TY - JOUR
T1 - A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies
AU - Moroney, John W.
AU - Schlumbrecht, Matthew P.
AU - Helgason, Thorunn
AU - Coleman, Robert L.
AU - Moulder, Stacy
AU - Naing, Aung
AU - Bodurka, Diane C.
AU - Janku, Filip
AU - Hong, David S.
AU - Kurzrock, Razelle
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, toDand A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted. Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations.
AB - Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, toDand A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted. Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations.
UR - http://www.scopus.com/inward/record.url?scp=80455173410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80455173410&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-0666
DO - 10.1158/1078-0432.CCR-11-0666
M3 - Article
C2 - 21890452
AN - SCOPUS:80455173410
SN - 1078-0432
VL - 17
SP - 6840
EP - 6846
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -