Nivolumab and Pembrolizumab Dose Optimisation in Solid Tumours With CURATE.AI Platform and Sequential ctDNA Measurements

Phase 1

Recruiting

• Conditions: Solid Tumor
• Interventions: Device: CURATE.AI; Drug: Nivolumab, Pembrolizumab

• Registration Number: NCT05175235
• Lead Sponsor: National University Hospital, Singapore

Brief Summary

CURATE.AI - a small data, AI-derived technology platform - allows personalised guidance of an individual's dose modulations based only on that individual's data. Additionally, CURATE.AI is mechanism-independent, and dynamically adapts to changes experienced by the subject, providing dynamic dose optimisation throughout the duration of the subject's treatment. This study aims to demonstrate the feasibility of applying CURATE.AI in standard of care settings for treatment of solid tumours with Nivolumab. An additional objective is to explore sequential ctDNA measurements as a response marker collected at a higher frequency of probing, with modulated doses.

Detailed Description

The first stage of the trial aims to identify patients who are responsive to the given treatment, determined from both SOC - radiology via criteria such as RECIST/immune-related RECIST (irRECIST) as well as the intended response marker for CURATE.AI. These patients will then proceed with the second stage of the trial.

The second stage of the trial aims to obtain a personalised CURATE.AI profile for each participant, based on their phenotypic response to a set of drug doses. The doses will be recommended by the CURATE.AI team, when relevant to the clinical decision-making process. For participants who started on the selected therapy prior to their engagement with the study, the previously recorded data, limited to: administered doses, corresponding phenotypic responses and treatment-related toxicities (optional) may be included in the CURATE.AI process. Once an actionable profile is obtained, dose recommendations are based on the profile and aimed to treat the participant.

Since there are no prior clinical trials using CURATE.AI in participant treated with combinational or single-agent immunotherapy with drugs such as nivolumab or pembrolizumab, this trial will comprise of participants diagnosed with the main tumour types: non-small cell lung cancer (NSCLC), gastric cancer (GC), hepatocellular carcinoma (HCC) or nasopharyngeal carcinoma (NPC), or other eligible tumours undergoing or planned for palliative-intent immune-oncology combinational or single-agent therapy with nivolumab/ pembrolizumab.

Nivolumab and Pembrolizumab are an immune checkpoint inhibitors and a novel therapeutic treatment modalities recently approved by the FDA and are becoming the standard of care treatment for a range of oncological indications, including NSCLC, GC, HCC and NPC. However, they are associated with significant semi-annual costs - approximately $140,000 per patient in the United States. In light of the evidence supporting dose personalization and dose reduction in immune-oncology treatments, patients may stand to benefit from CURATE.AI's personalized dose optimisation in maximizing clinical outcomes at reduced costs. Together with the increasing adoption of circulating tumour DNA (ctDNA) as an effective response marker for tumour burden in NSCLC, GC, HCC and NPC, CURATE.AI is ideally suited for pairing these findings with healthcare economics research towards the development of novel healthcare workflows integrating AI and serial measurements of ctDNA response to sustain the scalable implementation of N-of-1 dosing optimisation in cancer treatments.

Study Timeline

• Study Start: 2021-08-19
• Study First Submitted: 2021-12-14
• Study First Submitted QC: 2021-12-14
• Study First Posted: 2022-01-03
• Status Verified: 2023-01
• Last Update Submitted: 2023-03-02
• Last Update Posted: 2023-03-03
• Primary Completion: 2023-05-31
• Study Completion: 2023-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

1. Males and females ≥ 21 years of age

2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

3. Patients must meet the following clinical laboratory criteria within 21 days of starting treatment:

   1. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet ≥ 50,000/mm3
   2. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN of ≤ 5 ULN if involvement of the liver.
   3. Calculated creatinine clearance ≥ 30 mL/min or creatinine < 1.5 x ULN.

4. Main tumour types: Non-small cell lung cancer (NSCLC), gastric cancer (GC), hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC) or other metastatic solid tumours not for curative intent therapy;

5. Treatment with combinational immunotherapy or single-agent nivolumab/pembrolizumab. If patients have already started treatment on this regimen, they may still be eligible to enrol, provided they fulfil all other criteria and approval is sought by PI and Sponsor.

