A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer

Zahi Mitri, Cansu Karakas, Caimiao Wei, Brian Briones, Holly Simmons, Nuhad Ibrahim, Ricardo Alvarez, James L. Murray, Khandan Keyomarsi, Stacy Moulder

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Purpose, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (∼70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intrapatient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. Results, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the - 1 dose level. Conclusion, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

Original languageEnglish (US)
Pages (from-to)890-894
Number of pages5
JournalInvestigational New Drugs
Volume33
Issue number4
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Epirubicin
Febrile Neutropenia
Cyclin E
Maximum Tolerated Dose
Poisons
Anthracyclines
Syncope
Therapeutics
Vomiting
Protein Isoforms
Carcinogenesis
Molecular Weight
Cell Line
dinaciclib
Neoplasms

Keywords

  • Dinaciclib
  • Epirubicin
  • Metastatic
  • Phase 1 study
  • Systemic treatment
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology
  • Medicine(all)

Cite this

A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. / Mitri, Zahi; Karakas, Cansu; Wei, Caimiao; Briones, Brian; Simmons, Holly; Ibrahim, Nuhad; Alvarez, Ricardo; Murray, James L.; Keyomarsi, Khandan; Moulder, Stacy.

In: Investigational New Drugs, Vol. 33, No. 4, 01.08.2015, p. 890-894.

Research output: Contribution to journalArticle

Mitri, Zahi ; Karakas, Cansu ; Wei, Caimiao ; Briones, Brian ; Simmons, Holly ; Ibrahim, Nuhad ; Alvarez, Ricardo ; Murray, James L. ; Keyomarsi, Khandan ; Moulder, Stacy. / A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. In: Investigational New Drugs. 2015 ; Vol. 33, No. 4. pp. 890-894.
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AU - Karakas, Cansu

AU - Wei, Caimiao

AU - Briones, Brian

AU - Simmons, Holly

AU - Ibrahim, Nuhad

AU - Alvarez, Ricardo

AU - Murray, James L.

AU - Keyomarsi, Khandan

AU - Moulder, Stacy

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N2 - Purpose, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (∼70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intrapatient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. Results, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the - 1 dose level. Conclusion, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

AB - Purpose, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (∼70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intrapatient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. Results, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the - 1 dose level. Conclusion, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

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