Temsirolimus combined with sorafenib in hepatocellular carcinoma

A phase I dose-finding trial with pharmacokinetic and biomarker correlates

R. K. Kelley Dr., Halla S Nimeiri, P. N. Munster, M. T. Vergo, Y. Huang, C. M. Li, J. Hwang, Mary Frances Mulcahy, B. M. Yeh, P. Kuhn, M. S. Luttgen, J. A. Grabowsky, L. Stucky-Marshall, W. M. Korn, A. H. Ko, E. K. Bergsland, Al B Benson III, A. P. Venook

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Abstract

Background: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). Patients and methods: Patients with incurable HCC and Child Pugh score <B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. Results: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alphafetoprotein (AFP) declined >50% in 60% assessable patients. Conclusion: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Original languageEnglish (US)
Article numbermdt109
Pages (from-to)1900-1907
Number of pages8
JournalAnnals of Oncology
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2013

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Hepatocellular Carcinoma
Pharmacokinetics
Biomarkers
Maximum Tolerated Dose
Sirolimus
Safety
temsirolimus
sorafenib
Neoplasms

Keywords

  • Hepatocellular carcinoma
  • MTOR
  • Pharmacokinetics
  • Sorafenib
  • Temsirolimus

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Kelley Dr., R. K., Nimeiri, H. S., Munster, P. N., Vergo, M. T., Huang, Y., Li, C. M., ... Venook, A. P. (2013). Temsirolimus combined with sorafenib in hepatocellular carcinoma: A phase I dose-finding trial with pharmacokinetic and biomarker correlates. Annals of Oncology, 24(7), 1900-1907. [mdt109]. https://doi.org/10.1093/annonc/mdt109
Kelley Dr., R. K. ; Nimeiri, Halla S ; Munster, P. N. ; Vergo, M. T. ; Huang, Y. ; Li, C. M. ; Hwang, J. ; Mulcahy, Mary Frances ; Yeh, B. M. ; Kuhn, P. ; Luttgen, M. S. ; Grabowsky, J. A. ; Stucky-Marshall, L. ; Korn, W. M. ; Ko, A. H. ; Bergsland, E. K. ; Benson III, Al B ; Venook, A. P. / Temsirolimus combined with sorafenib in hepatocellular carcinoma : A phase I dose-finding trial with pharmacokinetic and biomarker correlates. In: Annals of Oncology. 2013 ; Vol. 24, No. 7. pp. 1900-1907.
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abstract = "Background: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). Patients and methods: Patients with incurable HCC and Child Pugh score <B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. Results: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33{\%}), infection (22{\%}), thrombocytopenia (17{\%}), HFSR (11{\%}), and fatigue (11{\%}). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8{\%}) had a confirmed partial response (PR); 15 (60{\%}) had stable disease (SD). Alphafetoprotein (AFP) declined >50{\%} in 60{\%} assessable patients. Conclusion: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.",
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author = "{Kelley Dr.}, {R. K.} and Nimeiri, {Halla S} and Munster, {P. N.} and Vergo, {M. T.} and Y. Huang and Li, {C. M.} and J. Hwang and Mulcahy, {Mary Frances} and Yeh, {B. M.} and P. Kuhn and Luttgen, {M. S.} and Grabowsky, {J. A.} and L. Stucky-Marshall and Korn, {W. M.} and Ko, {A. H.} and Bergsland, {E. K.} and {Benson III}, {Al B} and Venook, {A. P.}",
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Kelley Dr., RK, Nimeiri, HS, Munster, PN, Vergo, MT, Huang, Y, Li, CM, Hwang, J, Mulcahy, MF, Yeh, BM, Kuhn, P, Luttgen, MS, Grabowsky, JA, Stucky-Marshall, L, Korn, WM, Ko, AH, Bergsland, EK, Benson III, AB & Venook, AP 2013, 'Temsirolimus combined with sorafenib in hepatocellular carcinoma: A phase I dose-finding trial with pharmacokinetic and biomarker correlates', Annals of Oncology, vol. 24, no. 7, mdt109, pp. 1900-1907. https://doi.org/10.1093/annonc/mdt109

Temsirolimus combined with sorafenib in hepatocellular carcinoma : A phase I dose-finding trial with pharmacokinetic and biomarker correlates. / Kelley Dr., R. K.; Nimeiri, Halla S; Munster, P. N.; Vergo, M. T.; Huang, Y.; Li, C. M.; Hwang, J.; Mulcahy, Mary Frances; Yeh, B. M.; Kuhn, P.; Luttgen, M. S.; Grabowsky, J. A.; Stucky-Marshall, L.; Korn, W. M.; Ko, A. H.; Bergsland, E. K.; Benson III, Al B; Venook, A. P.

In: Annals of Oncology, Vol. 24, No. 7, mdt109, 01.07.2013, p. 1900-1907.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Temsirolimus combined with sorafenib in hepatocellular carcinoma

T2 - A phase I dose-finding trial with pharmacokinetic and biomarker correlates

AU - Kelley Dr., R. K.

AU - Nimeiri, Halla S

AU - Munster, P. N.

AU - Vergo, M. T.

AU - Huang, Y.

AU - Li, C. M.

AU - Hwang, J.

AU - Mulcahy, Mary Frances

AU - Yeh, B. M.

AU - Kuhn, P.

AU - Luttgen, M. S.

AU - Grabowsky, J. A.

AU - Stucky-Marshall, L.

AU - Korn, W. M.

AU - Ko, A. H.

AU - Bergsland, E. K.

AU - Benson III, Al B

AU - Venook, A. P.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Background: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). Patients and methods: Patients with incurable HCC and Child Pugh score <B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. Results: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alphafetoprotein (AFP) declined >50% in 60% assessable patients. Conclusion: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

AB - Background: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). Patients and methods: Patients with incurable HCC and Child Pugh score <B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. Results: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alphafetoprotein (AFP) declined >50% in 60% assessable patients. Conclusion: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

KW - Hepatocellular carcinoma

KW - MTOR

KW - Pharmacokinetics

KW - Sorafenib

KW - Temsirolimus

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U2 - 10.1093/annonc/mdt109

DO - 10.1093/annonc/mdt109

M3 - Article

VL - 24

SP - 1900

EP - 1907

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 7

M1 - mdt109

ER -