6. Eligible for treatment combinational immunotherapy or single-agent nivolumab /pembrolizumab based on co-investigator's assessment of fitness for immunotherapy (e.g. not on high dose corticosteroid therapy or uncontrolled auto-immune disorder)

Exclusion Criteria

1. Patients who are lactating or pregnant.
2. Patients with clinically significant hypersensitivity to one or more of the selected regimen's constituent drug(s)
3. Contraindication to any of the required concomitant drugs or supportive treatments.
4. Any clinically significant medical disease or psychiatric condition that, in the co-investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
5. Major surgery within 28 days prior to start of the treatment,
6. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischaemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 4 months prior to informed consent obtained.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CURATE.AI	Nivolumab, Pembrolizumab	Participants will undergo two treatment periods: selection period and CURATE.AI modulation period. During the selection period, baseline ctDNA measurements and CT scans will be performed. Subsequently, participants will receive Standard of Care (SOC) doses of nivolumab/pembrolizumab and have their ctDNA measured at the end of the third cycle together with other SOC monitoring. After the first ctDNA measurement and CT scan, selected patients who responded to treatment through both ctDNA and CT scan may continue into the CURATE.AI modulation period. Non-responders will receive SOC doses of nivolumab/pembrolizumab for 2 cycles before having their ctDNA measured and CT scan at the end of the 2 cycles. Subsequent responders through both ctDNA and CT scans may then continue into the CURATE.AI modulation period. Only the dose of nivolumab/pembrolizumab will be modulated with CURATE.AI, based on measurements of the response marker (ctDNA).
CURATE.AI	CURATE.AI	Participants will undergo two treatment periods: selection period and CURATE.AI modulation period. During the selection period, baseline ctDNA measurements and CT scans will be performed. Subsequently, participants will receive Standard of Care (SOC) doses of nivolumab/pembrolizumab and have their ctDNA measured at the end of the third cycle together with other SOC monitoring. After the first ctDNA measurement and CT scan, selected patients who responded to treatment through both ctDNA and CT scan may continue into the CURATE.AI modulation period. Non-responders will receive SOC doses of nivolumab/pembrolizumab for 2 cycles before having their ctDNA measured and CT scan at the end of the 2 cycles. Subsequent responders through both ctDNA and CT scans may then continue into the CURATE.AI modulation period. Only the dose of nivolumab/pembrolizumab will be modulated with CURATE.AI, based on measurements of the response marker (ctDNA).

Primary Outcome Measures

Name	Time	Method
Percentage of participants in whom we successfully apply CURATE.AI profile.	up to 12 months	CURATE.AI applicability: Percentage of participants in whom we successfully apply CURATE.AI profile. Based on percentages, outcomes will be classified as Green (\>70%) / Yellow (10-70%) / Red (\<10%).; A decision on whether we "successfully apply" the CURATE.AI profile requires expert judgement and cannot be made based on a purely numerical process. The expert panel will consider the following factors with careful regard for the individual circumstances of each participant: Error/variance (biological/analytical) is sufficiently small to allow accurate predictions Profile can be generated sufficiently early for the participant to potentially benefit; Dose-dependent relationship is observed; Profile is actionable (i.e. fulfils the clinical investigator's pre-specified safety requirements); Systemic changes in the participant which require profile recalibration are rare or readily assimilated into the CURATE.AI algorithm

Secondary Outcome Measures

Name	Time	Method
Patient adherence	Up to 12 months	Percentage of participants who always adhered to the prescribed dose whenever they took their medication, as measured by the standardised pharmacovigilance protocol. Based on percentages, outcomes will be classified as Green (\>90%) / Yellow (10-90%) / Red (\<10%).
Timely delivery of CURATE.AI recommendations to the clinician	Up to 12 months	Percentage of CURATE.AI recommendations provided in time for the next chemotherapy cycle, across all participants and cycles. Based on percentages, outcomes will be classified as Green (100%) / Yellow (10-99%) / Red (\<10%).
Physician adherence	Up to 12 months	Percentage of CURATE.AI recommended doses that were used by the clinical investigator. Based on percentages, outcomes will be classified as Green (\>70%) / Yellow (10-70%) / Red (\<10%).
CURATE.AI relevance	Up to 12 months	Percentage of dosing events across all participants and cycles in which CURATE.AI recommendation is considered in the clinical decision-making process. Based on percentages, outcomes will be classified as Green (100%) / Yellow (10-99%) / Red (\<10%).
Clinically significant dose changes	Up to 12 months	Percentage of participants in whom the CURATE.AI-guided cumulative dose is substantially (≥10%) different from the projected standard-of-care cumulative dose. Based on percentages, outcomes will be classified as Green (\>20%) / Yellow (1-20%) / Red (0%).

Trial Locations

Locations (1)

National University Hospital; 🇸🇬 Singapore, Singapore