI was 0.059 (+/-0.002) and for sorafenib + CPI was 0.581 (+/-0.052). In vivo, CPI-613 synergized with doxorubicin; median survival improved from 12 days with doxorubicin to 16 days with CPI-613 plus doxorubicin (p=0.0001). In the phase I clinical trial, 7 of 13 evaluable patients had a response of stable disease or better, for an overall response rate of 54% (see table). CPI-613 was well tolerated, with no evidence of marrow suppression and no dose limiting toxicity identified. Conclusions: The novel agent CPI-613 has activity against a variety of hematological malignancies, including acute leukemias. The therapeutic index appears high, with only minor toxicities observed. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.6524
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    A phase I study of the first-in-class mitochondrial metabolism inhibitor CPI-613 in patients with advanced hematologic malignancies.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 2516-2516
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2516-2516
    Abstract: 2516^ Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets pyruvate dehydrogenase complex.This trial was designed to determine the maximally tolerated dose (MTD), safety, and efficacy of CPI-613 given as a single agent by IV infusion. Methods: CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m 2 . The dose was escalated in 6 cohorts to a final dose of 3780 mg/m 2 . Treatment could be continued if the patient experienced clinical benefit. Results: A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m 2 the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m 2 , one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m 2 over 2 hours with no DLTs observed, establishing this as the MTD. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. Responses included a complete remission maintained over 27 cycles in one AML patient and clearance of marrow blasts in another, sustained partial response in both a Burkitt's and a cutaneous T cell lymphoma patient maintained over 17 and 8 cycles respectively, and stable disease in 2 multiple myeloma and 2 myelodysplasia patients. Conclusions: To our knowledge this is the first report of an agent with activity in aggressive hematological malignancies that is not myelosuppressive. The therapeutic index appears high suggesting CPI-613 should be further studied in phase II trials. Clinical trial information: NCT01034475.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.2516
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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