Neoadjuvant Camrelizumab With Dalpiciclib for Resectable Esophageal or Head and Neck Squamous Cell Carcinomas

Study Overview
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Brief Summary
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The purpose of this study is to explore the safety and feasibility of anti-programmed cell death protein 1(PD-1) immunotherapy, Camrelizumab, combined with cyclin-dependent kinase 4/6 blockade, Dalpiciclib, as a new neoadjuvant treatment regimen for patients with resectable esophageal squamous cell carcinoma (ESCC) or or head and neck squamous cell carcinoma(HNSCC).

Detailed Description
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Esophageal cancer is the seventh leading cause of cancer related mortality worldwide and esophagus squamous cell carcinoma (ESCC) is the main histological type in China. Combination with operation and neoadjuvant therapy including chemotherapy with/without radiotherapy is considered the standard therapy for local advanced esophagus cancer. Nevertheless, in a phase 3 clinical trial，the 5-year overall survival rate and cumulative incidence of recurrence were 59.9% and 32.2%. It shows the limitations of current treatment modalities. Immunotherapy such as PD-1/PD-L1 inhibitors have shown great improvement in first-line recurrent/metastatic and postoperative ESCC. It motivates recent phase I/II trials investigating the incorporation of ICB in the neoadjuvant treatment of ESCC. However, a phase 1b trial of neoadjuvant adebrelimab in locally advanced resectable ESCC showed only 24% major pathologic response (MPR; tumor regression >90%). To improve the efficacy of ICB in neoadjuvant treatment of ESCC, a combined regimen should be explored. Head and Neck Squamous Cell Carcinoma (HNSCC) is the most common malignancies of the head and neck, accounting for 90% of head and neck cancer. The 5-year survival rate under standard treatment is only 50%. 70% 80% of first diagnosed patients already developed into locally advanced status (stage II-Iva). In recent years, the use of neoadjuvant therapy (NAC) followed by surgery or radiotherapy has been advocated because of its higher probability of local/regional failure and distant metastasis after treatment. TPF (Docetaxel + Cisplatin + Fluorouracil) regimen is considered as the standard regimen of induced chemotherapy for head and neck squamous cell carcinoma (especially in laryngeal cancer), which can significantly reduce the patient's distant metastasis rate and prolong overall survival (OS). However, the therapeutic effect of neoadjuvant therapy on head and neck squamous cell carcinoma has reached a bottleneck. In recent years, PD-1 inhibitors have achieved significant effects in the field of tumor therapy and have been approved for the treatment of various tumors including recurrent metastatic head and neck tumors. There are also several prospective clinical research attempting to combine ICB with targeted therapeutic drugs for neoadjuvant therapy of HNSCC. The efficacy and safety results show potential synergy between these drugs. Recent preclinical studies have shown that CDK4/6 inhibitors promote efficacy of PD-1/PD-L1 inhibitors through tumor antigen presentation enhancing, suppressed proliferation of regulatory T (Treg) cells, effector T- cell activation enhancing, and induction of T- cell memory. The previous study confirmed that CDK4/6 inhibitor combined with ICB can be administered safely in patients with recurrent or metastatic head and neck squamous cell carcinoma(HNSCC) and non-small cell lung carcinoma(NSCC). In summary, the investigators designed this study to explore the safety and efficacy of anti-PD1 immunotherapy, Camrelizumab, combined with CDK4/6 inhibitor, dalpiciclib, as a new neoadjuvant treatment regimen for patients with resectable ESCC and HNSCC. It will also provide new ideas, strategies, and experimental evidence for the development of immunotherapy.

Official Title
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The Safety and Feasibility of Neoadjuvant Camrelizumab With Dalpiciclib for the Treatment of Resectable Esophageal or Head and Neck Squamous Cell Carcinoma：A Phase 1 Trial

