Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Albert Lockhart, R. Bukowski, M. L. Rothenberg, K. K. Wang, W. Cooper, J. Grover, L. Appleman, P. R. Mayer, M. Shapiro, A. X. Zhu

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Purpose: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results: Five dose levels of MAC-321 ranging from 25 to 75 mg/m2 were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m2). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m2; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m2 had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C max value of less than 1 h. Mean C max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). Conclusions: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m2. The major DLT was neutropenic fever. Four subjects had disease stabilization.

Original languageEnglish (US)
Pages (from-to)203-209
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume60
Issue number2
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

Fingerprint

Tumors
Toxicity
Neoplasms
Pharmacokinetics
Fever
Stabilization
MAC321
Chondrosarcoma
Small Cell Carcinoma
Maximum Tolerated Dose
Mesothelioma
Paclitaxel
Neutropenia
Heterografts
Human Activities
Refractory materials
Area Under Curve
Fatigue
Half-Life
Prostate

Keywords

  • Clinical trial
  • Docetaxel
  • MAC-321
  • Paclitaxel
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Lockhart, A., Bukowski, R., Rothenberg, M. L., Wang, K. K., Cooper, W., Grover, J., ... Zhu, A. X. (2007). Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors. Cancer Chemotherapy and Pharmacology, 60(2), 203-209. https://doi.org/10.1007/s00280-006-0362-y

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors. / Lockhart, Albert; Bukowski, R.; Rothenberg, M. L.; Wang, K. K.; Cooper, W.; Grover, J.; Appleman, L.; Mayer, P. R.; Shapiro, M.; Zhu, A. X.

In: Cancer Chemotherapy and Pharmacology, Vol. 60, No. 2, 01.07.2007, p. 203-209.

Research output: Contribution to journalArticle

Lockhart, A, Bukowski, R, Rothenberg, ML, Wang, KK, Cooper, W, Grover, J, Appleman, L, Mayer, PR, Shapiro, M & Zhu, AX 2007, 'Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors', Cancer Chemotherapy and Pharmacology, vol. 60, no. 2, pp. 203-209. https://doi.org/10.1007/s00280-006-0362-y
Lockhart, Albert ; Bukowski, R. ; Rothenberg, M. L. ; Wang, K. K. ; Cooper, W. ; Grover, J. ; Appleman, L. ; Mayer, P. R. ; Shapiro, M. ; Zhu, A. X. / Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors. In: Cancer Chemotherapy and Pharmacology. 2007 ; Vol. 60, No. 2. pp. 203-209.
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AU - Cooper, W.

AU - Grover, J.

AU - Appleman, L.

AU - Mayer, P. R.

AU - Shapiro, M.

AU - Zhu, A. X.

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N2 - Purpose: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results: Five dose levels of MAC-321 ranging from 25 to 75 mg/m2 were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m2). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m2; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m2 had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C max value of less than 1 h. Mean C max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). Conclusions: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m2. The major DLT was neutropenic fever. Four subjects had disease stabilization.

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