Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer.

BACKGROUND: Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response. METHODS: Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m2 IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2. RESULTS: 32 patients enrolled from 11/2012-5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress ßII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with ßII and BAX overexpression, OS was significantly shorter in those with ßIII and BAX overexpression. These associations remained after multivariate analysis. CONCLUSIONS: Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. ßII, ßIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.

Phase II study of gemcitabine and docetaxel in recurrent platinum resistant ovarian cancer.

UNLABELLED: To evaluate the activity of gemcitabine and docetaxel in patients with recurrent ovarian cancer. METHODS: Patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with docetaxel on day 1 and gemcitabine on days 1 and 8, repeated every three weeks. RESULTS: Twenty patients, with a platinum-free interval of three months, were enrolled. Overall response rate was 25%. Treatment was associated with significant myelosuppression. CONCLUSIONS: In chemotherapy-resistant patients, this regimen exhibited encouraging activity. Excessive myelosuppression led to early closure. This was prevented by administering docetaxel on day 8 (instead of day 1) and prophylactic use of G-CSF.

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin.

BACKGROUND: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. PATIENTS AND METHODS: Patients were treated with intravenous topotecan (0.75-1.25 mg/m2) for 3 days followed by PLD (25-40 mg/m2) on Day 4. The following dose combinations (topotecan/PLD, mg/m2) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. RESULTS: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m2 every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m2 every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. CONCLUSIONS: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m2 on Days 1-3 followed by PLD 40 mg/m2 on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m2 on Days 1-3 and PLD 30 mg/m2 on Day 4 of a 21-day cycle.

Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer.

OBJECTIVE: The purpose of this study is to evaluate the activity of gemcitabine and weekly paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Thirty-five patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with paclitaxel 80 mg/m(2) IV over 60 min, followed by gemcitabine 1000 mg/m(2) IV administered on days 1, 8, and 15. Cycles were repeated every 4 weeks. RESULTS: All patients had platinum-resistant disease and all had received prior treatment with paclitaxel. Patients were heavily pretreated as the median number of chemotherapy regimens for recurrent disease was 2 (0-3). The overall response rate was 40% (95% confidence intervals (24%, 58%) and 37% of patients achieved stable disease. The median time to progression was 5.7 months (95% CI, 4.6, 8.5) and median overall survival 13.1 months (95% CI, 10.6, 15.9). More than 50% of patients were alive at 12 months, including six patients (17%) who were alive at 24 months. Treatment was well tolerated. Grades 3-4 neutropenia occurred in 17 patients (48.5%), grade 3 thrombocytopenia in 7 (20%), grade 3 anemia in 3 (8.5%). The most common serious non-hematological toxicities were nausea (14%), vomiting (14%), and fatigue (34%). CONCLUSIONS: The regimen of weekly paclitaxel and gemcitabine exhibits significant activity in heavily pretreated patients, is well tolerated, and is associated with encouraging survival. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.