ERASE

Trial summary:

Up to three rounds of response-adapted SABR (Pilot Part A) and response-adapted and anatomically adapted SABR (Pilot Part B) to up to 5 new or SABR-naïve lesions not achieving a complete metabolic response (CMR) at 3, 6 and 9 months following start of treatment with standard of care anti-programmed death (PD)-1 based immunotherapy. The metastases must be radiologically defined targets and be suitable for treatment with SABR.

The first 5 participants will form the cohort for Pilot Part A and will be treated with response-adapted SABR if they satisfy criteria to receive SABR treatment (response criteria defined in next paragraph). If 4 of these 5 participants are successfully treated then the trial will proceed to Pilot Part B. In Pilot Part B another 5 participants will be treated with response-adapted and anatomically adapted SABR if they are eligible to receive SABR. If 4 of the 5 participants from Pilot Part B are successfully treated then the trial will progress to the ERASE Phase 2 study.

Responses to immunotherapy will be based on a fluorodeoxyglucose- positron emission tomography (FDG-PET) scan. At 3 months post-initiation of immunotherapy participant’s response will be used to determine whether the participant is eligible to receive SABR treatment. Participants whose lesions show a CMR at 3 months will not receive any SABR. Participants who do not achieve a CMR to immunotherapy at 3 months post-initiation of immunotherapy, with a maximum of five lesions, will be eligible for SABR treatment. At 6 and 9 months post-start of immunotherapy the participant’s responses will determine whether the participant is eligible to receive further rounds of SABR treatment. Participants who were not eligible for SABR at 3 months post start of immunotherapy may proceed to SABR based on their responses at the 6- and/or 9-month follow-up timepoints. At 6 and 9 months post-start of immunotherapy if the participant has no new or worsening lesions that have not been treated with SABR before or the participant has more than 5 new or worsening lesions that have not been treated with SABR then they will not be eligible for SABR. Participants not requiring SABR will serve as a non-SABR comparator group.

All participants eligible for SABR will have a radiotherapy planning session. The planning session will involve a computed tomography (CT) scan that will help the radiation oncologist to plan the treatment. Treatment for all parts of this study will be performed on the Varian Ethos™ treatment platform using local standard clinical guidelines for the delivery of stereotactic treatment for oligometastases. Participants will receive treatment in the same position and immobilised with the same stabilisation equipment used at the radiotherapy planning appointment. SABR treatment will be delivered by a radiation oncologist.

Response Adapted SABR
Participants in both Pilots Part A and B will receive response adapted SABR. Taking into account the biological response to immunotherapy could avoid over-treating participants who respond well to immunotherapy and allow for higher doses for participants who don’t respond as well.

Participants who do not achieve a CMR to immunotherapy at 3 months post-initiation of immunotherapy, with a maximum of five lesions, will receive response-adapted SABR. The SABR dose regimen will be a minimum of 6 Gy per fraction, in 3-5 fractions, dependent on lesion size, location and biology. The SABR dose will be tailored based on the objective Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST). The SABR doses used will be as below:
1) For patients with partial metabolic response (PMR): 24 Gy in 3 fractions or 30 Gy in 5 fractions.
2) For patients with stable metabolic disease (SMD): 27 Gy in 3 fractions or 34 Gy in 5 fractions.
3) For patients with progressive metabolic disease or new lesions: 30 Gy in 3 fractions or 37.5 Gy in 5 fractions.
Participants with up to five new or SABR-naïve progressive lesions at 6 and/or 9 months will be eligible to receive further rounds of SABR. Participants with a CMR to immunotherapy at 3, 6 and 9 months will not receive SABR. Previously treated lesions will not receive any further SABR. A patient can receive a maximum of 3 rounds of SABR treatment based on their response to immunotherapy.

Anatomically Adapted SABR
In the Pilot Part B study anatomical adaptation will also be used to deliver SABR. This is achieved through daily adaptation of the treatment plan to accommodate for variations in internal anatomy from the original treatment plan (e.g. deformations and/or differences in location). By adjusting for the shape and position of the cancer the radiation dose to the important nearby organs can be minimised and higher doses of radiation can potentially be delivered. The treating radiation oncologist will have oversight of all adaptations to the treatment plan.

Receptor status / problem studied: