## Protocol Section
### Identification Module
**NCT ID:** NCT06422403

**Acronym:** VALUE-CHECK

**Brief Title:** A Value-Driven Study on Reducing Immune Checkpoint Inhibitor Dosing Frequency in Advanced Cancers

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

#### Organization Study ID Info
**ID:** 2024/00217
#### Organization
**Class:** OTHER
**Full Name:** National University Hospital, Singapore
### Status Module
#### Completion Date
**Date:** 2029-12-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-21

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-15

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2029-03-30

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-07-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-01

#### Study First Post Date
**Date:** 2024-05-21
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-15
**Study First Submit QC Date:** 2024-05-15
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** National University Hospital, Singapore

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** 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.

**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, non-small cell lung cancer with PDL1 TPS≥50% and locally advanced/metastatic head and neck squamous cell carcinoma with PDL1 CPS ≥1% that have no prior treatment.

Secondary Objective To investigate the safety, overall survival (OS) of ICI at extended dosing interval of the standard versus extended dosing interval groups.

Exploratory endpoints We would detect minimal residual disease (MRD) using multiomics and compare the progress of the disease or the outcome of patients besides clinical assessments.

### Conditions Module

**Conditions:**

- Carcinoma, Hepatocellular

- Gastric Adenocarcinoma

- GastroEsophageal Cancer

- Oesophageal Cancer

- Non-small Cell Lung Cancer

- Head and Neck Squamous Cell Carcinoma

**Keywords:**

- Nivolumab

- Atezolizumab

- Pembrolizumab

- Extended dosing interval

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** This study is a prospective, open label, multi-centre phase 2 trial

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 310

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Nivolumab, XELOX/FOLFOX

**Intervention Names:**

- Drug: Standard of Care - A

**Label:** Cohort A (SOC)

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** Nivolumab, XELOX/FOLFOX

**Intervention Names:**

- Drug: Extended Dosing Interval - A

**Label:** Cohort A (EDI)

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** Bevacizumab, Atezolizumab

**Intervention Names:**

- Drug: Standard of Care - B

**Label:** Cohort B (SOC)

**Type:** ACTIVE_COMPARATOR

#### Arm Group 4

**Description:** Bevacizumab, Atezolizumab

**Intervention Names:**

- Drug: Extended Dosing Interval - B

**Label:** Cohort B (EDI)

**Type:** EXPERIMENTAL

#### Arm Group 5

**Description:** Pembrolizumab

**Intervention Names:**

- Drug: Standard of Care - C

**Label:** Cohort C (SOC)

**Type:** ACTIVE_COMPARATOR

#### Arm Group 6

**Description:** Pembrolizumab

**Intervention Names:**

- Drug: Extended Dosing Interval - C

**Label:** Cohort C (EDI)

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cohort A (EDI)

**Description:** Nivolumab 360mg 6 weekly (up to 2 years) + XELOX Nivolumab 240mg 4 weekly (up to 2 years) + FOLFOX

**Name:** Extended Dosing Interval - A

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Cohort B (EDI)

**Description:** Bevacizumab + Atezolizumab 1200mg 6 weekly (up to 2 years)

**Name:** Extended Dosing Interval - B

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Cohort C (EDI)

**Description:** Pembrolizumab 200mg 6 weekly (up to 2 years)

**Name:** Extended Dosing Interval - C

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Cohort A (SOC)

**Description:** Nivolumab 360mg 3 weekly (up to 2 years) + XELOX Nivolumab 240mg 2 weekly (up to 2 years) + FOLFOX

**Name:** Standard of Care - A

**Type:** DRUG

#### Intervention 5

**Arm Group Labels:**

- Cohort B (SOC)

**Description:** Bevacizumab + Atezolizumab 1200mg 3 weekly (up to 2 years)

**Name:** Standard of Care - B

**Type:** DRUG

#### Intervention 6

**Arm Group Labels:**

- Cohort C (SOC)

**Description:** Pembrolizumab 200mg 3 weekly (up to 2 years)

**Name:** Standard of Care - C

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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).

**Measure:** Progression-free survival (PFS)

**Time Frame:** Up to 2 years

#### Secondary Outcomes

**Description:** As defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

**Measure:** Number of participant with treatment related haematological and non-haematological toxicities

**Time Frame:** Up to 2 years

**Description:** 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

**Measure:** Objective response rate

**Time Frame:** Up to 2 years

**Description:** 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.

**Measure:** Duration of Response

**Time Frame:** Up to 2 years

**Description:** 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)

**Measure:** Disease control rate

**Time Frame:** Up to 2 years

**Description:** Overall survival will be assessed based on the date of first dose and survival status at the time of analysis.

**Measure:** Overall survival

**Time Frame:** Up to 2 years

### Eligibility Module

**Eligibility Criteria:** 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.

**Maximum Age:** 99 Years

**Minimum Age:** 21 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** Wei_Peng_YONG@nuhs.edu.sg

**Name:** Wei Peng Yong

**Phone:** +65 6908 2222

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Singapore

**Contacts:**

***Contact 1:***

- **Email:** Wei_Peng_YONG@nuhs.edu.sg

- **Name:** Wei Peng Yong

- **Phone:** +65 6908 2222

- **Role:** CONTACT

**Country:** Singapore

**Facility:** Department of Hematology-Oncology, National University Hospita

#### Overall Officials

**Official 1:**

**Affiliation:** National University Hospital, Singapore

**Name:** Wei Peng Yong

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009375

- Term: Neoplasms, Glandular and Epithelial

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000002294

- Term: Carcinoma, Squamous Cell

- ID: D000000230

- Term: Adenocarcinoma

- ID: D000006258

- Term: Head and Neck Neoplasms

- ID: D000008113

- Term: Liver Neoplasms

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000008107

- Term: Liver Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M5546

- Name: Carcinoma, Non-Small-Cell Lung

- Relevance: LOW

- As Found: Unknown

- ID: M5534

- Name: Carcinoma

- Relevance: HIGH

- As Found: Carcinoma

- ID: M5550

- Name: Carcinoma, Squamous Cell

- Relevance: LOW

- As Found: Unknown

- ID: M11172

- Name: Lung Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M9613

- Name: Carcinoma, Hepatocellular

- Relevance: HIGH

- As Found: Carcinoma, Hepatocellular

- ID: M3585

- Name: Adenocarcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M1689

- Name: Squamous Cell Carcinoma of Head and Neck

- Relevance: HIGH

- As Found: Head and Neck Squamous Cell Carcinoma

- ID: M12320

- Name: Neoplasms, Glandular and Epithelial

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M9348

- Name: Head and Neck Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M11113

- Name: Liver Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11107

- Name: Liver Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T2141

- Name: Esophageal Cancer

- Relevance: HIGH

- As Found: Oesophageal Cancer

### Condition Browse Module - Meshes

- ID: D000002277

- Term: Carcinoma

- ID: D000077195

- Term: Squamous Cell Carcinoma of Head and Neck

- ID: D000006528

- Term: Carcinoma, Hepatocellular

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M246

- Name: Bevacizumab

- Relevance: LOW

- As Found: Unknown

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M349416

- Name: Pembrolizumab

- Relevance: LOW

- As Found: Unknown

- ID: M1854

- Name: Nivolumab

- Relevance: LOW

- As Found: Unknown

- ID: M349417

- Name: Atezolizumab

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
