Ignite Creation Date:
2024-05-06 @ 6:36 PM
Last Modification Date:
2024-10-26 @ 2:51 PM
Study NCT ID:
NCT05721443
Status:
RECRUITING
Last Update Posted:
2023-02-10
First Post:
2022-11-09
Brief Title:
Cetuximab Plus Dalpicilib in Patients With HPV Negative PD-1 Resistant RM HNSCC
Sponsor:
Shanghai Ninth Peoples Hospital Affiliated to Shanghai Jiao Tong University
Organization:
Shanghai Ninth Peoples Hospital Affiliated to Shanghai Jiao Tong University
Study Overview
Official Title:
Cetuximab Plus Dalpicilib in the Second-line Treatment of Patients With HPV Negative PD-1 Resistant RecurrentMetastatic Head and Neck Squamous Cell Carcinoma an Open-labelSingle ArmPhase 2 Trial
Status:
RECRUITING
Status Verified Date:
2022-10
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:
None
Brief Summary:
This study is the first clinical study in PD-1 resistant patients with head and neck squamous cell carcinoma with drugs targeting EGFR signaling pathway combined with CDK46 inhibitors which explores the new combination therapies urgently needed in clinical practice and lays a foundation for subsequent studies with important scientific research significance and clinical value
Detailed Description:
Head and neck cancer is the sixth most common cancer in the world with more than 550000 incidences and 300000 deaths per year worldwide more than 95 of head and neck cancers are squamous cell carcinomas and head and neck squamous cell carcinoma HNSCC has a devastating and HNSCC affects the quality of life of patients by damaging and affecting their appearance and basic physical sensory and speech functions Due to the difficulty of early detection more than 60 of head and neck squamous cell carcinoma patients are already at locally advanced stage when detected and the prognosis of locally advanced head and neck carcinoma is poor and even after receiving aggressive treatment it is prone to local recurrence and distant metastasis after treatment
About 25 of patients with squamous head and neck cancer are associated with human papillomavirus HPV infection of which the most common subtype is HPV 16 accounting for more than 80 of all HPV-induced head and neck cancers HPV infection suppresses the function of oncogenes TP53 and RB and promotes immune escape and promote the development of head and neck cancer In China more than 70 of head and neck squamous carcinomas are not associated with HPV infection and compared with HPV-associated HNSCC HPV-negative HNSCC has a lower response rate to treatment and the overall prognosis of patients is worse
Head and neck squamous cell carcinoma has a high rate of Treg cell as well as NK cell infiltration in the tumor microenvironment forming an immunosuppressive tumor microenvironment and is a group of malignancies with high immunodeficiency Studies have shown high levels of PD-L1 expression in tumor tissue in 46-100 of HNSCC Therefore blockade of immune checkpoint inhibitors represented by PD-L1PD-1 is a theoretically feasible therapeutic approach for the treatment of HNSCC The results of previous clinical trials of immunotherapy in patients with recurrent or metastatic head and neck squamous carcinoma showed that anti-PD-1 antibodies led to durable remission and improved survival in patients with either first- or second-line therapy The KEYNOTE-048 study confirmed that pembrolizumab in combination with chemotherapy prolonged overall survival in patients with recurrent or metastatic head and neck squamous carcinoma and in 2021 recommended by CSCO guidelines as a first-line expert recommendation for the first-line treatment of recurrent or metastatic head and neck squamous carcinoma Level of Evidence 1A However patients with recurrent or metastatic head and neck squamous carcinoma after failure of first-line applied anti-PD-1 therapy enter second-line therapy The current guideline recommended second-line treatment regimens are cetuximab afatinib or methotrexate but the overall prognosis of patients is poor the drug response rate is not high the highest objective remission rate reported in the literature is only 13 and the time to tumor progression is only 23 months therefore exploring new second-line treatment options for patients with recurrent or metastatic head and neck squamous carcinoma after failure of anti-PD-1 therapy is a pressing clinical need
In addition the results of previous clinical trials showed that HPV-negative HNSCC had poorer sensitivity and prognosis to immunotherapy than HPV-associated HNSCC In KEYNOTE-012 patients with HPV-positive HNSCC had higher objective remission 32 vs 14 and progression-free survival 4 months vs 2 months with pablizumab and similar results were confirmed by KEYNOTE-055 Furthermore in a meta-analysis of 11 studies HPV-positive HNSCC patients showed a 129-fold higher response rate to immunotherapy and a twofold higher overall survival 115 months vs 63 months than HPV-negative HNSCC patients
