Decitabine Plus Penpulimab as Second-line Therapy for Advanced ESCC Treated With PD-1 Blockade

An Single-arm Open-label Phase II Study of Decitabine Plus Penpulimab as Second-line Therapy for Advanced Esophageal Squamous Cell Carcinoma Treated With PD-1 Blockade

The purpose of this study is to observe and evaluate the efficacy and safety of Decitabine plus Penpulimab as second-line therapy for advanced esophageal squamous cell carcinoma treated with PD-1 blockade

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Decitabine plus Penpulimab

Detailed Description

Although immune checkpoint inhibitors (ICIs) have been tested in esophageal squamous cell carcinoma(ESCC) with demonstrated clinical efficacy，a significant number of patients have an initial response will develop a secondary resistance and relapse. recent studies on the role of epigenetics in immune evasion have exposed a key role for epigenetic modulators in augmenting the tumour microenvironment and restoring immune recognition and immunogenicity. These discoveries have established a highly promising basis for studies using combined epigenetic and immunotherapeutic agents as anti-cancer therapies. Decitabine is a novel orally active benzamide-type histone deacetylase inhibitor that has shown in vitro activities against a wide array of neoplasms. Hence, the study of decitabine plus penpulimab(AK-105) as second-line therapy for advanced ESCC treated with PD-1 blockade was performed.

• Study Type: Interventional
• Enrollment (Anticipated): 85
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments.
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
3. Histologically confirmed diagnosis of ESCC.
4. Have PD after first-line of PD-1 blockade treatment for unresectable, locally advanced, recurrent or metastatic ESCC.
5. Measurable disease per RECIST v1.1 assessed by the local investigator
6. ECOG PS 0 or 1
7. Newly obtained (preferred) or archival tissue sample available
8. Negative urine or serum pregnancy test within 72 h before randomization (females)
9. Willing to use an adequate method of contraception throughout the study and for 120 days after the last dose of study medication and up to 180 days after the last dose of cisplatin
10. Adequate haematologic function, defined as ANC ≥ 1500/μl, platelet count ≥ 100,000/μl and haemoglobin ≥ 9.0 g/dl or ≥5.6 mmol/l
11. Adequate renal function, defined as creatinine ≤ 1.5 × ULN or measured or calculated creatinine clearance ≥ 60 mL/min for those with creatinine levels 1.5 × ULN
12. Adequate hepatic function, defined as total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for those with total bilirubin levels 1.5 × ULN, and ALT/AST levels ≤ 2.5 × ULN
13. Adequate coagulation function, defined as INR ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy, in which case PT or aPTT should be within the therapeutic range
14. Written informed consent

Exclusion Criteria:

1. Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta).
2. Evidence of complete esophageal obstruction not amenable to treatment.
3. Active leptomeningeal disease or uncontrolled, untreated brain metastasis.
4. Active autoimmune diseases or history of autoimmune diseases that may relapse
5. Any active malignancy ≤ 2 years before randomization except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
6. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days before initial treatment .
7. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks after intervention).
8. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc.
9. Infection (including tuberculosis infection, etc) that requires systemic antibacterial, antifungal or antiviral therapy within 14 days beforeinitial treatment
10. A history of severe hypersensitivity reactions to chidamide and monoclonal antibodies.
11. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to ≤Grade 2 or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific laboratory abnormalities).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Decitabine plus Penpulimab; Pts received decitabine 10mg/d IV daily x5 every 3 weeks and penpulimab(AK-105) 200 mg intravenously every 3 weeks until disease progression, unacceptable adverse events (AEs) or withdrawal of consent.	Drug: Decitabine plus Penpulimab; Pts received decitabine 10mg/d IV daily x5 every 3 weeks and penpulimab(AK-105) 200 mg intravenously every 3 weeks until disease progression, unacceptable adverse events (AEs) or withdrawal of consent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	From date of initial treatment until the date of death from any cause	up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	Defined as the proportion of patients with a documented complete response, partial response(CR+PR)	up to 24 months
PFS	From date of initial treatment until the date of first documented progression or date of death from any cause	Up to 24 months
DOR	Refers to the time when the tumor is first evaluated as CR or PR until the first assessment is PD (Progressive Disease) or any cause of death.	up to 24 months
DCR	Defined as the proportion of patients with a documented complete response, partial response and stable response(CR+PR+SD)	up to 24 months
Adverse Events (Safety)	Adverse Events	up to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor mutation burden (TMB)	Total number of non-synonymous mutations in each coding region of the tumor genome	up to 24 months
PD-L1 CPS	Number of PD-L1 staining cells (tumor cells)/Total tumor cellsk*100%	up to 24 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: February 7, 2022
• First Submitted That Met QC Criteria: February 23, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): March 4, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: WF-ESCC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No