Abstract C69: Preliminary activity of temsirolimus, an mTOR inhibitor, in patients with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix: An NCIC-CTG phase II clinical trial.
Authors: Tinker Anna , MacKay Helen , Ellard Susan , Welch Stephen , Eisenhauer Elizabeth 
Published: June 2012

Abstract
Background: The PI3K-Akt-mTOR pathway is deregulated in invasive cervical carcinomas, possibly as a result of HPV infection. This NCIC CTG 2-stage phase II study aimed to assess the activity of intravenous (IV) temsirolimus, an ester derivative of rapamycin that inhibits mTOR, in patients with metastatic and/or locally advanced recurrent carcinoma of the cervix.
Methods: Eligibility criteria included: squamous, adenosquamous or adenocarcinoma histology, measurable disease, and PFS ≤2. Prior concurrent chemoradiation and 1 prior line of chemotherapy were permitted. Primary endpoint was objective response (by RECIST 1.1), secondary endpoints included response duration, time to progression and molecular correlates of outcome in archival tissue. Temsirolimus 25 mg i.v. was administered weekly in 4 week cycles. Tumor response was assessed every 8 weeks. One response amongst the first 18 patients was required to proceed to the second stage of accrual.
Results: 35 pts (data on 31 available) have been enrolled to date, 28 are now evaluable for toxicity and 23 for response. Follow up is ongoing. 20 pts had received prior chemoradiation and 15 prior chemotherapy for metastatic disease. 19 pts had squamous, 8 adeno and 4 adenosquamous histology. Median age was 52 (range 26–77) yrs. A total of 110 cycles of treatment (median 3; range 1–12) were delivered. 33% of patients received &gt;/= 90% of the planned dose intensity. To date 1 had a partial response (4.3%) lasting 7.2 months, and 15 stable disease (65.2%) median duration of 6.9 months (range 2.4–12.0 months), 11 pts remain on treatment. The median progression free survival was 5.49 months [95% CI (3.65–7.62)]. The most common drug related adverse events of any grade (% of pts) were: fatigue (39%), mucositis (36%), rash maculo-papular (32%), diarrhea (29%), rash-acneiform (21%), and anorexia (18%). Grade 3 hematologic and biochemical toxicites included: lymphopenia (41%), anemia (15%), hyponatremia (11%), hypertriglyceridemia (11%), hyperglycemia (11%), and hypokalemia (7%). No toxicity &gt; grade 3 was observed. Two patients came off study because of adverse events (thromboembolic event and pneumonitis). Six patients experienced 7 serious and possibly drug related adverse events [rash (1), anemia (2), abdominal pain (1), thromboembolism (1), parasthesia (1), edema (1), and diarrhea (1)]. Seven pts required dose reductions, most commonly for the occurrence of rash or mucositis.
Conclusions: Single agent temsirolimus has modest levels of activity in cervical carcinoma with a notably high proportion and duration of disease stabilization. Correlative studies of PI3K pathway will examine which tumor characteristics are associated with PR + SD and this will assist in focusing future investigation of temsirolimus.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C69.