Title: INTERIM: a randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted therapy In patients with BRAF mutant unresectable or metastatic Melanoma
Funder: Department of Health and Social Care

Abstract: Over 13,000 melanomas are diagnosed yearly in the UK and this is rising rapidly. One fifth of patients will develop metastatic spread, after which life expectancy may be measured in months. Two BRAF and MEK inhibitor (BRAF+MEKi) combination regimens (dabrafenib+trametinib and vemurafenib+cobimetinib) have shown a significant improvement in survival and quality of life (QoL) when administered to patients with BRAF mutant metastatic melanoma, who make up 45% of the advanced melanoma population. With BRAF+MEKi combination therapy, median life expectancy has increased incrementally to 24 months from around 18 using a BRAF inhibitor alone. However, most patients will die of their cancer and chronic side effects from the combination regimens, particularly affecting the skin, diminish QoL. Acquired resistance develops while receiving BRAF targeted therapy and remains a key challenge for development of more effective treatment, as does chronic toxicity associated with continuous daily dosing of these oral agents. Clinical experience shows that intermittent therapy can successfully manage drug-induced toxicity and sustain patients on BRAF targeted treatment without loss of disease control. Intermittent drug dosing may delay the onset of disease progression, as continuous dosing promotes clonal expansion of drug resistant cells. In a mouse model, vemurafenib resistant tumour cells become drug-dependent. Resistant cells suffer a fitness deficit in the absence of drug suggesting that intermittent dosing can delay or prevent the emergence of resistant tumour clones. Mice survived twice as long (200 days compared with 100 days) on an intermittent dosing schedule of vemurafenib (4 weeks on 2 weeks off) compared with continuous daily dosing. Clinical case reports suggest that interrupted dosing of BRAF inhibitors can reverse resistance to the drugs and improve tolerability. Intermittent dosing can also attenuate relief of upstream feedback within the MAPkinase pathway, a mechanism known to contribute to drug resistance. Our hypothesis is that pre-planned intermittent dosing with BRAF+MEKi will sustain patients on treatment for longer periods, delay the onset of disease progression and improve QoL on treatment. This feasibility study is designed to assess whether and how best this hypothesis should be tested definitively in a phase III trial. We also need better tools to monitor skin side effects. 150 patients with histologically/cytologically confirmed BRAFV600 mutant unresectable/metastatic melanoma will be randomised (1:1) to standard continuous dosing with BRAF+MEKi, or the same drugs given with planned breaks. All treatments will be given orally on a 4-weekly cycle until disease progression. Patients will be assessed 2 weekly for the first 8 weeks, then 4 weekly until disease progressed and then 3 monthly. Trial arm (28 day cycles) Dabrafenib+trametinib Standard (continuous) Dabrafenib 150mg bid d1-28 Trametinib 2mg od d1-28 Experimental (intermittent) Dabrafenib 150mg bid d1-21 Trametinib 2mg od d1-14 The primary endpoints are recruitment rate (to assess patients and doctors acceptance of randomisation to a trial evaluating less treatment than usual), treatment compliance (to assess the compliance of the intermittent dosing schedule), QoL (to evaluate the improvement in global health status derived from the standard EORTC QLQ-C30 questionnaire; to explore and develop new tools to better capture the toxicity of kinase inhibitors in melanoma patients) and progression-free survival (PFS) (to estimate the size of PFS efficacy). The decision to proceed with a phase III trial will be based on pre-specified criteria. If adopted, intermittent dosing would lead to considerable reduction in health care costs for treating this type of cancer and may have implications for the management of other cancers treated with similar high cost drugs.

Lay abstract: Melanoma is diagnosed in 13,000 people each year and this number is rising. In one in five patients, melanoma spreads from the skin to other organs, dramatically reducing life expectancy. A gene called BRAF is abnormal in about half of melanomas, causing the disease to grow and spread. Drugs which block BRAF and another related protein called MEK are used to stop this process. Giving BRAF and MEK inhibitor drugs together offers the best anti-cancer treatment for such patients. Taken orally every day, the combination can increase life expectancy to two years compared with 18 months using a BRAF inhibitor alone. However most patients suffer side-effects, often affecting the skin, diminishing their quality of life, and will still die of their cancer. Laboratory experiments and case reports suggest intermittent treatment makes these drugs work for longer, helping patients live longer and reduce side-effects. Our trial will look into this more intensively. We will see if less treatment than usual is acceptable to patients and doctors and, potentially, more beneficial. We also aim to develop better tools to monitor skin side-effects. We will recruit 150 patients whose melanoma has the defective BRAF gene. All participants will receive BRAF+MEK inhibitor treatment, with half chosen randomly to have planned breaks in their treatment and the other half treated continuously. Comparing these groups will reveal how successful we are in recruiting participants and delivering intermittent therapy, the effects on patients quality of life and an initial estimate of how long the drugs work. The study s design is based on patient feedback. Patient representatives will serve on the steering committee. Findings will be presented at conferences, published in journals, distributed through all PPI networks and cancer charities, used to inform future trials and shared widely with doctors if changes to current treatment practices are indicated.

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