Ignite Creation Date:
2024-05-06 @ 12:10 PM
Last Modification Date:
2024-10-26 @ 12:55 PM
Study NCT ID:
NCT03694977
Status:
UNKNOWN
Last Update Posted:
2019-04-09
First Post:
2018-09-19
Brief Title:
Biomarker Study of PDR001 in Combination With MCS110 in Gastric Cancer
Sponsor:
Seoul National University Hospital
Organization:
Seoul National University Hospital
Study Overview
Official Title:
Biomarker Study of PDR001 in Combination With MCS110 in Gastric Cancer
Status:
UNKNOWN
Status Verified Date:
2019-04
Last Known Status:
RECRUITING
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:
None
Brief Summary:
Background
1 Current status of treatment options in advanced gastric cancer
The cytotoxic chemotherapy usually fluoropyrimidine platinum combination regimen is current standard of care In case of HER2 gastric cancer the addition of trastuzumab on top of cytotoxic chemotherapy is standard of care
In second-line setting the cytotoxic chemotherapy in combination with Ramucirumab improved the patients survival compared with cytotoxic chemotherapy alone
There are few treatment options for gastric cancer patients who have been treated with more than two lines of palliative chemotherapy Patients with good performance status even after failure to 2 kinds of palliative chemotherapy still need the active anticancer treatment options Therefore this is the high unmet medical need
2 Current status of immunotherapy development in gastric cancer
3 The importance of tumor microenvironment
4 The role of polarized macrophage in TME
5 The role of polarized macrophage in gastric cancer
6 Potential of combination of PD1 inhibitor and CSF-1 inhibitor
Based on these rationales we hypothesized that the combination of PD1 inhibitor and CSF1R inhibitor might be synergistic in gastric cancer However the exact in vivo immune modulation by each inhibitor has not been revealed so far Therefore we will conduct this biomarker study of PDR001 in combination with MCS110 in gastric cancer to see the biologic dynamic modulation with MCS110 and combination MCS110PDR001 and to see preliminary efficacy signal with this combination
Trial objectives Primary objective To see biomarker changes PDL1 TAM TIL by MCS110 monotherapy and MCS110PDR001 combination To see the biomarker changes by MCS110 monotherapy at first then by MCS110PDR001 combination in gastric cancer Secondary objective To see preliminary efficacy ORR irRR PFS DOR DCR OS and safety
1 Current status of treatment options in advanced gastric cancer
The cytotoxic chemotherapy usually fluoropyrimidine platinum combination regimen is current standard of care In case of HER2 gastric cancer the addition of trastuzumab on top of cytotoxic chemotherapy is standard of care
In second-line setting the cytotoxic chemotherapy in combination with Ramucirumab improved the patients survival compared with cytotoxic chemotherapy alone
There are few treatment options for gastric cancer patients who have been treated with more than two lines of palliative chemotherapy Patients with good performance status even after failure to 2 kinds of palliative chemotherapy still need the active anticancer treatment options Therefore this is the high unmet medical need
2 Current status of immunotherapy development in gastric cancer
3 The importance of tumor microenvironment
4 The role of polarized macrophage in TME
5 The role of polarized macrophage in gastric cancer
6 Potential of combination of PD1 inhibitor and CSF-1 inhibitor
Based on these rationales we hypothesized that the combination of PD1 inhibitor and CSF1R inhibitor might be synergistic in gastric cancer However the exact in vivo immune modulation by each inhibitor has not been revealed so far Therefore we will conduct this biomarker study of PDR001 in combination with MCS110 in gastric cancer to see the biologic dynamic modulation with MCS110 and combination MCS110PDR001 and to see preliminary efficacy signal with this combination
Trial objectives Primary objective To see biomarker changes PDL1 TAM TIL by MCS110 monotherapy and MCS110PDR001 combination To see the biomarker changes by MCS110 monotherapy at first then by MCS110PDR001 combination in gastric cancer Secondary objective To see preliminary efficacy ORR irRR PFS DOR DCR OS and safety
Detailed Description:
Background
1 Current status of treatment options in advanced gastric cancer
2 Current status of immunotherapy development in gastric cancer
Harnessing immune system to fight against cancer cells is one of highlighting strategy in new drug development in almost all kinds of solid tumor including gastric cancer
In PD L1expressing gastric cancer the anti-PD1 antibody monotherapy pembrolizumab shows the antitumor efficacy Bang YJ et al 2015
Anti-PDL1 antibody Avelumab used in the first-line maintenance setting or 2nd-line setting of biomarker-unselected gastric cancer also shows promising antitumor efficacy Chung HC et al ECCOESMO 2015 Oh DY et al ASCO GI 2016
There are many clinical trials using immune-oncology IO agents are ongoing in 1st-line setting 2nd-line setting 3rd-line setting and refractory setting Several strategies are being used that is IO monotherapy in biomarker-selected population IOIO combination IOcytotoxic chemotherapy and IOother targeted agents to improve the efficacy of harnessing immune system
Still we dont know the exact biomarker for these IO agents in gastric cancer Not all patients get the benefit with these agents
3 The importance of tumor microenvironment
From the immunotherapy point of view the tumor microenvironment TME should be considered for the successful immunotherapy
In TME many components working for antitumor immunity and intratumoral immunosuppression exist Pitt JM et al 2016
The most crucial and direct control of tumor cells is performed by CD4 T helper cell and CD8 cytotoxic T lymphocyte CTL Th1 response characterized by T cell production of IFN-ɣ TNF-α IL-2 are considered to be the essential subset for tumor rejection However Th1 response also contributes to tumor escape via IFN-ɣ-mediated expression of the inhibitory checkpoint molecules PDL1 or via the selection of resistant clones through tumor immunoediting
Long-term exposure to tumor antigen induces Th1 cells and other T cells that lack the typical poly-functional phenotype and that express inhibitory receptors such as PDL1 LAG-3 and TIM-3
Other subsets of CD4T cells inhibit antitumor immune responses CD4Tregs is the example Tregs inhibit the antitumor activity of CTLs and NK cells either directly or indirectly via APCs In addition to Tregs Th2 cells can also block Tcell-induced tumor rejection
TME can also directly impair intratumoral T cell proliferation acting as another mechanism for tumor evasion of immune surveillance IDO production within the TME is the example IDO produced by myeloid cells and cancer cells catabolizes tryptophan to generate kynurenine which together promotes the conversion of naïve T cells to Tregsinhibition of Treg reprogramming to potentially anti-tumoral Th cells and increases MDSC functions through upregulation of IL-6 expression
4 The role of polarized macrophage in TME
Macrophages are one of the major components of the TME are recruited by chemokines such as M-CSF and chemokine C-C motif ligand 2 and are produced mainly be tumor cells Wiktor-Jedrzejczak W et al 1996
Macrophages are dynamic cells that can express different functional programs in response to microenvironmental signals Mantovani A et al 2004
Bacterial stimuli IFN-ɣ and GM-CSF promote a proinflammatory M1-polarized phenotype whereas M-CSF IL-4 and IL-13 favor the generation of folate receptor b positive IL-10 producing immunosuppressive M2-polarized macrophages Murray PJ et al 2011 M1 macrophages also amplify TH1 responses providing a positive feedback loop in the antitumor response
Macrophages that infiltrate tumor tissues also termed tumor-associated macrophages TAMs can be driven by tumor-derived and T-cell derived cytokines to acquire such a polarized phenotype and have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression Mantovani A et al 2002
Fully polarized M1 and M2 macrophages are the extremes of a continuum of functional states in contrast to this binary M1M2 definition there are several other distinct populations that share features of both types Ojalvo LS et al 2009
The M2-polarized macrophages promote tumor progression and metastasis by activating circuits that regulate tumor growth adaptive immunity stroma formation and angiogenesis and can be used as prognostic indicators Balkwill F et al 2001
5 The role of polarized macrophage in gastric cancer
In gastric cancer infiltration of polarized TAMs is an independent prognostic factor Zhang et al 2015
The number of peritoneal macrophages with the M2 phenotype CD68CD163 or CD68CD204 was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination Yamaguchi et al 2015
Higher expression of M2-related messenger RNA IL-10 VEGF-A VEGF-C MMP-1 amphiregulin lower expression of M1-related messenger RNA TNF-am CD80 CD86 IL-12p40 were confirmed in the TAM of gastric cancer
Interestingly macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype Moreover the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model
In our hospital we investigated the prognostic significance of TAM in MSI-high gastric cancers using IHC Kim et al 2015 CD68 and CD163 were used as markers for total infiltrating macrophages and M2-polarized macrophages respectively The density of CD68 or CD163 TAMs in four different areas epithelial and stromal compartments of both the tumor center and invasive front were analyzed in 143 cases of MSI-high advanced gastric cancers
In multivariate survival analysis CD163 TAMs in four combined areas stromal and epithelial compartments of both tumor center and invasive front were independent prognostic indicator in MSI-high gastric cancers
Polarized CD163 TAM was also reported to be associated with increased angiogenesis and CXCL12 expression in gastric cancer Park et al 2015
We investigated the role of cytokine and angiogenic factors in the gastric cancer Ock et al 2015 Ock et al 2016 High serum level of M-CSF is associated with poor survival outcome in gastric cancer patients who received standard 1st-line chemotherapy
6 Potential of combination of PD1 inhibitor and CSF-1 inhibitor
