Personalised Immunotherapy Platform

Recruiting

• Conditions: Basal Cell Carcinoma; Solid Tumor; Melanoma; Cutaneous Squamous Cell Carcinoma; Merkel Cell Carcinoma
• Interventions: Other: Predictive model

• Registration Number: NCT06536257
• Lead Sponsor: Melanoma Institute Australia

Brief Summary

This is a non-interventional study to prospectively test a suite of predictive biomarker models of immunotherapy resistance in patients with melanoma, non-melanoma skin cancers and other solid tumours. The study will evaluate the documentation, processes, accuracy and utility of the predictive biomarker model in clinical practice.

Detailed Description

The Personalised Immunotherapy Program (PIP) is a multicenter biomarker discovery and validation program of multi-omic biomarker based predictive models which aim to identify patients with immunotherapy resistant disease. PIP developed predictive models in retrospective setting, with validation within a prospective clinical observational study.

Immune checkpoint inhibitors targeting the cytotoxic T-cell lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) receptors have revolutionised the treatment of advanced melanoma, resulting in long-term durable responses and a 5-year overall survival of 52% with combination immunotherapy. However, clinical benefit is not universal, and half of these patients do not respond. Therefore, there is an urgent need for clinically validated biomarkers which can identify patients who are at high risk of not responding to standard-of-care immunotherapies and determine which emerging clinical trial agent is most appropriate for a particular patient's disease.

Researchers performed mutation, gene expression and tumour immune profiling on tumour biopsies from melanoma patients treated with anti-PD-1 monotherapy or combined anti-PD-1 and anti-CTLA-4 therapy. From this dataset PIP has developed predictive models to identify patients with immunotherapy resistant disease.

The subsequent PIP-PREDICT is a prospective clinical study that enrols advanced cancer patients who are eligible to receive approved immunotherapies. PIP testing and biomarker reporting is used to screen potential patients. Each patient enrolled in the study receives an individual PIP Biomarker Report, which is presented as part of the established Biomarker Multidisciplinary Team (MDT) meeting of clinical oncologists, pathologists, molecular biologists, trials nursing, PIP, and biospecimen staff on a fortnightly basis.

PIP-PREDICT has a primary goal of determining the accuracy of biomarker predictions from PIP prospectively within oncology clinics. Secondary goals include assessing the feasibility of biomarker assay workflows within diagnostic providers, conducting a cost-benefit ratio analysis, evaluating the effect of biomarker reports on treatment selection within multidisciplinary teams (MDTs), and performing a post-implementation analysis of personalised immunotherapy biomarker reports in treatment decision making.

Study Timeline

• Study Start: 2021-06-08
• Study First Submitted: 2024-03-30
• Study First Submitted QC: 2024-07-31
• Status Verified: 2024-08
• Study First Posted: 2024-08-02
• Last Update Submitted: 2024-08-18
• Last Update Posted: 2024-08-20
• Primary Completion: 2027-06-01
• Study Completion: 2037-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1000

Inclusion Criteria

1. Written informed consent to participation for the use of tumour tissue, blood and stool and collection of standard clinical data.
2. Histologically confirmed resected stage II (at high risk of recurrence of disease), III or stage IV melanoma (including cutaneous, mucosal, acral, subungual, uveal or unknown primary melanoma) and unresectable Stage III or IV melanoma
3. Eligible to receive immunotherapy
4. Availability of a melanoma tissue sample which was obtained at surgery and where no systemic treatments (e.g. adjuvant treatment) were administered between sample procurement and proposed PIP testing
5. Patients who have received adjuvant or neoadjuvant systemic therapy in the past are eligible if they have had recurrence after neoadjuvant or adjuvant therapy has been completed and the biopsy represents this relapsed disease
6. RECIST version 1.1 measurable disease.
7. Tissue sample must be representative of the whole tumour and therefore excision biopsies are preferred over core biopsies.
8. A life expectancy over 6 months.
9. Prior treatment with BRAF (B-Raf proto-oncogene) / MEK (mitogen-activated protein kinase) inhibitors are acceptable, providing the other eligibility criteria are met.
10. If a patient has had prior radiotherapy for melanoma, the biopsy to be used for the biomarker test must be from an area that was not within the radiotherapy field.

Exclusion Criteria

1. Patients will be excluded if they have had a positive test result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. If receiving treatment and from HCV for at least one year, patients are allowed to participate. No new testing is required for the sole purpose of this pilot phase. Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). No new testing is required

NON-MELANOMA:

Inclusion Criteria:

1. Written informed consent to participation for the use of tumour tissue and collection of standard clinical data

2. Histologically confirmed cancer and eligibility to receive immunotherapy treatment.

3. Availability of a tissue sample where no systemic treatments were administered between sample procurement and proposed PIP testing

4. If treatment has been administered since the last tissue sample was obtained, a new biopsy should be planned for routine testing or clinical trial screening, where a portion of the sample can be used for the predictive assay. No new biopsies are required for the sole purpose of this study.

5. Patients who have received adjuvant or neoadjuvant systemic therapy in the past are eligible if they have had recurrence after neoadjuvant or adjuvant therapy has been completed and the biopsy represents this relapsed disease.

6. Have clinically detectable disease defined as one of more of the following:

   • RECIST measurable. Lesions situated in a previously irradiated area are considered measurable if RECIST-defined disease progression since radiotherapy has been demonstrated in such lesions, OR,
   • Positron Emission Tomography (PET) avid, OR,
   • Clinically evident disease: photographically, detectable on CT or palpable, OR
   • Clinical status measured by observable and diagnosable signs or symptoms.

