Organoid-based Functional Precision Therapy for Advanced Breast Cancer

NCT ID: NCT06102824

Last Updated: 2024-11-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

252 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-10-01

Study Completion Date

2028-06-30

Brief Summary

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This is a phase II, multicenter, open-label, randomized controlled trial to compare the efficacy of organoid-guided treatment (OGT) to treatment of physician's choice (TPC) in previously treated, HER2-negative locally advanced or metastatic breast cancer. The study will seek to provide evidence for utilizing patient-derived organoid (PDO) model to personalize treatment strategies and inform clinical care for advanced breast cancer. Subjects randomized to the OGT group will undergo PDO generation and receive treatment dictated by subsequent PDO drug sensitivity screening. Subjects randomized to the TPC group will receive empirical therapy as selected by the treating physician.

Detailed Description

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Treatment for advanced-stage breast cancer has long been challenging. Genomic-based precision medicine was able to facilitate treatment selection in some patients, but there were considerable instances where genomic profiling failed to assign effective interventions or patients exhibited refractoriness to the drugs nominated by genomic alterations. Patient-derived organoids (PDOs) represent a tractable tool that may compensate for the drawbacks of genomic medicine to identify therapeutic opportunities in rare or metastatic cancers. Previous research has demonstrated that PDOs displayed strong biological fidelity to their original tumors and functional precision medicine based on PDO drug screening could confer survival benefits in breast cancer patients.

This multicenter, open-label, randomized phase II trial aims to investigate the safety and efficacy of organoid-guided treatment (OGT) versus treatment of physician's choice (TPC) in previously treated, HER2-negative locally advanced or metastatic breast cancer. Randomization will be stratified by hormone receptor status and prior chemotherapy for the advanced or metastatic disease. Subjects in the OGT group will receive treatment predicted to be the most efficacious by the PDO drug sensitivity screening, and subjects in the TPC group will receive treatment selected by the treating physician. Treatments tested in PDO drug screening or chosen by the treating physician will be guided by NCCN guidelines. Treatment that subjects have previously received before randomization is no longer subjected to PDO sensitivity screening. This study will provide valuable evidence on the real-time application of PDOs in the context of clinical care.

Conditions

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HER2-negative Breast Cancer Advanced Breast Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Organoid-guided treatment

Subjects randomized to the organoid-guided treatment (OGT) group will be treated with the drugs predicted to be the most sensitive through PDO drug sensitivity screening. Drugs that the subjects have progressed on before randomization will not be screened. The drugs selected for organoid screening are from the following options: taxane, anthracycline, 5-fluorouracil, gemcitabine, vinorelbine, eribulin, utidelone, carboplatin, sacituzumab govitecan, and trastuzumab deruxtecan (for HER2-low patients).

Group Type EXPERIMENTAL

Organoid-guided treatment

Intervention Type DRUG

The drugs predicted to be the most sensitive through organoid drug sensitivity screening. The drugs selected for sensitivity screening are from the following options: taxane, anthracycline, 5-fluorouracil, gemcitabine, vinorelbine, eribulin, utidelone, carboplatin, sacituzumab govitecan, and trastuzumab deruxtecan (for HER2-low patients).

Treatment of physician's choice

Subjects randomized to the treatment of physician's choice (TPC) group will receive physician-chosen therapy from the following options: taxane, anthracycline, 5-fluorouracil, gemcitabine, vinorelbine, eribulin, utidelone, carboplatin, sacituzumab govitecan, and trastuzumab deruxtecan (for HER2-low patients).

