Title: PROgesterone as a Steroid SParing agent against oEdema occurring with secondary bRain cancers
Funder: Medical Research Council

Abstract: Patients with cancers affecting their brain often have brain swelling caused by the tumour that can cause problems including headaches, sickness and sometimes seizures (epileptic fits). The swelling is normally treated using a steroid medicine called dexamethasone. Unfortunately, dexamethasone has side effects including mood changes, sleep problems and weight gain. Patients with cancers affecting their brain often have to take dexamethasone for a long time and these side effects can make their quality of life worse. _x000D_ Progesterone is another steroid that is produced naturally in the body at quite high levels in premenopausal women; it is also present at low levels in men, in whom it is converted to the “male” hormone testosterone. Progesterone has been used for almost 60 years as a contraceptive (to prevent pregnancy) and has fewer side effects than dexamethasone. _x000D_ In laboratory research looking at head injury, progesterone does reduce brain swelling, suggesting it may allow lower doses of dexamethasone to be used in people with cancer affecting the brain. The PROSSPER study is looking to establish the dose of progesterone to give to people with cancer that has affected the brain and to look for signs that taking progesterone may reduce the dose of dexamethasone such people need. _x000D_ _x000D_ The study will take place in 2 stages. Both stages will include patients with cancer that has spread to the brain who fit criteria to take part in the trial. After checking it is safe for them to take part in the study, including having blood taken, patients who agree will enter the trial. At that time, they will have been taking 8 milligrams (mg)/day of dexamethasone for at least 2 days; that dose of dexamethasone may be changed, or even stopped, depending on their symptoms during the period of the trial. _x000D_ Stage 1 - 6 patients _x000D_ On Day 1, patients will take 8mg dexamethasone and the first dose of progesterone. On Days 2-10, patients will continue take dexamethasone as clinically indicated, except on one day (between days 5-10) when the second dose of progesterone is given. On this day 8mg dexamethasone must be taken._x000D_ Depending on these results, an extra 6 patients may enter Stage 1 but take a different dose of progesterone. At the end of Stage 1 the study team will know the progesterone dose to be used in Stage 2. _x000D_ _x000D_ Stage 2 - 36 patients _x000D_ Stage 2 patients will be asked to complete quality of life questionnaires. They will be put into one of two groups randomly. One group will take progesterone at the dose chosen in Stage 1 and the other will take a placebo or “dummy” tablet that looks the same but does not contain progesterone. Patients will take the progesterone or dummy tablets for 14 days with the study team looking to see if there is any difference between the two groups in terms of the dose of dexamethasone patients need to control their symptoms. Patients will have extra blood tests taken on Day 1, 4, 8, 15 and 22, and an extra CT or MRI brain scan on Day 14. They will be asked to keep a diary and speak with a research nurse daily to check if they are having any side effects. After Day 14 patients will stop the progesterone or placebo and their doctors will continue normal care. Patients will be interviewed by the research team to discuss how they felt during the trial and have a final review by the research team on Day 21.

Lay abstract: Corticosteroids, and in particular dexamethasone, are central to the management of patients with brain tumours and cerebral oedema. Whilst dexamethasone is cheap, quick acting and effective, it has many, often serious side-effects that increase with cumulative dose. Furthermore, there is increasing evidence that patients with malignant gliomas who remain on corticosteroids fare worse than those in whom steroids can be withdrawn and not simply because they have worse disease; possible explanations include steroid myopathy, impaired immunity, adrenal insufficiency and a potential radioprotective effect of steroids. The need for an alternative to corticosteroids has become increasingly recognised, but to date no such alternative has been identified._x000D_ _x000D_ Progesterone is a naturally occurring steroid that been used safely for decades, including as an oral contraceptive agent. Progesterone also has neuroprotective and anti-inflammatory properties, but far fewer side-effects than dexamethasone; it is neuroprotective in animal models, with demonstrable anti-oedema effects, enhancing BBB function by reducing inflammatory cytokines and expression of VEGF and matrix metalloproteases. These mechanisms closely mimic those of dexamethasone on cerebral oedema. Initial trials in patients with neurotrauma were promising; in randomised clinical trials, however, progesterone was safe but ineffective. This may be due to the very high i.v. doses of progesterone used. Of note, dexamethasone is equally ineffective in neurotrauma despite being highly effective in patients with brain tumours; this likely represents the different mechanisms of raised intracranial pressure between patients with trauma and brain tumours, with the latter having significantly more vasogenic oedema. _x000D_ _x000D_ Therefore, progesterone warrants investigation as an alternative to corticosteroids for patients with brain tumours and oedema. Unfortunately, animal models of brain tumours do not replicate the oedema seen in patients, so laboratory studies would be of limited value. In addition, the optimal dose of progesterone in this setting is not known. _x000D_ _x000D_ PROSSPER is a two stage trial in patients with brain metastases and symptomatic cerebral oedema. The overall objective is to provide pharmacokinetic data to guide the dosing of progesterone as a steroid-sparing agent for the treatment of brain tumour oedema and to provide evidence of feasibility and preliminary evidence of efficacy to underpin a subsequent definitive randomised controlled trial comparing progesterone and placebo. _x000D_ _x000D_ In Stage 1, we will undertake a pharmacokinetic study to identify the oral dose to achieve our target plasma progesterone levels. We then need to confirm safety and tolerability of oral progesterone at this dose. In this second stage patients will be randomised (1:1) between progesterone and placebo and we will record tolerability. From Study Day 3 the dexamethasone dose will be reduced, if clinically appropriate. For this we will pilot a structured dexamethasone reduction protocol to allow a preliminary assessment of the efficacy of progesterone as a dexamethasone sparing agent. Patient reported outcome measures of quality of life will also be assessed._x000D_ _x000D_ If PROSSPER is successful, we will propose a larger definitive Phase 3 trial studying the efficacy of progesterone as a dexamethasone sparing agent in patients with primary and metastatic brain tumours and oedema. This larger trial would be a double blind, randomised controlled trial that could transform the experience and QoL of patients with brain tumours.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS