Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma

M. M. Mita, E. Poplin, C. D. Britten, W. D. Tap, E. H. Rubin, B. B. Scott, L. Berk, V. M. Rivera, J. W. Loewy, P. Dodion, F. Haluska, J. Sarantopoulos, A. Mita, A. Tolcher

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3+3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5 for all patients and 27.1 for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372.

Original languageEnglish (US)
Article numbermds602
Pages (from-to)1104-1111
Number of pages8
JournalAnnals of Oncology
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2013

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Sirolimus
Sarcoma
Neoplasms
Half-Life
Pharmacokinetics
Safety
Stomatitis
Maximum Tolerated Dose
ridaforolimus

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Keywords

  • MTOR
  • Rapamycin
  • Ridaforolimus
  • Sarcoma

Cite this

Mita, M. M. ; Poplin, E. ; Britten, C. D. ; Tap, W. D. ; Rubin, E. H. ; Scott, B. B. ; Berk, L. ; Rivera, V. M. ; Loewy, J. W. ; Dodion, P. ; Haluska, F. ; Sarantopoulos, J. ; Mita, A. ; Tolcher, A. / Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma. In: Annals of Oncology. 2013 ; Vol. 24, No. 4. pp. 1104-1111.
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abstract = "Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3+3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5 for all patients and 27.1 for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372.",
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author = "Mita, {M. M.} and E. Poplin and Britten, {C. D.} and Tap, {W. D.} and Rubin, {E. H.} and Scott, {B. B.} and L. Berk and Rivera, {V. M.} and Loewy, {J. W.} and P. Dodion and F. Haluska and J. Sarantopoulos and A. Mita and A. Tolcher",
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Mita, MM, Poplin, E, Britten, CD, Tap, WD, Rubin, EH, Scott, BB, Berk, L, Rivera, VM, Loewy, JW, Dodion, P, Haluska, F, Sarantopoulos, J, Mita, A & Tolcher, A 2013, 'Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma', Annals of Oncology, vol. 24, no. 4, mds602, pp. 1104-1111. https://doi.org/10.1093/annonc/mds602

Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma. / Mita, M. M.; Poplin, E.; Britten, C. D.; Tap, W. D.; Rubin, E. H.; Scott, B. B.; Berk, L.; Rivera, V. M.; Loewy, J. W.; Dodion, P.; Haluska, F.; Sarantopoulos, J.; Mita, A.; Tolcher, A.

In: Annals of Oncology, Vol. 24, No. 4, mds602, 01.04.2013, p. 1104-1111.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma

AU - Mita, M. M.

AU - Poplin, E.

AU - Britten, C. D.

AU - Tap, W. D.

AU - Rubin, E. H.

AU - Scott, B. B.

AU - Berk, L.

AU - Rivera, V. M.

AU - Loewy, J. W.

AU - Dodion, P.

AU - Haluska, F.

AU - Sarantopoulos, J.

AU - Mita, A.

AU - Tolcher, A.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3+3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5 for all patients and 27.1 for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372.

AB - Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3+3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients and methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5 for all patients and 27.1 for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier: NCT00112372.

KW - MTOR

KW - Rapamycin

KW - Ridaforolimus

KW - Sarcoma

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U2 - 10.1093/annonc/mds602

DO - 10.1093/annonc/mds602

M3 - Article

C2 - 23211938

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VL - 24

SP - 1104

EP - 1111

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

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