Conditions
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Esophageal Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Camrelizumab
* Drug: Dalpiciclib 100mg
* Drug: Dalpiciclib 150mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with esophageal squamous cell cancer by gastroscopic biopsies. 1.1. The primary tumor should be located in the thorax; the primary site is decided by the upper margin of the mass (upper thoracic esophagus: from the thoracic inlet to inferior margin of azygos arch, the endoscopic examination shows 20-25cm to the incisor; middle thoracic esophagus: from inferior margin of azygos arch to the inferior pulmonary vein level, the endoscopic examination shows 25-30cm to the incisor; lower thoracic esophagus: from the inferior pulmonary vein level to the stomach, the endoscopic examination shows 30-40cm to the incisor). 1.2. The patients should be evaluated to be able to have surgical resection before the surgery according to the examinations (use enhanced thoracic and abdominal CT, cervical lymph node ultrasound to evaluate whether the tumor has obvious invasion, whether there are enlarged mediastinal lymph nodes; use examinations including positron emission computed tomography (PET-CT), endoscopic ultrasonography (EUS) to make further clinical staging if considering the primary tumor as T4b, multiple mediastinal lymph nodes metastasis or distant metastasis). 1.3. The patients should be at the range of 18-75 years old, Eastern Cooperative Oncology Group (ECOG) 0-1. 1.4. The patients should be able to understand our research and be willing to accept surgical treatment and sign the informed consent. Patient diagnosed with locally advanced head and neck squamous cell carcinoma confirmed by histology or cytology. 2.1. Patients who are recommended to perform surgery 2.2. Patients between 18 and 70 years old 2.3. ECOG: 0～2 points 2.4. Estimated survival time ≥ 6 months 2.5. The patients should be able to understand our research and be willing to accept surgical treatment and sign the informed consent. Exclusion Criteria: 1.The stage of tumor is T4b (AJCC/International Union Against Cancer (UICC) 8th Edition) which can not be resected according to imaging examinations like thoracic and abdominal enhanced CT, cervical lymph nodes ultrasound, whole body PET-CT scan (optional) or endobronchial ultrasonography (EBUS) (optional); several enlarged lymph nodes existed (≥3 estimated lymph nodes metastasis); multiple station enlarged lymph nodes existed (≥2 estimated stations of lymph nodes metastasis); distant metastasis existed. 2.The patients have accepted or are on the process of other chemotherapy, radiotherapy, targeted therapy or immunotherapy. 3.History of other malignancies (except for the history of malignant tumors that have been cured and have not recurred within 5 years, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, in situ cervical cancer, and gastrointestinal mucosal cancer, etc.） 4. Have an active autoimmune disease requiring systemic treatment or a documented history of clinically severe autoimmune disease. 5. Any history of allergic disease, or a sever hypersensitivity reaction to drugs, or allergy to the study drug components. 6.With serious medical diseases, such as grade II and above cardiac dysfunction (NYHA criteria), ischemic heart disease, supraventricular or ventricular arrhythmia, poorly controlled diabetes mellitus, poorly controlled hypertension, echocardiographic ejection fraction < 50%, etc. 7.With interstitial pneumonitis, non-infectious pneumonitis, active pulmonary tuberculosis, or history of pulmonary tuberculosis infection that were not controlled by treatment. 8.The patients have severe systematic intercurrent disease, such as active infection or poorly controlled diabetes; coagulation disorders; hemorrhagic tendency or under treatment of thrombolysis or anticoagulant therapy. 9.The patients have active infection of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) or be HIV serum positive; or HBV, HCV RNA positive. 10.Female who is positive for serum pregnancy test or during lactation period, or people at child bearing stage who are reluctant to use contraception measures during the research. 11.History of a clear neurological or psychiatric disorder. 12.History of a clear neurological or psychiatric disorder. 13.Received any investigational drug within 4 weeks prior to the first dose, or concurrently enrolled in another clinical trial. 14.Any other factors that are not suitable for inclusion in this study judged by investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ESCC:Camrelizumab+Dalpiciclib(100mg) 3 patients<br>Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery Dalpiciclib will be given at a dose of 100 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles. For dalpiciclib, there is 2 dose levels, 100mg qd and 150 mg qd, and if no patients experience DLT on 100mg level, 150mg level will be administered. | Drug: Camrelizumab<br>* Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery<br>Drug: Dalpiciclib 100mg<br>* Dalpiciclib will be given at a dose of 100 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles.<br>|
| Experimental: ESCC:Camrelizumab+Dalpiciclib(150mg) 3 patients<br>Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery Dalpiciclib will be given at a dose of 150 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles. For dalpiciclib, there is 2 dose levels, 100mg qd and 150 mg qd, and if no patients experience DLT on the 100mg level, the 150mg level will be administered. | Drug: Camrelizumab<br>* Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery<br>Drug: Dalpiciclib 150mg<br>* Dalpiciclib will be given at a dose of 150 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles.<br>|
| Experimental: HNSCC:Camrelizumab+Dalpiciclib(100mg) 3 patients<br>Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery Dalpiciclib will be given at a dose of 100 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles. For dalpiciclib, there is 2 dose levels, 100mg qd and 150 mg qd, and if no patients experience DLT on 100mg level, 150mg level will be administered. | Drug: Camrelizumab<br>* Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery<br>Drug: Dalpiciclib 100mg<br>* Dalpiciclib will be given at a dose of 100 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles.<br>|
| Experimental: HNSCC:Camrelizumab+Dalpiciclib(150mg) 3 patients<br>Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery Dalpiciclib will be given at a dose of 150 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles. For dalpiciclib, there is 2 dose levels, 100mg qd and 150 mg qd, and if no patients experience DLT on 100mg level, 150mg level will be administered. | Drug: Camrelizumab<br>* Camrelizumab will be given at at a dose of 200 mg intravenously every three weeks on day 1 of a planned 21-day cycle, and two doses before surgery<br>Drug: Dalpiciclib 150mg<br>* Dalpiciclib will be given at a dose of 150 mg every day orally with three weeks on and one week off. Four weeks is a cycle and it will be given for two cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of combination camrelizumab and dalpiciclib as assessed by number of participants who experience adverse events | Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). | Through the study completion, an average of 12 weeks | 
| Feasibility of combination camrelizumab and dalpiciclib as assessed by number of participants who experience adverse events | Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). | Through the study completion, an average of 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT) | Maximum tolerated dose will be determined by the maximum dose at which the least number of participants experience dose-limiting toxicity. The dose limiting toxicity is defined using the Common Terminology Criteria for Adverse Events (CTCAE). | Through the study completion, an average of 12 weeks | 
| Major Pathologic Response | Major Pathologic Response (MPR) was defined as fewer than 10% viable tumor cells. | Time of surgery | 
| Objective response rate (ORR) | Proportion of participants with measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria after 2 doses of Proportion of participants with measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria after 2 doses of nivolumab and ipilimumab. | Through the study completion, an average of 12 weeks | 
| Progression free survival(PFS) | Proportion of participants who achieve progression free survival post treatment | Up to 2 years | 
| Overall survival (OS) | Proportion of participants who achieve survival post treatment | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal Squamous Cell Carcinoma, Head and Neck Squamous Cell Carcinoma, Neoadjuvant therapy, Immunotherapy, CDK4/6 inhibitor