There are a large number of ongoing clinical trials of combination targeted therapies and immunotherapies The basic rationale supporting these combinations is that the two therapies combine different immunological and tumor biological mechanisms that enhance antitumor activity in addition some evidence suggests that targeted therapies can enhance certain aspects of the cancer-immune cycle eg tumor antigenicity T-cell initiationtransportinfiltration etc to immunotherapy In addition it has been shown that targeted therapies can synergistically enhance certain aspects of the cancer-immune cycle eg tumor antigenicity T cell initiationtransportinfiltration etc for immunotherapy CDK4 one of the key cell cycle regulators is involved in cell growth proliferation dormancy or apoptosis by binding to cell cycle protein D which regulates the transition from G1 phase pre-DNA synthesis to S phase DNA synthesis In 2013 the US Food and Drug Administration FDA approved the CDK4 inhibitor Palbociclib as a breakthrough new drug for the treatment of advanced breast cancer and the National Comprehensive Cancer Network NCCN guidelines recommend piperacillin in combination with an aromatase inhibitor as a first-line treatment option for HRHER2-advanced or metastatic breast cancer Recent studies have found that CDK4 gene inhibition in combination with afatinib synergistically enhances the inhibition of the PI3k pathway in head and neck cancer cells which in turn reduces tumor proliferation providing a strong rationale for combination therapy
P16 deletion is a hallmark event in HPV-negative HNSCC patients and p16 inactivation would lead to CDK46 hyperactivation making CDK46 theoretically a potential target for HPV-negative HNSCC Some progress has been made with CDK46 inhibitors in HPV-negative head and neck squamous carcinoma In a multicenter multicohort phase II clinical trial cohort 1 enrolled in first-line treatment of platinum-resistant HPV-negative patients with recurrentmetastatic HNSCC and cohort 2 enrolled in first-line treatment of cetuximab-resistant HPV-negative cohort 3 enrolled patients with cetuximab-resistant HPV-positive recurrentmetastatic oropharyngeal cancer and all three groups received Palbociclib in combination with cetuximab showing objective remission rates of up to 39 in cohort 1 and 19 in cohort 2 but only 4 in cohort 3 indicating that CDK46 inhibitors in combination with cetuximab has a promising application in the treatment of HPV-negative HNSCC
This clinical study involved dalpiciclib which was developed by Jiangsu Hengrui Pharmaceutical Co In December 2021 the State Drug Administration approved the drug in combination with fulvestrant for patients with recurrent or metastatic breast cancer with hormone receptor-positive human epidermal growth factor receptor 2-negative disease progression after previous endocrine therapy through a priority review and approval process Patients Preclinical studies have shown that dalpiciclib has comparable in vivo efficacy and safety compared to its foreign counterparts
This study is also the first clinical study of a drug targeting CDK46 in combination with cetuximab for the treatment of HPV-negative head and neck squamous carcinoma after progression of PD-1 therapy in China which is of great scientific significance and clinical value in exploring new combination therapies for HPV-negative patients a population with poor clinical outcome and laying the foundation for subsequent studies
About 25 of patients with squamous head and neck cancer are associated with human papillomavirus HPV infection of which the most common subtype is HPV 16 accounting for more than 80 of all HPV-induced head and neck cancers HPV infection suppresses the function of oncogenes TP53 and RB and promotes immune escape and promote the development of head and neck cancer In China more than 70 of head and neck squamous carcinomas are not associated with HPV infection and compared with HPV-associated HNSCC HPV-negative HNSCC has a lower response rate to treatment and the overall prognosis of patients is worse
Head and neck squamous cell carcinoma has a high rate of Treg cell as well as NK cell infiltration in the tumor microenvironment forming an immunosuppressive tumor microenvironment and is a group of malignancies with high immunodeficiency Studies have shown high levels of PD-L1 expression in tumor tissue in 46-100 of HNSCC Therefore blockade of immune checkpoint inhibitors represented by PD-L1PD-1 is a theoretically feasible therapeutic approach for the treatment of HNSCC The results of previous clinical trials of immunotherapy in patients with recurrent or metastatic head and neck squamous carcinoma showed that anti-PD-1 antibodies led to durable remission and improved survival in patients with either first- or second-line therapy The KEYNOTE-048 study confirmed that pembrolizumab in combination with chemotherapy prolonged overall survival in patients with recurrent or metastatic head and neck squamous carcinoma and