Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated.Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy.Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety. BACKGROUND: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination. METHODS: This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible. RESULTS: Five patients were enrolled. Their median age was 56 years (range 39-61), and the ECOG status was 0-2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL -1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL -1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1-3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9-2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68-23.4). CONCLUSION: In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed no clinical activity. Although the study was closed early because of toxicity concerns, future studies assessing combinations of sorafenib with new-generation immunomodulator drugs or other immunomodulatory agents, should consider lower starting doses of sorafenib to avoid excessive toxicity.

Pemetrexed in patients with locally advanced or metastatic breast cancer who had received previous anthracycline and taxane treatment: phase II study.

PURPOSE: The objective of this study was to assess the efficacy and safety of pemetrexed in pretreated patients with advanced-stage breast cancer. PATIENTS AND METHODS: Patients with advanced-stage or metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-2, and progressive or relapsed disease after treatment with regimens containing anthracyclines and taxanes were eligible. Pemetrexed 500 mg/m2 was administered as a 10-minute intravenous infusion on day 1 every 21 days. RESULTS: Seventy-nine women were enrolled. After protocol amendment, 43 patients received folic acid and vitamin B12 supplementation to control pemetrexed-related toxicity. A median of 4 cycles (range, 1-23 cycles) was administered. Overall response rate was 9% (95% confidence interval, 3.7%-17.6%), median duration of response was 5.5 months, median progression-free survival was 3.1 months, and median survival was 10.5 months. Major grade 3/4 toxicities were lymphopenia (53.3%), neutropenia (36.4%), leukopenia (26.9%), and anemia (7.7%). In general, the toxicities were less frequent in patients who received vitamin supplementation than in those who did not receive vitamin supplementation. CONCLUSION: The response to pemetrexed salvage treatment was low in this study of heavily pretreated patients with breast cancer. Pemetrexed was generally well tolerated in patients with previously treated breast cancer. Vitamin supplementation appeared to ameliorate toxicity.

Phase II study of pemetrexed in patients pretreated with an anthracycline, a taxane, and capecitabine for advanced breast cancer.

BACKGROUND: This phase II study evaluated the efficacy, safety, and health outcomes of pemetrexed treatment in heavily pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Women with metastatic breast cancer, Karnofsky performance status > or = 70, and previous treatment with > or = 3 regimens containing anthracyclines, taxanes, and capecitabine were eligible. Pemetrexed 500 mg/m2 intravenous infusion was administered on day 1 of a 21-day treatment cycle. RESULTS: Eighty patients were enrolled, and 60 received concurrent folic acid and vitamin B12 supplements per protocol amendment to minimize possible pemetrexed-related toxicity. The median numbers of cycles delivered were 3 for vitamin-supplemented patients and 2 for non-vitamin-supplemented patients. Regardless of vitamin supplementation, the overall response rate was 8% (95% CI, 3%-16.6%), stable disease was exhibited in 36% of patients, median time to disease progression was 2.9 months, and median survival was 8.2 months. Improvements in patient-reported symptoms ranged from 16.2% for pain intensity to 32.1% for nausea. Major grade 3/4 toxicities were hematologic, with grade 4 neutropenia in 10% of patients and grade 3 toxicities consisting primarily of neutropenia (29%) and leukopenia (21%). There were no clear trends of the effect of supplementation on toxicity. CONCLUSION: Pemetrexed has modest antitumor activity and is well tolerated in heavily pretreated patients with breast cancer. Further evaluation of this multitargeted antifolate in advanced breast cancer is warranted.

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies.

BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single-agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies. METHODS: Twenty-six patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m(2) and gemcitabine 1000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. RESULTS: The MTD was PEG-LD 20 mg/m(2) and gemcitabine 2000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were observed in a second patient during Cycle 2 after administration of PEG-LD 25 mg/m(2) and gemcitabine 2000 mg/m(2). Other side effects included palmar-plantar erythrodysesthesia, nausea, and fatigue. One complete and two partial responses were observed. CONCLUSIONS: The recommended Phase II dose is PEG-LD 20 mg/m(2) with gemcitabine 2000 mg/m(2) on Days 1 and 15 of a 28-day cycle. A trial with this combination is currently ongoing at this institution comprising patients with refractory ovarian carcinoma.