A Value-Driven Study on Reducing Immune Checkpoint Inhibitor Dosing Frequency in Advanced Cancers (VALUE-CHECK)

A Value-Driven Study on Reducing Immune Checkpoint Inhibitor Dosing Frequency in Advanced Cancers: Phase 2 Randomized Trial (VALUE-CHECK)

This study is a prospective, open label, multi-centre phase 2 trial which assesses the efficacy and safety of standard dosing compared to extended dosing interval of nivolumab, atezolizumab or pembrolizumab in advanced/unresectable gastric/gastroesophageal junction/oesphageal adenocarcinomas with PDL1 CPS ≥5%, hepatocellular carcinoma andnon-small cell lung cancer with PDL1 TPS≥50% with no prior treatment. The investigators hypothesize that nivolumab, pembrolizumab and atezolizumab can be used efficiently at extended dosing intervals, compared to their approved labels with comparable clinical outcome.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Hepatocellular; Gastric Adenocarcinoma; Non-small Cell Lung Cancer; Head and Neck Squamous Cell Carcinoma; Oesophageal Cancer; GastroEsophageal Cancer
• Intervention / Treatment: Drug: Standard of Care - A; Drug: Extended Dosing Interval - A; Drug: Standard of Care - B; Drug: Extended Dosing Interval - B; Drug: Standard of Care - C; Drug: Extended Dosing Interval - C

Detailed Description

This study aims to assess the noninferiority of progression free survival of standard dosing compared to extended dosing interval of nivolumab, pembrolizumab and atezolizumab in advanced/unresectable gastric/gastroesophageal junction/oesphageal adenocarcinomas with PDL1 CPS ≥5%, hepatocellular carcinoma, and non-small cell lung cancer with PDL1 TPS≥50%.

Secondary Objective

• To investigate the safety, overall survival (OS) of ICI at extended dosing interval of the standard versus extended dosing interval groups.
• To investigate the pharmacokinetics (PK) of nivolumab, atezolizumab or pembrolizumab.

• Study Type: Interventional
• Enrollment (Estimated): 360
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Wei Peng Yong; Phone Number: +65 6908 2222; Email: Wei_Peng_YONG@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • Department of Hematology-Oncology, National University Hospita
    • Contact: Wei Peng Yong; Phone Number: +65 6908 2222; Email: Wei_Peng_YONG@nuhs.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of informed consent prior to any study-specific procedure

2. Patients with one of the following:

   • Cohort A: Previously untreated locally advanced/metastatic HER2 -ve gastric/gastroesophageal junction/esophageal (PDL1 CPS ≥5% adenocarcinomas not amenable to curative surgery or radiotherapy who are above to begin platinum double and nivolumab.
   • Cohort B: Previously untreated locally advanced/metastatic Child's A hepatocellular carcinoma not amenable to curative surgery or radiotherapy who are above to begin atezolizumab and bevacizumab.
   • Cohort C: Previously untreated locally advanced/metastatic lung adenocarcinoma (PDL1 TPS≥50%, EGFR/ALK wildtype) not amenable to curative surgery or radiotherapy who are above to begin pembrolizumab monotherapy
3. Measurable disease per RECIST 1.1 criteria
4. ECOG Performance status is 0-2

5. Normal organ and bone marrow function measured within 28 days before the study as defined below:

   • Haemoglobin ≥ 8.0 g/dL and no blood transfusions in the 28 days prior to entry
   • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
   • No features suggestive of MDS/AML on peripheral blood smear
   • White blood cells (WBC) > 3x10^9/L
   • Platelet count ≥ 100 x 10^9/L
   • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
   • AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN
   • Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
6. A life expectancy ≥ 12 weeks in all patients.
7. Females in childbearing age should be using adequate contraceptive measures, should not be breastfeeding and their pregnancy test prior to the start of treatment must be negative. Evidence of non-child-bearing potential is fulfilled by one of the following criteria at screening:
8. The post-menopausal period defined as age ≥50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
9. Women <50 years old they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range.
10. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not a tubal ligatio
11. Male patients should be willing to use barrier contraception
12. The patient is willing to comply with the protocol during the study including undergoing treatment and scheduled visits and examinations including follow up.
13. At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and is considered suitable for accurate repeated measurements

Exclusion Criteria:

1. Patients who have previously received immune checkpoint inhibitors or investigational monoclonal antibody therapy.
2. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years
3. Unstable spinal cord compression/brain metastases unless asymptomatic and not requiring steroids for at least 2 weeks prior to the start of study treatment. For patients with brain metastases, gamma knife or stereotactic brain surgery is allowed prior to study treatment.
4. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. Minor surgery is allowed.
5. Severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which based on investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or having active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
6. Autoimmune disorders
7. Males and females of reproductive potential who are not using an effective method of contraception and females who are pregnant or breastfeeding or have a positive serum pregnancy test prior to study entry
8. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
9. Previous allogeneic bone marrow transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort A (SOC); Nivolumab, XELOX/FOLFOX	Drug: Standard of Care - A; Nivolumab 360mg 3 weekly (up to 2 years) + XELOX Nivolumab 240mg 2 weekly (up to 2 years) + FOLFOX
Experimental: Cohort A (EDI); Nivolumab, XELOX/FOLFOX	Drug: Extended Dosing Interval - A; Nivolumab 360mg 6 weekly (up to 2 years) + XELOX Nivolumab 240mg 4 weekly (up to 2 years) + FOLFOX
Active Comparator: Cohort B (SOC); Bevacizumab, Atezolizumab	Drug: Standard of Care - B; Bevacizumab + Atezolizumab 1200mg 3 weekly (up to 2 years)
Experimental: Cohort B (EDI); Bevacizumab, Atezolizumab	Drug: Extended Dosing Interval - B; Bevacizumab + Atezolizumab 1200mg 6 weekly (up to 2 years)
Active Comparator: Cohort C (SOC); Pembrolizumab	Drug: Standard of Care - C; Pembrolizumab 200mg 3 weekly (up to 2 years)
Experimental: Cohort C (EDI); Pembrolizumab	Drug: Extended Dosing Interval - C; Pembrolizumab 200mg 6 weekly (up to 2 years)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the time from date of first dosing until the date of objective disease progression as defined by Response Evaluation Criteria in Solid Tumor (RECIST 1.1) or death (by any cause in the absence of progression).	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participant with treatment related haematological and non-haematological toxicities	As defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	Up to 2 years
Objective response rate	Percentage of patients who have at least one confirmed response of 'complete response' or 'partial response' as defined by Response Evaluation Criteria in Solid Tumor (RECIST 1.1), that is confirmed at least 4 weeks later	Up to 2 years
Duration of Response	Duration of response will be defined as the time from the date of first documented response, that is subsequently confirmed until the date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.	Up to 2 years
Disease control rate	Disease control rate is defined as the proportion of patients with a best overall response of CR = complete response, PR = partial response, or SD = stable disease, as defined by Response Evaluation Criteria in Solid Tumor (RECIST 1.1)	Up to 2 years
Overall survival	Overall survival will be assessed based on the date of first dose and survival status at the time of analysis.	Up to 2 years

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Investigators: Principal Investigator: Wei Peng Yong, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2024
• Primary Completion (Estimated): March 30, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: May 15, 2024
• First Submitted That Met QC Criteria: May 15, 2024
• First Posted (Actual): May 21, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 8, 2025
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Nivolumab; Pembrolizumab; Atezolizumab; Extended dosing interval
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Head and Neck Neoplasms; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 2024-3881

Drug and device information, study documents

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