Quadratic Phenotypic Optimisation Platform (QPOP) Utilisation to Enhance Selection of Patient Therapy Through Patient Derived Organoids in Breast Cancer (QUEST)

April 16, 2023 updated by: National University Hospital, Singapore
Based on proof-of-concept study, the investigators hypothesise that the QPOP prediction model can be further extended into use in solid tumors. Using breast cancer as a model, the investigators intend to investigate the feasibility of QPOP as a clinical decision support platform to identify patient-specific drug combinations across a range of breast cancer patients. The investigators propose a pilot phase I clinical study to test the feasibility of using QPOP to guide therapy in patients with advanced breast cancer.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Breast cancer (BC) is highly heterogeneous with more than 20 genetically, morphologically and clinically distinct subtypes. Despite improved diagnosis and a wide repertoire of clinically-approved therapies, metastatic BC patients have a dismal 5-year survival rate of about 20%. Systemic treatment options for breast cancer are empiric based on large clinical studies, and the ability to tailor choices individualized to each patient may aid optimization of patient's responses to treatment.

A major obstacle for drug development is the lack of clinically relevant cell model systems. The use of conventional two-dimensional (2D) cell cultures presents limitations in the recapitulation of the primary disease characteristics. In particular, monolayer cultures have been demonstrated for not being able to recapitulate the heterogeneous nature of primary patient tumor tissues. Despite the establishment of the National Cancer Institute 60 Panel (NCI-60) in an attempt to capture the heterogeneous nature of nine different cancer types, it is still unable to comprehensively represent the diversity which cancer patients exhibit, and is currently being phased out. Studies comparing the molecular profiles of cell lines with primary tumors have reported that conventional cell lines are unable to represent all cancer subtypes. Recently, patient-derived organoids (PDOs) has been demonstrated to faithfully preserve and maintain heterogeneity of several primary cancer types including BC and are being used to evaluate drug sensitivity and their associated genomic variations. PDOs have also been shown to retain the molecular profiles of the parental tumors and can be effectively used to investigate drug responses and mechanisms ex vivo. Thus, human PDOs can provide more clinically relevant models that can recapitulate disease heterogeneity for more accurate studies of drug responses as compared to conventional cell line-based models.

Identifying the most suitable patient-specific drug combinations remains a challenge due to the complex molecular networks that contribute to feedback mechanisms of drug resistance and compensatory oncogenic drivers that limit efficacy of targeted inhibitors. Pharmacogenomics is highly useful in predicting drug sensitivity and clinical outcome and define appropriate subpopulations for specific drugs based on genetic biomarkers. These approaches are largely limited to monotherapy and cannot identify patient-specific drug combinations nor do they consider other genomic alterations that are unaccounted for by the specific biomarkers used. In order to address this critical deficit in combination therapy, the investigators have developed an experimental-analytical hybrid platform, Quadratic Phenotypic Optimisation Platform (QPOP), that can rank potential drug combination response in biological model systems. The investigators initially applied QPOP towards identifying novel drug combinations against bortezomib-resistant multiple myeloma. As the investigators have improved the efficiency of the QPOP platform and applied QPOP towards primary patient samples and patient-derived organoids, it has become clear that QPOP may be useful as a clinical decision support platform that may be able to suggest clinically actionable and suitable patient-specific drug combinations derived from drug sensitivity tests using patient-derived materials.

The investigators hypothesise that the QPOP prediction model can be further extended into use in solid tumors. Using breast cancer as a model, we intend to investigate the feasibility of QPOP as a clinical decision support platform to identity patient-specific drug combinations across a range of breast cancer patients. The Investigators propose a pilot phase I clinical study to test the feasibility of using QPOP to guide therapy in patients with advanced breast cancer.

Eligible patients will undergo a fresh biopsy of tumour lesion to obtain cells that will be used to generate patient-derived tumour organoids. After successful organoid generation, organoids will be subjected to a 12-drug panel screening including 10 fixed drugs and 2 drugs that may be selected by physician based on treatment history of individual patients. The drug panel is curated taking into account standard drugs commonly used in breast cancer treatment as well as drugs/combinations being tested at ongoing therapeutic trials at the National University Cancer Institute Singapore (NCIS) which enrolled patients can gain access to. Fixed drug panel will include chemotherapy (cisplatin, 5-fluorouracil, paclitaxel), endocrine therapy (tamoxifen, fulvestrant), HER2-directed therapy (lapatinib) and small molecule tyrosine kinase inhibitors (abemaciclib, olaparib, alpelisib, lenvatinib).

QPOP analysis results will be reported to treating physician once available to aid selection of therapy. To prevent delay in patient treatment while awaiting QPOP results, patients are allowed to receive next line of therapy at physician's discretion (termed "empirical therapy"), and QPOP analyses results can be used to guide further lines of treatment upon progression on "empirical therapy".

