Short summary

Despite response to chemotherapy around 80% of patients with ovarian cancer (OC) will experience recurrence of disease, which is incurable in almost all cases. 

This project will investigate the effect of bevacizumab and tocotrienol based on the level of methylated circulating tumor DNA in recurrent ovarian cancer. This circulating marker driven phase II trial allocates patients according to methylated HOXA9 after the first treatment cycle, with the perspective to identify patients, who can benefit from palliative chemotherapy.

Rationale

Ovarian cancer (OC) remains the most lethal disease among gynecological malignancies. Up to 80% of the patients will experience recurrence of disease, despite partial or complete clinical response to primary treatment. Recurrent OC is an incurable disease in almost all cases and leaves the patients with few or no treatment options.

The monoclonal antibody bevacizumab has been established as an integrated part of both first and second line treatment of OC. Bevacizumab is well tolerated in most patients.

Tocotrienols are parts of the natural E-vitamin. In-vivo experiments have shown that ?-tocotrienol inhibits angiogenesis and tumor growth resulting in prolonged survival. It has an additive effect to cytostatics as summarized in a recent review based on the available in vitro, in vivo and clinical studies.

Aberrant DNA methylation in OC is observed in early cancer development. Part of the methylated DNA is shed in the circulation and can be detected in plasma as circulating tumor DNA (ctDNA).

Methylation of the HOXA9 gene has especially been associated with OC and is found in plasma of the majority of patients with advanced OC. HOXA9 methylated ctDNA (HOXA9 meth-ctDNA), however, is not found in the blood from healthy individuals. 

A recent study at the Department of Oncology, Vejle Hospital, investigated bevacizumab and tocotrienol in recurrent OC patients and concurrently monitored the level of HOXA9 meth-ctDNA in plasma. The rate of disease control was 70% with a median progression free and overall survival of 6.9 months and 10.9 months, respectively, which is higher than other studies using bevacizumab alone. The toxicity was very low and attributed to bevacizumab only.

The results also allowed for a division of the patients into two groups after the first cycle of treatment. The group of patients (30%) with a significant increase of HOXA9 meth-ctDNA had a median progression free survival of 1.4 months and a median overall survival of 4.3 months. In contrast, the group with stable or decreasing HOXA9 meth-ctDNA had a median progression free survival and overall survival of 7.8 and 12 months, respectively. The first group did obviously not benefit from the treatment as opposed to the other group with a considerably prolonged survival.

The results were based on 23 patients and call for confirmation in a new study. The present protocol aims at addressing the issue in a new phase II trial with treatment continuation based on the level of HOXA9 meth-ctDNA after the first cycle.

Objective:

To investigate the effect of bevacizumab and tocotrienol based on the level of HOXA9 meth-ctDNA after the first treatment cycle assessed by progression free survival.

Design:

Comparison of the level of HOXA9 meth-ctDNA before start of treatment and three weeks after the first cycle forms the basis of dividing the patients into two groups. Arm A: Patients with an increase of HOXA9 meth-ctDNA above the 95% confidence interval of the baseline value will discontinue protocol treatment. Arm B: Patients with stable or decreasing HOXA9 meth-ctDNA below the 95% confidence interval of the baseline value will continue protocol treatment until progression, unacceptable toxicity, or patient wish to discontinue.

Expected impact: 

Detection of HOXA9 meth-ctDNA will improve selection of patients for palliative therapy and thereby reduce the number of patients receiving ineffective therapy with a wide range of side-effects and impact on quality-of-life.

Description of the cohort

The study is a two-arm non-randomized phase II trial based on HOXA9 meth-ctDNA in the blood of recurrent OC patients (all stages) during treatment with bevacizumab and tocotrienol at the Department of Oncology, Vejle Hospital. 

Data and biological material

Blood.

A blood sample will be drawn before start of treatment and then 3 weeks after the first cycle, where allocation in regard to HOXA9 methylation status will take place. For patients in Arm B blood samples will be drawn at every cycle until progression or stop of treatment for other reasons.

Collaborating researchers and departments

Department of Oncology, Vejle Hospital

• Professor Karina Dahl Steffensen, PhD, MD

Department of Biochemistry and Immunology, Vejle Hospital

• Molecular biologist Rikke Fredslund Andersen, PhD

Publications associated with the project