Ignite Creation Date:
2024-05-06 @ 5:26 PM
Last Modification Date:
2024-10-26 @ 2:28 PM
Study NCT ID:
NCT05304546
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-06-05
First Post:
2022-03-16
Brief Title:
Overcoming Primary Resistance to Immunotherapy in Metastatic Melanoma
Sponsor:
Dr Ronnie Shapira
Organization:
Sheba Medical Center
Study Overview
Official Title:
Overcoming Primary Resistance to Immunotherapy in Metastatic Melanoma Patients by Transient Addition of BRAF and MEK Inhibitors Followed by Pembrolizumab A Pivotal Open Label Single-site Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MK3475-C01
Brief Summary:
This study will enroll metastatic Stage IV or inoperable stage III melanoma MM patients carrying a BRAF V600EK mutation with confirmed primary resistance to standard of care immunotherapy single agent PD-1 or a combination of CTLA-4PD-1 blockade Patients must be naïve to therapy with BRAFMEK inhibitors with an Eastern Cooperative Oncology Group ECOG performance status of 0 or 1
Detailed Description:
Treatment groups single-arm
During Weeks 1-4 of the study subjects will receive intravenous pembrolizumab 400 mg every 6 weeks Q6W oral encorafenib 450 mg once daily and oral binimetinib 45mg twice daily From Week 5-13 participants will receive intravenous pembrolizumab 400 mg every 6 weeks From Week 13 to 2 years subjects with a response of stable disease or better determined by CT every 3 months will receive pembrolizumab 400mg Q6W until evident progressive disease by Response Evaluation Criteria In Solid Tumors RECIST unacceptable toxicity withdrawal of consent or until completion of 17 treatment cycles approximately 2 years with pembrolizumab
Participants who stop study treatment after receiving 17 administrations of pembrolizumab for reasons other than disease progression or intolerability or participants who attain a complete response CR and stop study treatment may be eligible for up to 1 year of treatment with pembrolizumab 8 cycles upon experiencing disease progression Second Course Phase
Tumor biopsies and blood peripheral blood mononuclear cells PMBC and plasma will be obtained upon patient recruitment during the screening period after 4 weeks of treatment and at 13 weeks
Primary Translational Objectives Hypothesis
1 To determine the decrease in nuclear c-MYC levels in situ in tumor biopsies and blood following treatment
2 To determine the increase in mitochondrial activity protein profile Acetyl-CoA acetyltransferase ACAT1 and Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha HADHA in the tumor cells1 in situ following treatment
3 To determine the increase in CD8 counts in situ following treatment Hypothesis c-MYC impairs interferon gamma IFNγ responsiveness and drives anaerobic metabolismwhich reduces antigenicity MAPK activation through the BRAF V600 mutation leads to c-MYC activation and its nuclear translocation in MM patients directly inhibiting aerobic metabolism in melanoma cells in-vitro Thus BRAF V600 seems to drive both mechanisms 1 and 2 highlighting its potential targeting to revert primary immune resistance
The investigators hypothesize that BRAF inhibition will deactivate c-MYC and drive tumor cell metabolism towards oxidative phosphorylation c-MYC deactivation is expected to alleviate IFNγ resistance Aerobic metabolism of tumor cells is expected to increase their immunogenicity The combined effect is expected to overcome primary resistance and reinvigorate local immune response This is expected to be evident by increased T cell influx which is associated with successful checkpoint inhibition and could be further perpetuated with PD-1 blockade
Primary Clinical Objectives Hypothesis
To determine the best overall response rate BORR to pembrolizumab Hypothesis The immunological alteration in the tumor and its microenvironment will provide the grounds for pembrolizumab to induce a clinical response
During Weeks 1-4 of the study subjects will receive intravenous pembrolizumab 400 mg every 6 weeks Q6W oral encorafenib 450 mg once daily and oral binimetinib 45mg twice daily From Week 5-13 participants will receive intravenous pembrolizumab 400 mg every 6 weeks From Week 13 to 2 years subjects with a response of stable disease or better determined by CT every 3 months will receive pembrolizumab 400mg Q6W until evident progressive disease by Response Evaluation Criteria In Solid Tumors RECIST unacceptable toxicity withdrawal of consent or until completion of 17 treatment cycles approximately 2 years with pembrolizumab
Participants who stop study treatment after receiving 17 administrations of pembrolizumab for reasons other than disease progression or intolerability or participants who attain a complete response CR and stop study treatment may be eligible for up to 1 year of treatment with pembrolizumab 8 cycles upon experiencing disease progression Second Course Phase
Tumor biopsies and blood peripheral blood mononuclear cells PMBC and plasma will be obtained upon patient recruitment during the screening period after 4 weeks of treatment and at 13 weeks
Primary Translational Objectives Hypothesis
1 To determine the decrease in nuclear c-MYC levels in situ in tumor biopsies and blood following treatment
2 To determine the increase in mitochondrial activity protein profile Acetyl-CoA acetyltransferase ACAT1 and Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha HADHA in the tumor cells1 in situ following treatment
3 To determine the increase in CD8 counts in situ following treatment Hypothesis c-MYC impairs interferon gamma IFNγ responsiveness and drives anaerobic metabolismwhich reduces antigenicity MAPK activation through the BRAF V600 mutation leads to c-MYC activation and its nuclear translocation in MM patients directly inhibiting aerobic metabolism in melanoma cells in-vitro Thus BRAF V600 seems to drive both mechanisms 1 and 2 highlighting its potential targeting to revert primary immune resistance
The investigators hypothesize that BRAF inhibition will deactivate c-MYC and drive tumor cell metabolism towards oxidative phosphorylation c-MYC deactivation is expected to alleviate IFNγ resistance Aerobic metabolism of tumor cells is expected to increase their immunogenicity The combined effect is expected to overcome primary resistance and reinvigorate local immune response This is expected to be evident by increased T cell influx which is associated with successful checkpoint inhibition and could be further perpetuated with PD-1 blockade
Primary Clinical Objectives Hypothesis
To determine the best overall response rate BORR to pembrolizumab Hypothesis The immunological alteration in the tumor and its microenvironment will provide the grounds for pembrolizumab to induce a clinical response
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None