Study Type

Interventional

Enrollment (Anticipated)

26

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Singapore
      • Singapore, Singapore
        • Recruiting
        • National University Hospital Singapore

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Part A - Inclusion and exclusion criteria to be fulfilled both prior to study enrolment and prior to commencement of study drug

Inclusion Criteria:

  • Age >= 21 years.
  • Histological confirmed breast carcinoma of any subtype (any estrogen receptor, progesterone receptor and HER2 receptor status)
  • ECOG 0-1.
  • At least 1 tumour lesion (primary or metastatic) amenable to fresh biopsy
  • At least 1 measurable tumour lesions based on RECIST 1.1 criteria
  • Estimated life expectancy of at least 12 weeks.
  • Has documented progressive disease from last line of therapy.
  • Has received at least 1 line of palliative systemic therapy
  • Expected adequate organ function (bone marrow, hepatic, renal) after recovering from treatment-induced acute toxicities at the time of study treatment.
  • Signed informed consent from patient or legal representative.
  • Able to comply with study-related procedures.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons:

  • Pregnancy.
  • Breast feeding.
  • Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
  • Active bleeding disorder or bleeding site.
  • Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
  • History of significant neurological or mental disorder, including seizures or dementia.

Part B - Additional inclusion and exclusion criteria to be fulfilled prior to commencement of study drug

Inclusion criteria

Patients may be included in the study only if they meet all of the following criteria:

• Adequate organ function including the following:

Bone marrow:

  • Absolute neutrophil (segmented and bands) count (ANC) >= 1.5 x 109/L
  • Platelets >= 100 x 109/L
  • Hemoglobin >= 8 x 109/L

Hepatic:

  • Bilirubin <= 1.5 x upper limit of normal (ULN),
  • ALT or AST <= 2.5x ULN, (or <=5 X with liver metastases)

Renal:

- Creatinine <= 1.5x ULN

Exclusion criteria

Patients will be excluded from the study for any of the following reasons:

  • Treatment within the last 30 days with any investigational drug.
  • Concurrent administration of any other tumour therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy at time of commencement of study drug.
  • Major surgery within 28 days of study drug administration.
  • Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
  • Non-healing wound.
  • Poorly controlled diabetes mellitus.
  • Symptomatic brain metastasis.
  • Contraindication to receiving specific QPOP-directed study treatment within drug that has been recommended based on QPOP analyses (e.g., poorly controlled diabetes mellitus for alpelisib, left ventricular ejection fraction of <50% for trastuzumab-emtansine)
  • Received more than 2 lines of empirical therapy between tumor biopsy for organoids growth and commencement on QPOP-directed study treatment (including endocrine therapy, chemotherapy, targeted therapy or immunotherapy)
  • Biopsy for organoids growth performed more than 12 months from time of study drug commencement
  • Has not recovered from acute toxicities from prior anti-cancer therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: QPOP-based drug screen assay using patient tumour-derived organoids

Patients with Histological confirmed breast carcinoma of any subtype (any estrogen receptor, progesterone receptor and HER2 receptor status) with at least 1 tumour lesion (primary or metastatic) amendable to fresh biopsy and measurable based on RECIST 1.1 criteria will undergo biopsy to obtain a sample of cancer tissue that will be used to generate Patient Derived Organoids (PDOs).

Patients' cells will be subjected to testing with 10-12 anti-cancer drugs and a table for treatment sensitivity to each drug will be derived after 8 to 12 weeks of treatment in the laboratory. Results will be reviewed at an expert panel discussion to decide on the most suitable anti-cancer drug treatment
Device: QPOP
QPOP will be used as a clinical decision support platform to identity suitable patient-specific drug combinations across a range of breast cancer patients, which are derived from drug sensitivity tests using patient-derived materials.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Objective response rate measured by RECIST 1.1 criteria to anti-cancer therapy selected by QPOP (prospective analysis).
Time Frame: 3 years
3 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Clinical benefit rate as determined by proportion of patients with complete response, partial response or stable disease as best response on RECIST 1.1 criteria (prospective analysis)
Time Frame: 3 years
3 years
Progression-free survival of QPOP-guided therapy as measured by RECIST 1.1 criteria (prospective analysis)
Time Frame: 3 years
3 years
Correlating QPOP prediction score of immediate past line of therapy and objective response rate to that therapy (retrospective correlative analysis)
Time Frame: 3 years
3 years
Correlating objective response rate (ORR) measured by RECIST v1.1 of the tumor lesion biopsied for QPOP analyses with QPOP guided therapy (retrospective correlative analysis)
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National University Hospital, Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 6, 2021

Primary Completion (Anticipated)

January 3, 2025

Study Completion (Anticipated)

December 31, 2025

Study Registration Dates

First Submitted

November 10, 2021

First Submitted That Met QC Criteria

December 14, 2021

First Posted (Actual)

January 4, 2022

Study Record Updates

Last Update Posted (Actual)

April 18, 2023

Last Update Submitted That Met QC Criteria

April 16, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BR02/03/21

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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