Group Type ACTIVE_COMPARATOR

Taxane

Intervention Type DRUG

Albumin-bound paclitaxel 260mg/m2, IV, q3w, or 100-125mg/m2, IV, days 1, 8, and 15, q4w OR Liposomal paclitaxel 175mg/m2, IV, q3w

Capecitabine

Intervention Type DRUG

1000-1250mg/m2, PO, bid, days1-14, q3w

Gemcitabine

Intervention Type DRUG

800-1200mg/m2, IV, days 1, 8, q3w

Vinorelbine

Intervention Type DRUG

20-35mg/m2, IV, days 1 and 8, q3w

Eribulin

Intervention Type DRUG

1.4mg/m2, IV, days 1 and 8, q3w

Anthracycline

Intervention Type DRUG

Liposomal doxorubicin 50mg/m2, IV, q3w OR Liposomal doxorubicin 40mg/m2+Cyclophosphamide 600mg/m2, IV, q3w

Carboplatin

Intervention Type DRUG

Carboplatin AUC 6, IV, q3w or q4w OR Carboplatin AUC 2+Gemcitabine 1000mg/m2, IV, days 1 and 8, q3w OR Carboplatin AUC 2+Albumin-bound paclitaxel 125mg/m2, IV, days 1 and 8, q3w

Utidelone

Intervention Type DRUG

30mg/m2, IV, once per day on days 1-5, q3w

Trastuzumab deruxtecan

Intervention Type DRUG

5.4mg/kg, IV, q3w

Sacituzumab govitecan

Intervention Type DRUG

10mg/kg, IV, days 1 and 8, q3w

Interventions

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Organoid-guided treatment

The drugs predicted to be the most sensitive through organoid drug sensitivity screening. The drugs selected for sensitivity screening are from the following options: taxane, anthracycline, 5-fluorouracil, gemcitabine, vinorelbine, eribulin, utidelone, carboplatin, sacituzumab govitecan, and trastuzumab deruxtecan (for HER2-low patients).

Intervention Type DRUG

Taxane

Albumin-bound paclitaxel 260mg/m2, IV, q3w, or 100-125mg/m2, IV, days 1, 8, and 15, q4w OR Liposomal paclitaxel 175mg/m2, IV, q3w

Intervention Type DRUG

Capecitabine

1000-1250mg/m2, PO, bid, days1-14, q3w

Intervention Type DRUG

Gemcitabine

800-1200mg/m2, IV, days 1, 8, q3w

Intervention Type DRUG

Vinorelbine

20-35mg/m2, IV, days 1 and 8, q3w

Intervention Type DRUG

Eribulin

1.4mg/m2, IV, days 1 and 8, q3w

Intervention Type DRUG

Anthracycline

Liposomal doxorubicin 50mg/m2, IV, q3w OR Liposomal doxorubicin 40mg/m2+Cyclophosphamide 600mg/m2, IV, q3w

Intervention Type DRUG

Carboplatin

Carboplatin AUC 6, IV, q3w or q4w OR Carboplatin AUC 2+Gemcitabine 1000mg/m2, IV, days 1 and 8, q3w OR Carboplatin AUC 2+Albumin-bound paclitaxel 125mg/m2, IV, days 1 and 8, q3w

Intervention Type DRUG

Utidelone

30mg/m2, IV, once per day on days 1-5, q3w

Intervention Type DRUG

Trastuzumab deruxtecan

5.4mg/kg, IV, q3w

Intervention Type DRUG

Sacituzumab govitecan

10mg/kg, IV, days 1 and 8, q3w

Intervention Type DRUG

Other Intervention Names

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Abraxane, Lipusu Xeloda Gemzar Navelbine Halaven Doxil, Lipodox Paraplatin UTD1 Enhertu Trodelvy

Eligibility Criteria

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Inclusion Criteria

1. Must be competent and able to comprehend, sign, and date a written informed consent form (ICF) before performance of any study-specific procedures or tests.
2. Men or women ≥18 years old.
3. Pathologically documented unresectable locally advanced or metastatic breast cancer that:

3.1 Confirmed as HER2-negative status, defined as IHC 0, IHC 1+, or IHC 2+/ISH- according to American Society of Clinical Oncology College of American Pathologists (ASCO/CAP) guidelines evaluated at a local laboratory.

3.2 Is HR-positive or HR-negative. Positive for estrogen receptor or progesterone receptor if a finding of ≥1% of tumor cell nuclei is immunoreactive according to ASCO/CAP guidelines.