in 2021 recommended by CSCO guidelines as a first-line expert recommendation for the first-line treatment of recurrent or metastatic head and neck squamous carcinoma Level of Evidence 1A However patients with recurrent or metastatic head and neck squamous carcinoma after failure of first-line applied anti-PD-1 therapy enter second-line therapy The current guideline recommended second-line treatment regimens are cetuximab afatinib or methotrexate but the overall prognosis of patients is poor the drug response rate is not high the highest objective remission rate reported in the literature is only 13 and the time to tumor progression is only 23 months therefore exploring new second-line treatment options for patients with recurrent or metastatic head and neck squamous carcinoma after failure of anti-PD-1 therapy is a pressing clinical need
In addition the results of previous clinical trials showed that HPV-negative HNSCC had poorer sensitivity and prognosis to immunotherapy than HPV-associated HNSCC In KEYNOTE-012 patients with HPV-positive HNSCC had higher objective remission 32 vs 14 and progression-free survival 4 months vs 2 months with pablizumab and similar results were confirmed by KEYNOTE-055 Furthermore in a meta-analysis of 11 studies HPV-positive HNSCC patients showed a 129-fold higher response rate to immunotherapy and a twofold higher overall survival 115 months vs 63 months than HPV-negative HNSCC patients
There are a large number of ongoing clinical trials of combination targeted therapies and immunotherapies The basic rationale supporting these combinations is that the two therapies combine different immunological and tumor biological mechanisms that enhance antitumor activity in addition some evidence suggests that targeted therapies can enhance certain aspects of the cancer-immune cycle eg tumor antigenicity T-cell initiationtransportinfiltration etc to immunotherapy In addition it has been shown that targeted therapies can synergistically enhance certain aspects of the cancer-immune cycle eg tumor antigenicity T cell initiationtransportinfiltration etc for immunotherapy CDK4 one of the key cell cycle regulators is involved in cell growth proliferation dormancy or apoptosis by binding to cell cycle protein D which regulates the transition from G1 phase pre-DNA synthesis to S phase DNA synthesis In 2013 the US Food and Drug Administration FDA approved the CDK4 inhibitor Palbociclib as a breakthrough new drug for the treatment of advanced breast cancer and the National Comprehensive Cancer Network NCCN guidelines recommend piperacillin in combination with an aromatase inhibitor as a first-line treatment option for HRHER2-advanced or metastatic breast cancer Recent studies have found that CDK4 gene inhibition in combination with afatinib synergistically enhances the inhibition of the PI3k pathway in head and neck cancer cells which in turn reduces tumor proliferation providing a strong rationale for combination therapy
P16 deletion is a hallmark event in HPV-negative HNSCC patients and p16 inactivation would lead to CDK46 hyperactivation making CDK46 theoretically a potential target for HPV-negative HNSCC Some progress has been made with CDK46 inhibitors in HPV-negative head and neck squamous carcinoma In a multicenter multicohort phase II clinical trial cohort 1 enrolled in first-line treatment of platinum-resistant HPV-negative patients with recurrentmetastatic HNSCC and cohort 2 enrolled in first-line treatment of cetuximab-resistant HPV-negative cohort 3 enrolled patients with cetuximab-resistant HPV-positive recurrentmetastatic oropharyngeal cancer and all three groups received Palbociclib in combination with cetuximab showing objective remission rates of up to 39 in cohort 1 and 19 in cohort 2 but only 4 in cohort 3 indicating that CDK46 inhibitors in combination with cetuximab has a promising application in the treatment of HPV-negative HNSCC
This clinical study involved dalpiciclib which was developed by Jiangsu Hengrui Pharmaceutical Co In December 2021 the State Drug Administration approved the drug in combination with fulvestrant for patients with recurrent or metastatic breast cancer with hormone receptor-positive human epidermal growth factor receptor 2-negative disease progression after previous endocrine therapy through a priority review and approval process Patients Preclinical studies have shown that dalpiciclib has comparable in vivo efficacy and safety compared to its foreign counterparts
This study is also the first clinical study of a drug targeting CDK46 in combination with cetuximab for the treatment of HPV-negative head and neck squamous carcinoma after progression of PD-1 therapy in China which is of great scientific significance and clinical value in exploring new combination therapies for HPV-negative patients a population with poor clinical outcome and laying the foundation for subsequent studies
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