7. The tissue sample must be representative of the whole tumour and therefore excision biopsies are preferred over core biopsies.

8. A life expectancy over 6 months.

9. Prior treatment with targeted therapies are acceptable, providing the other eligibility criteria are met.

10. If a patient has had prior radiotherapy for melanoma, the biopsy to be used for the biomarker test must be from an area that was not within the radiotherapy field

Exclusion Criteria:

1. Patients will be excluded if they have had a positive test result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. If receiving treatment and from HCV for at least one year, patients are allowed to participate. No new testing is required for the sole purpose of this pilot phase. Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). No new testing is required

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Melanoma cohort	Predictive model	Patients with melanoma who are yet to receive immunotherapy will undergo predictive biomarker testing and biomarker reporting.
Solid tumour cohort	Predictive model	Patients with non-melanoma, non-skin cancer, solid tumours who are yet to receive immunotherapy will have tumour tested using the predictive model.
Non-melanoma skin cancer cohort	Predictive model	Patients with non-melanoma skin cancers (basal cell carcinoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma) who are yet to receive immunotherapy will have tumour tested using the predictive model.

Primary Outcome Measures

Name	Time	Method
Assessment of the accuracy of predictive test results in melanoma	6 months	Proportion of correctly predicted responders and non-responders to the immunotherapy treatment decision by the MDT, based on the 6 month progression-free survival (PFS)

Secondary Outcome Measures

Name	Time	Method
Evaluation of a test request form - completion rate	2 years	Proportion of required data completed by the referring clinician
Conduct qualitative surveys to evaluate a test result report from consumers' viewpoint	1 year	Survey results from consumer responses on the comprehension of risk probability (mean score from a 7 point scale), communication efficacy (mean score from a 4 point scale), significance and actionability (mean score from a 7 point scale) of the information within the report
A cost analysis of the predictive model testing protocol	2 years	Calculation of the cost per individual test (to include staff time, reagents, proportionate use of analytical equipment, assay costs, pathology service fee for sample preparation and shipping)
Evaluation of the predictive test report in shaping clinician treatment decision making	1 year	Index of the quality of team decision making using the multidisciplinary team (MDT) metric of decision making (MODe) framework
Concordance of clinician treatment decision making with predictive test results	2 years	Concordance of treatment recommendation(s) before and after provision of the predictive test report per patient case
Evaluation of potential new biomarkers of immunotherapy response or resistance in blood and stool samples on the accuracy of the predictive model	5 years	Impact of the inclusion of blood and/or stool biomarkers to the accuracy of the predictive model on predicting response to immunotherapy at 6 months post-treatment
Conduct qualitative surveys to evaluation of a test result report from the clinicians' viewpoint	2 years	Survey results from clinicians on the utility (mean score from a 7 point scale) and comprehension (mean score from a 7 point scale) of the report
Evaluation of the predictive model workflow on result completion	2 years	Identification of workflow barriers from request form to result delivery
Evaluation of the predictive model workflow turnaround timeframes	2 years	Proportion of test results received within 2 weeks (10 business days) from request
Evaluation of the predictive model workflow processes	2 years	Identification of processes that require change (if required), the number of identified issues found and the result of implemented changes.
Discordance of clinician treatment decision making with predictive test results	2 years	For treatment choice discordance, proportion of theoretical decisions based on the report that would be adhered to
Assessment of the accuracy of predictive test results in non-melanoma skin cancer and non-melanoma tumours	6 months	Proportion of correctly predicted responders and non-responders to immunotherapy treatment based on the 6 month progression-free survival
Assessment of the inaccuracy of predictive test results	6 months	Identification of patient populations for which the predictive model did not predict response (6 month PFS) to immunotherapy
Analysis of potential barriers to complete a test request form	2 years	Identification of barriers to completion of the request form
Qualiaitive evaluation of a test result report from consumers' viewpoint	1 year	Interviewer notes and transcriptions of consumers' answers to structured interview questions coded in software for qualitative data to identify and evaluate the most significant problems, highlight cases of poor comprehension, and assess the degree to which the reports met consumers' information needs
Availability of suitable tissue for the predictive model testing protocol	2 years	Proportion of patients who could not be tested because no suitable tissue available (and reasons why).
Data quality for the predictive model testing protocol	2 years	Proportion of patients who could not be tested because of missing clinical data (and which data and why missing)
Evaluation of accessible data in medical records for completion of a test request form	2 years	Proportion of required data that is readily available in routine patient medical records
Evaluation of a test request form from clinician feedback via qualitative surveys	2 years	Summarised feedback from clinicians in narrative format
Qualiaitive evaluation of a test result report from clinicians' viewpoint	2 years	Summarised feedback from clinicians to structured interview questions
Evaluation of the predictive model workflow delays	2 years	Summary of reasons for delay in providing test result
Exploratory evaluation of potential new biomarkers of immunotherapy response or resistance in blood and stool samples	5 years	Identification of biomarkers in blood and/or stools predictive of response or resistance to immunotherapy that can be incorporated into the predictive model
Evaluation of the predictive model workflow on result delivery	2 years	Time from request form submission to predictive test result delivery (business days)
Evaluation of the impact of predictive test result in shaping clinician treatment decision making	2 years	Decision making with and without the knowledge of the predictive test report (Decision Impact Analysis) by the MDT

Trial Locations

Locations (3)

Chris O'Brien Lifehouse; 🇦🇺 Sydney, New South Wales, Australia

Melanoma Institute Australia; 🇦🇺 Sydney, New South Wales, Australia

Westmead Hospital; 🇦🇺 Sydney, New South Wales, Australia