3.3 Has been treated with at least 1 prior line of systemic therapy in the advanced or metastatic setting. If \>10% ER expression, the subject should have been treated with a CDK4/6 inhibitor. If recurrence occurred within 6 months of adjuvant chemotherapy, adjuvant therapy would count as 1 line of systemic therapy. If recurrence occurred within 12 months of adjuvant CDK4/6 inhibitor and endocrine therapy, adjuvant therapy would count as 1 line of systemic therapy.
4. Documented radiologic progression (during or after most recent treatment).
5. Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. All subjects must have a recent tumor sample after the most recent treatment regimen or agree to undergo a tissue biopsy prior to randomization.
8. No visceral crisis.
9. Life expectancy of ≥ 6 months as assessed by the treating investigator.
10. Complete all required baseline laboratory tests and imaging examinations within 28 days before randomization.
11. Normal organ and bone marrow function measured within 28 days prior to administration of study treatment.
12. Male and female subjects of reproductive/childbearing potential must have a documented negative pregnancy test within 2 weeks prior to randomization and agree to acceptable birth control (non-hormonal) during and up to 6 months after trial therapy.

Subjects must satisfy all of the following additional criteria to be included in the OGT group:

1. No absolute contraindication for invasive procedures to obtain samples for organoid generation.
2. Sufficient material for organoid generation: biopsied samples (length\>1cm, 2-3 pieces), surgically resected samples (\>1cm×1cm×0.5cm, weight\>200mg), malignant effusion samples collected by thoracentesis, abdominocentesis or lumbar puncture (pleural fluid\>50mL, ascites\>50mL, cerebrospinal fluid≥4 tubes with each tube ≥4mL).
3. Successful acquisition of a solid tumor biopsy sample containing ≥ 20% tumor content, or malignant effusion sample (e.g., pleural, or pericardial effusion or ascites) confirmed to contain malignant cells.

Exclusion Criteria

1. Ineligible for all 5 of the study treatments either because of previously having received treatment in the advanced or metastatic setting or having a contraindication to treatment.
2. Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious.
3. Known active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of CNS metastases or spinal cord compression are eligible if they are clinically and radiologically stable for at least 4 weeks before first dose of trial treatment and have not required high-dose steroid treatment in the last 4 weeks).
4. Inflammatory breast cancer.
5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
6. Major surgery within 3 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
7. Systemic treatment with anticancer therapy, antibody-based therapy, hormonal therapy, or radiotherapy within 3 weeks before study treatment.
8. Participation in a therapeutic clinical study within 3 weeks before study treatment, or current participation in other investigational procedures.
9. Has multiple primary malignancies within 3 years, except adequately resected nonmelanoma skin cancer, curatively treated in situ disease, or contralateral breast cancer.
10. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline.
11. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that would, in the opinion of the Investigator, increase the safety risk to the subject or interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
12. Has known human immunodeficiency virus infection or active hepatitis B or C infection.
13. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
14. Has gastrointestinal disorders likely to interfere with absorption of the study medication.
15. Is pregnant or breastfeeding or planning to become pregnant.
16. Any concurrent condition which in the Investigator's opinion makes it inappropriate for the patient to participate in the trial or which would jeopardize compliance with the protocol.
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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First Affiliated Hospital, Sun Yat-Sen University

OTHER

Sponsor Role collaborator

Sun Yat-sen University

OTHER

Sponsor Role collaborator

Shantou Central Hospital

OTHER

Sponsor Role collaborator

Guangdong Provincial People's Hospital

OTHER

Sponsor Role lead

Responsible Party

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Kun Wang

M.D.

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Guangdong Provincial People's Hospital

Guangzhou, Guangdong, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Kun Wang, M.D.

Role: CONTACT

00862083827812 ext. 50910

Hong-Fei Gao, M.D.

Role: CONTACT

Facility Contacts

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Kun Wang, M.D.

Role: primary

02083827812

Other Identifiers

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20231028

Identifier Type: -

Identifier Source: org_study_id

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