The biggest change in CLOVER (between Version 6 03/30/26 and Version 8 09/03/2026) is that CYDY added an optional open label cohort where patients who progress on leronlimab + TAS 102 + bevacizumab can switch to:
• Leronlimab 700 mg weekly
• Pembrolizumab 200 mg every 3 weeks
This change required rewriting the Brief Summary, Detailed Description, Outcome Measures, Eligibility Criteria, Arms & Interventions sections, but what it means is that we want to capture patients who progress early and test CCR5 blockade + PD 1 inhibition. This expands the scope of the trial and, as I understand it, there are now + 12 optional patients in the pembrolizumab cohort.
Also, not less important, there are expanded outcome measures and changes relevant to ctDNA, PD-L1 and CCR biomarkers. For example, now there is an explicit ctDNA endpoint added as a longitudinal biomarker (to cover up to 2 years and aligning the trial with modern oncology standards where ctDNA decline is a strong early indicator of treatment response, especially in MSS colorectal cancer.)
Additionally, PD-L1 was not present in version 6 (I believe), and CTCs and CAMLs were added. This helps with ascertain immune activation (in the context of pembrolizumab responsiveness and correlate CCR5 blockade with PD 1/PD L1 axis changes.) On top, a new exploratory endpoint was mentioned for CCL2 / CCL3 / CCL4 / CCL5 chemokines (ligands of CCR5), in my opinion, trying to (mechanistically) understand better chemokine shifts as markers.
But, beyond pure changes my question is: why between March and September this has been included? i.e.: why would I add Pembrolizumab to the trial?? Speculating my answer is: because it can benefit (some) patients. As we know, there are some criteria that new to be met to use an ICI (for example CPS > X number). Does this mean that in the open-label trial we know this is the case?? Otherwise, why incorporate these changes??? Where those to be included regardless of whatever (large quantity of) data is available now?
I leave these questions open ...
• Leronlimab 700 mg weekly
• Pembrolizumab 200 mg every 3 weeks
This change required rewriting the Brief Summary, Detailed Description, Outcome Measures, Eligibility Criteria, Arms & Interventions sections, but what it means is that we want to capture patients who progress early and test CCR5 blockade + PD 1 inhibition. This expands the scope of the trial and, as I understand it, there are now + 12 optional patients in the pembrolizumab cohort.
Also, not less important, there are expanded outcome measures and changes relevant to ctDNA, PD-L1 and CCR biomarkers. For example, now there is an explicit ctDNA endpoint added as a longitudinal biomarker (to cover up to 2 years and aligning the trial with modern oncology standards where ctDNA decline is a strong early indicator of treatment response, especially in MSS colorectal cancer.)
Additionally, PD-L1 was not present in version 6 (I believe), and CTCs and CAMLs were added. This helps with ascertain immune activation (in the context of pembrolizumab responsiveness and correlate CCR5 blockade with PD 1/PD L1 axis changes.) On top, a new exploratory endpoint was mentioned for CCL2 / CCL3 / CCL4 / CCL5 chemokines (ligands of CCR5), in my opinion, trying to (mechanistically) understand better chemokine shifts as markers.
But, beyond pure changes my question is: why between March and September this has been included? i.e.: why would I add Pembrolizumab to the trial?? Speculating my answer is: because it can benefit (some) patients. As we know, there are some criteria that new to be met to use an ICI (for example CPS > X number). Does this mean that in the open-label trial we know this is the case?? Otherwise, why incorporate these changes??? Where those to be included regardless of whatever (large quantity of) data is available now?
I leave these questions open ...
8
