PRaG Regimens Rechallenge for Patients With Resistance to PD1/PD-L1 Inhibitors in Refractory Advanced Solid Tumors.

Phase II Multi-center Clinical Study of PD-1 Inhibitor Combined With Hypofractionated Radiotherapy and GM-CSF With IL-2(PRaG2.0 Regimens) Rechallenge for Patients With Resistance to PD1/PD-L1 Inhibitors in Refractory Advanced Solid Tumors.

Finding an effective treatment to rescue with resistance of PD-1/PD-L1 inhibitor has been an urgent problem.The PRaG trial as a salvage therapy in advanced solid tumors has obtained satisfactory results.We found that patients with PD-1/PD-L1 inhibitors resistance are more likely to benefit from the PRaG regimens(PD-1 inhibitors combined with radiotherapy and GM-CSF with IL-2). Further phase II clinical trial was conducted to confirm the efficacy and safety of PRaG regimen rechallenge for patients with resistance to PD1/PD-L1 inhibitors in refractory advanced solid tumors.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Solid Tumor
• Intervention / Treatment: Radiation: Hypofractionated radiotherapy; Drug: PD-L1 inhibitor; Drug: GM-CSF; Drug: IL-2

Detailed Description

Patinets with PD-1/PD-L1 inhibitors resistance have limited treatment.ICIs rechallenge is one of the attractive and challenging selection strategies.The efficacy and safety of PD-1/PD-L1 inhibitor rechallenge remain unclear.PRaG regimens realize the sensitization of the efficacy of PD-1 inhibitors, broaden the anti-cancer spectrum of PD-1 immunotherapy, and achieve precise and minimally invasive tumor treatment.PRaG regimens might benefit the survival of patients with resistance to PD1/PD-L1 inhibitors in refractory advanced solid tumors.A phase II clinical study is planned to explore the efficacy and safety of PRaG regimens in advanced refractory solid malignancies after resistance of PD-1/PD-L1 therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 56
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Meiling Xu; Phone Number: +8615106203097; Email: xumeiling1115@163.com

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. Aged≥18 years;
2. The patients must conform to the advanced solid cancer with multiple metastases(may be accompanied by metastasis of other organs),progression after first-line systemic therapy and have clear pathological diagnosis report;
3. Disease progression after PD-1/PD-L1 therapy in the past, except for the permanent discontinuation of the drug due to immune-related toxicity of grade 3 or above;
4. Enrolled patients must improve the detection of PD-L1, TMB, MSI and other immune-related indicators;
5. No congestive heart failure, unstable angina pectoris, unstable arrhythmia within the past 6 months;
6. Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-3, and life expectancy 3 months or more;
7. There was no history of serious hematopoietic function, abnormal heart, lung, liver, kidney function and immune deficiency;
8. One week before enrollment,absolute value of T lymphocytes≥0.5 times of normal lower limit,neutrophil ≥ 1.0×109/L,AST and ALT ≤3.0 times normal upper limit(Liver cancer/liver metastasis patients ≤5.0 times normal upper limit),creatinine ≤ 3.0 times normal upper limit,serum calcium≥2.0mmol/L;
9. Patients must have the ability to understand and voluntarily sign an informed consent form.

Exclusion Criteria:

1. Pregnant or lactating women;
2. Patients with a history of other malignant diseases in the last 2 years,except cured skin cancer and carcinoma in situ;
3. Patients with a history of uncontrolled epilepsy, central nervous system diseases or mental disorders, whose clinical severity may hinder the signing of informed consent or affect the patient's compliance with drug treatment as judged by the investigator;
4. Clinically significant (ie, active) heart disease, such as symptomatic coronary heart disease, congestive heart failure New York Heart Association (NYHA) Class II or greater, or severe arrhythmia requiring drug intervention, or a history of myocardial infarction within the last 12 months;
5. Organ transplantation requiring immunosuppressive therapy;
6. Known active infection, or significant hematological, renal, metabolic,gastrointestinal, endocrine function or metabolic disorders, or other serious uncontrolled concomitant diseases as judged by the investigator;
7. Hypersensitivity to any component of the study drug;
8. History of immunodeficiency, including positive HIV test or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation, or other related diseases requiring long-term oral hormone therapy (greater than 10 mg/d prednisone);
9. Patients who are in the period of acute and chronic tuberculosis infection(patients with positive T-spot test and suspicious tuberculosis lesions on chest radiography), are in the period of acute hepatitis infection or have chronic hepatitis B virus copy number higher than the normal range;
10. Other conditions considered unsuitable by the investigator.

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: Radiotherapy, PD-L1 inhibitors Sequential GM-CSF and IL-2	Radiation: Hypofractionated radiotherapy; 24Gy/8Gy/3f; Drug: PD-L1 inhibitor; q3w; Drug: GM-CSF; 200μg, D1-D7; Drug: IL-2; at a dose of 2 million IU, D8-D14

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	objective response rate	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	progression-free survival	Up to 3 years
DCR	CR+PR+SD(RECIST 1.1)	Up to 3 years
OS	overall survival	Up to 3 years
Treatment Related Severe Adverse Effects	Number of participants with treatment-related severe adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.	Up to 3 years

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Soochow University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2022
• Primary Completion (ANTICIPATED): December 1, 2024
• Study Completion (ANTICIPATED): June 1, 2025

Study Registration Dates

• First Submitted: September 3, 2022
• First Submitted That Met QC Criteria: September 3, 2022
• First Posted (ACTUAL): September 7, 2022

Study Record Updates

• Last Update Posted (ACTUAL): September 7, 2022
• Last Update Submitted That Met QC Criteria: September 3, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immune Checkpoint Inhibitors
• Other Study ID Numbers: JD-LK-2022-102-01

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