TORCMEK update

 We caught up with Professors Peter Schmid and Gary Middleton of the TORCMEK study team about the challenges and successes of their ongoing trial.

Q. What is the anticipated patient benefit of the TORCMEK trial?

TORCMEK aims to establish the feasible dose, regimen and efficacy of the mTOR inhibitor AZD2014 and the MEK inhibitor selumetinib when given in combination.

elumetinib and AZD2014 are two new anticancer treatments that AstraZeneca is developing, neither of which are yet approved for clinical use. Selumetinib acts by blocking a protein called MEK, which has been linked to the development and growth of multiple cancers. AZD2014 blocks a protein called mTOR that is involved in the growth and spread of cancer. Blocking the action of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs may control cancer growth and spread better than if selumetinib or AZD2014 are used alone. Although selumetinib and AZD2014 given alone and in combination with other anticancer drugs have been tested in people with advanced cancer, TORCMEK is the first trial to try this specific combination.  It is hoped that this study will offer a new treatment option for cancer patients.

TORCMEK is sponsored by Queen Mary University of London and conducted in four hospitals in the UK:

• Barts Health NHS Trust (PI & CI: Prof Peter Schmid)
• University Hospitals Birmingham NHS Foundation Trust (PI: Prof Gary Middleton)
• University College London Hospitals NHS Foundation Trust (PI: Dr Martin Foster)
• The Christie NHS Foundation Trust (PI: Dr Yvonne Summers)

It consists of two phases:

1. Phase Ib:  a dose-escalation phase in patients with advanced solid tumours that are resistant to treatment. 25 patients were recruited and completed in August 2016. The objective of Phase Ib of the trial was to establish the maximum tolerated dose and define the recommended Phase IIa dose and regimen (RP2D).

2. Phase IIa: a larger phase for the following types of cancers:

o   squamous cell cancers

o   non-squamous cell cancers with KRAS mutations 

o   non-squamous cell cancers with wild-type KRAS

o   triple-negative breast cancer .

Phase IIa is currently open to recruitment. The phase is looking to assess the clinical activity of AZD2014 in combination with selumetinib. In this phase AZD2014 is administered using an intermittent dosing schedule of two days on and five days off treatment, and selumetinib is given continuously. 

Q. What have been the particular challenges for the set-up and delivery of TORCMEK to date?

The set-up of the trial was quite challenging only in terms of local hospital approval. This is mainly due to the number of assessments involved in a Phase I trial, and the budget available. However, thanks to the early phase experience of clinicians and their local team at the sites, we were able to set-up and continue to deliver successfully on the study.

Q. TORCMEK opened in June 2015, can you tell us what has been achieved and what is yet to be realised?

The recruitment target for Phase I was met within timelines. Since June 2015, 25 patients have been treated in Phase Ib of the trial, and early data suggests that some patients are benefiting from this treatment. Phase Ib has established the recommended Phase IIa dose (RP2D) and that the administration of AZD2014 in combination with selumetinib is safe.

Recruitment to Phase IIa has begun successfully. Following completion of this phase, the efficacy of the drug combination will be assessed in different tumour groups to allow the optimal target population to be identified. This will establish the basis for future development of this novel combination.

Q. Has the experience been different working through the Combinations Alliance? What would you say are the key benefits of working through the Alliance?

Working with the Combinations Alliance has been a beneficial experience and has made the process very smooth. The scientific peer review carried out by the CRUK New Agents Committee was very helpful in assisting with the final protocol design and regulatory applications and approvals. The support offered through regular structured communication, plus the yearly workshops and coordinator meetings where we share experiences and lessons learned have all been key benefits.

Following confirmation of additional funding from AstraZeneca, we are currently writing a protocol amendment to open the trial to different disease cohorts which will provide us with valuable information on the efficacy of this combination in a variety of tumour types. It is this close collaboration with the Alliance that allowed us to discuss the possibility of adding a new cohort.

Q. Would you have any advice to others about to undertake a similar role?

The Alliance is a valuable resource that we would encourage investigators to use. The infrastructure and support offered helps to deliver a successful trial within the necessary timelines. The set-up of a clinical trial can be challenging, however, having the support of an Alliance streamlines the process, as well as providing the necessary input to any queries and hurdles that may occur.