Blockade of colony-stimulating factor-1 CSF-1 limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy Ruffell B et al Cancer Cell 2014
In BRAF mutant melanoma model CSF1R inhibitor PLX3397 reduced the recruitment of CD11bC Gr1lo and CD11bC Gr1int M2-like macrophages but this was accompanied by an accumulation of CD11bC Gr1hi cells PDL1 expression on remaining myeloid cells potentially dampened the antitumor efficacy of BRAF inhibitor PLX3397 and PLX4720 in combination since PD1PDL1 axis blockade improved outcome Ngiow SF et al 2015
In pancreatic cancer model inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses Zhu Y et al 2014 However CSF1R blockade also upregulated T-cell checkpoint molecules including PDL1 and CTLA4 thereby restraining beneficial therapeutic effects
In these cases combination of CSF1R blockade and PD1 or CTLA4 inhibitor potently decreased tumor progression
Trial design and plan Each dosing interval will be 3 weeks
1 Before 1st dosing of MCS110 1st fresh tumor biopsy will be done
2 After 1st dosing of MCS110 monotherapy 2nd fresh tumor biopsy will be done
3 Then combination of MCS110 with PDR001 will be initiated
4 After 1st dosing of MCS110PDR001 combination 3rd fresh tumor biopsy will be done
5 After that the MCS110PDR001 combination will be delivered to the patients until disease progression intolerable toxicity or patients consent withdrawal
6 At the time of disease progression fresh tumor tissue will be obtained if possible optional
7 In each tumor biopsy time point blood sampling will be accompanied
8 Tumor response evaluation will be done every 2 cycles of MCS110PDR001 combination treatment
Translational research that will be performed The description of biomarker changes will be the main purpose of this biomarker study Therefore the translational research is the main interest of this study
The candidate biomarkers are as below which was adopted from the MCS110Z2102 clinical trial However the exact analysis items will be chosen based on the tumor tissue amount and developing science during study period The main focus will be on PDL1 TAM TIL
1 Current status of treatment options in advanced gastric cancer
2 Current status of immunotherapy development in gastric cancer
Harnessing immune system to fight against cancer cells is one of highlighting strategy in new drug development in almost all kinds of solid tumor including gastric cancer
In PD L1expressing gastric cancer the anti-PD1 antibody monotherapy pembrolizumab shows the antitumor efficacy Bang YJ et al 2015
Anti-PDL1 antibody Avelumab used in the first-line maintenance setting or 2nd-line setting of biomarker-unselected gastric cancer also shows promising antitumor efficacy Chung HC et al ECCOESMO 2015 Oh DY et al ASCO GI 2016
There are many clinical trials using immune-oncology IO agents are ongoing in 1st-line setting 2nd-line setting 3rd-line setting and refractory setting Several strategies are being used that is IO monotherapy in biomarker-selected population IOIO combination IOcytotoxic chemotherapy and IOother targeted agents to improve the efficacy of harnessing immune system
Still we dont know the exact biomarker for these IO agents in gastric cancer Not all patients get the benefit with these agents
3 The importance of tumor microenvironment
From the immunotherapy point of view the tumor microenvironment TME should be considered for the successful immunotherapy
In TME many components working for antitumor immunity and intratumoral immunosuppression exist Pitt JM et al 2016
The most crucial and direct control of tumor cells is performed by CD4 T helper cell and CD8 cytotoxic T lymphocyte CTL Th1 response characterized by T cell production of IFN-ɣ TNF-α IL-2 are considered to be the essential subset for tumor rejection However Th1 response also contributes to tumor escape via IFN-ɣ-mediated expression of the inhibitory checkpoint molecules PDL1 or via the selection of resistant clones through tumor immunoediting
Long-term exposure to tumor antigen induces Th1 cells and other T cells that lack the typical poly-functional phenotype and that express inhibitory receptors such as PDL1 LAG-3 and TIM-3
Other subsets of CD4T cells inhibit antitumor immune responses CD4Tregs is the example Tregs inhibit the antitumor activity of CTLs and NK cells either directly or indirectly via APCs In addition to Tregs Th2 cells can also block Tcell-induced tumor rejection
TME can also directly impair intratumoral T cell proliferation acting as another mechanism for tumor evasion of immune surveillance IDO production within the TME is the example IDO produced by myeloid cells and cancer cells catabolizes tryptophan to generate kynurenine which together promotes the conversion of naïve T cells to Tregsinhibition of Treg reprogramming to potentially anti-tumoral Th cells and increases MDSC functions through upregulation of IL-6 expression
4 The role of polarized macrophage in TME
Macrophages are one of the major components of the TME are recruited by chemokines such as M-CSF and chemokine C-C motif ligand 2 and are produced mainly be tumor cells Wiktor-Jedrzejczak W et al 1996
