Triplex Checkpoint Inhibitors Therapy for Advanced Solid Tumors

Triplex CTLA4/PD1/PDL1 Checkpoint Inhibitors Combination Therapy for Advanced Solid Tumors

This trial is designed to investigate the safety, response rates and survival outcomes of patients with advanced solid tumors by infusion of CTLA4, PD1 and PDL1 antibodies combination through venous (IV), artery (IA) or intra-tumor (IT).

Study Overview

• Status: Recruiting
• Conditions: Sarcoma; Cervical Cancer; Breast Cancer; Head and Neck Cancer; Gastric Cancer; Colorectal Cancer; Esophageal Cancer; Lung Cancer; Pancreas Cancer; Liver Cancer; Ovary Cancer
• Intervention / Treatment: Drug: ipilimumab +pembrolizumab +durvalumab

Detailed Description

Malignant solid tumors including lung and liver cancers are the most common malignancy worldwide, and their mortality rates are very high. China has a huge population base with about 4,000,000 new cancer cases each year. More than 60% of the solid tumors in China are diagnosed at mid-to-late stage and have lost the chance of surgery. Recently a lot of therapeutic strategies have been developed and applied to clinic including targeted therapy and immunotherapy, but the overall therapeutic efficiency is still low. It is very difficult to treat patients with recurrent/refractory/metastatic advanced solid cancers and more alternative therapies are urgently needed.

Antibodies against CTLA4, PD1 and PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab, PD1 antibody and PDL1 antibody, so called triplex checkpoint inhibitors combination therapy, for advanced solid tumors. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the triplex checkpoint inhibitors combination therapy for cancer patients. This phase I-II clinical trial is designed to assess the safety and survival benefit of ipilimumab, pembrolizumab and durvalumab combination on patients with advanced solid cancers, including PFS, ORR, DCR, and median survival time.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510260
      • Recruiting
      • The Second Affiliated Hospital of Guangzhou Medical University
      • Contact: Bingjia He, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Cytohistological confirmation is required for diagnosis of cancer.
2. Signed informed consent before recruiting.
3. Age above 18 years with estimated survival over 3 months.
4. Child-Pugh class A or B/Child score > 7; ECOG score < 2
5. Tolerable coagulation function or reversible coagulation disorders
6. Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L; Hb≥90g/L； PLT ≥50×10E9/L；INR < 2.3 or PT < 6 seconds above control；Cr ≤ 145.5 umul/L；Albumin > 28 g/L；Total bilirubin < 51 μmol/L
7. At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1.
8. Birth control.
9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria:

1. Patients participated in clinical trials of equipment or drugs (signed informed consent) within 4 weeks;
2. Patients accompany by ascites, hepatic encephalopathy and esophageal and gastric varices bleeding;
3. Any serious accompanying disease, which is expected to have an unknown, impact on the prognosis, include heart disease, inadequately controlled diabetes and psychiatric disorders;
4. Patients accompanied with other tumors or past medical history of malignancy;
5. Pregnant or lactating patients, all patients participating in this trial must adopt appropriate birth control measures during treatment;

6. Patients have poor compliance.

   Any contraindications for hepatic arterial infusion procedure:

   A.Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%).

   B.Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C.Known severe atheromatosis. D.Known uncontrolled blood hypertension (> 160/100 mm/Hg).

7. Allergic to contrast agent;
8. Any agents which could affect the absorption or pharmacokinetics of the study drugs
9. Other conditions that investigator decides not suitable for the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 3 drugs; Three antibodies combination against PD1, PDL1, and CTLA4.

Drug: ipilimumab +pembrolizumab +durvalumab; This study has 3 subgroups: Ipilimumab +pembrolizumab +durvalumab is administrated with a total dose of 1-2mg/kg via vein, every 3 weeks.; Ipilimumab +pembrolizumab +durvalumab is administrated with a total dose of 1-2mg/kg via sustained (10min) micro-pump infusion via artery, every 3 weeks.; Ipilimumab +pembrolizumab +durvalumab is administrated with a total dose of 50-150mg via intra-tumor fine needle injection in 5 min, every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of remission (DOR)	DOR will be defined as the duration of the cancer remission	5 years
Disease control rate	Disease control rate will be defined as objective response rate + steady disease rate.	5 years
Safety of 3 drugs combination treatment	Safety will be assessed by recording all types of advise effects upon and after the treatment.	5 years
Progression-free survival	Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per RECIST 1.1) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.	5 years

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Guangzhou Medical University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2021
• Primary Completion (ANTICIPATED): October 30, 2024
• Study Completion (ANTICIPATED): October 30, 2025

Study Registration Dates

• First Submitted: December 28, 2021
• First Submitted That Met QC Criteria: December 28, 2021
• First Posted (ACTUAL): January 11, 2022

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: February 11, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Solid tumor; Interventional Radiology; Trans-artery infusion; Intra-tumor injection; PD1 antibody; PDL1 antibody; CTLA4 antibody
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Ovarian Neoplasms; Pancreatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Durvalumab; Pembrolizumab; Ipilimumab
• Other Study ID Numbers: ZZICI3-015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes