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 language | English (US) |
|---|---|
| Pages (from-to) | 203-209 |
| Number of pages | 7 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 60 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 1 2007 |
| Externally published | Yes |
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Keywords
- Clinical trial
- Docetaxel
- MAC-321
- Paclitaxel
- Phase I
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors
AU - Lockhart, Albert
AU - Bukowski, R.
AU - Rothenberg, M. L.
AU - Wang, K. K.
AU - Cooper, W.
AU - Grover, J.
AU - Appleman, L.
AU - Mayer, P. R.
AU - Shapiro, M.
AU - Zhu, A. X.
PY - 2007/7/1
Y1 - 2007/7/1
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.
AB - 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.
KW - Clinical trial
KW - Docetaxel
KW - MAC-321
KW - Paclitaxel
KW - Phase I
UR - http://www.scopus.com/inward/record.url?scp=34248335926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34248335926&partnerID=8YFLogxK
U2 - 10.1007/s00280-006-0362-y
DO - 10.1007/s00280-006-0362-y
M3 - Article
VL - 60
SP - 203
EP - 209
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 2
ER -