Macrophages are dynamic cells that can express different functional programs in response to microenvironmental signals Mantovani A et al 2004
Bacterial stimuli IFN-ɣ and GM-CSF promote a proinflammatory M1-polarized phenotype whereas M-CSF IL-4 and IL-13 favor the generation of folate receptor b positive IL-10 producing immunosuppressive M2-polarized macrophages Murray PJ et al 2011 M1 macrophages also amplify TH1 responses providing a positive feedback loop in the antitumor response
Macrophages that infiltrate tumor tissues also termed tumor-associated macrophages TAMs can be driven by tumor-derived and T-cell derived cytokines to acquire such a polarized phenotype and have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression Mantovani A et al 2002
Fully polarized M1 and M2 macrophages are the extremes of a continuum of functional states in contrast to this binary M1M2 definition there are several other distinct populations that share features of both types Ojalvo LS et al 2009
The M2-polarized macrophages promote tumor progression and metastasis by activating circuits that regulate tumor growth adaptive immunity stroma formation and angiogenesis and can be used as prognostic indicators Balkwill F et al 2001
5 The role of polarized macrophage in gastric cancer
In gastric cancer infiltration of polarized TAMs is an independent prognostic factor Zhang et al 2015
The number of peritoneal macrophages with the M2 phenotype CD68CD163 or CD68CD204 was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination Yamaguchi et al 2015
Higher expression of M2-related messenger RNA IL-10 VEGF-A VEGF-C MMP-1 amphiregulin lower expression of M1-related messenger RNA TNF-am CD80 CD86 IL-12p40 were confirmed in the TAM of gastric cancer
Interestingly macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype Moreover the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model
In our hospital we investigated the prognostic significance of TAM in MSI-high gastric cancers using IHC Kim et al 2015 CD68 and CD163 were used as markers for total infiltrating macrophages and M2-polarized macrophages respectively The density of CD68 or CD163 TAMs in four different areas epithelial and stromal compartments of both the tumor center and invasive front were analyzed in 143 cases of MSI-high advanced gastric cancers
In multivariate survival analysis CD163 TAMs in four combined areas stromal and epithelial compartments of both tumor center and invasive front were independent prognostic indicator in MSI-high gastric cancers
Polarized CD163 TAM was also reported to be associated with increased angiogenesis and CXCL12 expression in gastric cancer Park et al 2015
We investigated the role of cytokine and angiogenic factors in the gastric cancer Ock et al 2015 Ock et al 2016 High serum level of M-CSF is associated with poor survival outcome in gastric cancer patients who received standard 1st-line chemotherapy
6 Potential of combination of PD1 inhibitor and CSF-1 inhibitor
Blockade of colony-stimulating factor-1 CSF-1 limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy Ruffell B et al Cancer Cell 2014
In BRAF mutant melanoma model CSF1R inhibitor PLX3397 reduced the recruitment of CD11bC Gr1lo and CD11bC Gr1int M2-like macrophages but this was accompanied by an accumulation of CD11bC Gr1hi cells PDL1 expression on remaining myeloid cells potentially dampened the antitumor efficacy of BRAF inhibitor PLX3397 and PLX4720 in combination since PD1PDL1 axis blockade improved outcome Ngiow SF et al 2015
In pancreatic cancer model inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses Zhu Y et al 2014 However CSF1R blockade also upregulated T-cell checkpoint molecules including PDL1 and CTLA4 thereby restraining beneficial therapeutic effects
In these cases combination of CSF1R blockade and PD1 or CTLA4 inhibitor potently decreased tumor progression
Trial design and plan Each dosing interval will be 3 weeks
1 Before 1st dosing of MCS110 1st fresh tumor biopsy will be done
2 After 1st dosing of MCS110 monotherapy 2nd fresh tumor biopsy will be done
3 Then combination of MCS110 with PDR001 will be initiated
4 After 1st dosing of MCS110PDR001 combination 3rd fresh tumor biopsy will be done
5 After that the MCS110PDR001 combination will be delivered to the patients until disease progression intolerable toxicity or patients consent withdrawal
6 At the time of disease progression fresh tumor tissue will be obtained if possible optional
7 In each tumor biopsy time point blood sampling will be accompanied
8 Tumor response evaluation will be done every 2 cycles of MCS110PDR001 combination treatment
Translational research that will be performed The description of biomarker changes will be the main purpose of this biomarker study Therefore the translational research is the main interest of this study
The candidate biomarkers are as below which was adopted from the MCS110Z2102 clinical trial However the exact analysis items will be chosen based on the tumor tissue amount and developing science during study period The main focus will be on PDL1 TAM TIL
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?:
None
Is an FDA AA801 Violation?:
None