Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Urinary Bladder Neoplasms

Non-Muscle Invasive Bladder Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Anti-Infective Agents

Gemcitabine

Docetaxel

Epirubicin

Mitomycins

Mitomycin

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Alkylating Agents

Patients in that PDOs show highest response to this drug in-vitro will be treated with Epirubicin.

Patients in that PDOs show highest response to this drug in-vitro will be treated with Mitomycin.

Patients in that PDOs show highest response to this drug in-vitro will be treated with Gemcitabine.

Patients in that PDOs show highest response to this drug in-vitro will be treated with Docetaxel.

In PDOs from patients that show highest response to Epirubicin, this drug will be instilled intravesically once weekly for 6 times.

Epirubicin will be used as a concentrate for injection/instillation 2 mg/ml in total 50mg per vial. Prior to use, the concentrate for injection is diluted with 25ml of 0.9% saline solution to obtain the final Solution with 1mg/ml of Epirubicin.

In PDOs from patients that show highest response to Mitomycin, this drug will be instilled intravesically once weekly for 6 times.

Mitomycin C will be used as 20mg dry powder. Prior to use, the powder will be dissolved in 50ml of 0.9% saline solution according to the manufacturer instructions

In PDOs from patients that show highest response to Gemcitabine, this drug will be instilled intravesically once weekly for 6 times.

Gemcitabine will be used as 2000 mg/50ml. For intravesical application, 1000mg of gemcitabine (corresponding to 25ml) will be diluted in 25ml 0.9% saline solution, to obtain the gemcitabine concentration of 1000mg/50ml used for instillation.

In PDOs from patients that show highest response to Docetaxel, this drug will be instilled intravesically once weekly for 6 times.

Docetaxel will be used as 140mg/7ml solution. For intravesical application, 48.825ml of saline will be added to 1.875ml Docetaxel solution (according 37.5mg of Docetaxel). The concentration of this solution is 0.74mg/ml by a total volume of the instillation solution of 50,7.

Roland Seiler, Prof.

Based on the unmet clinical need to reduce invasiveness of treatment of low grade NMIBC, the investigators conduct this prospective, open label, single arm and single center phase II trial. The investigators aim to use drug screens in PDOs to guide neoadjuvant intravesical instillation therapy with either Epirubicin, Mitomycin C, Gemcitabine or Docetaxel to achieve chemoresection NMIBC.

Bladder cancer is a disease of the elderly patient and related to several interventions and operations. Patients with a low risk non-muscle invasive bladder cancer (NMIBC) are treated by transurethral resection of the bladder tumor (TURBT). Due to the high recurrence rate of approximately 50% within 2 years of diagnosis, patients are followed in outpatient clinic by cystoscopy for at least 5 years.

Beside recurrence of low grade NMIBC to low grade disease, progression to higher grade or stage is infrequent to rare. Therefore, expectant management and actives surveillance seems to be an option for selected patients that are unfit for surgery. Moreover, intravesical chemoresection has been attempted in order to avoid surgery. However, all patients were treated with the same chemotherapeutic agent and anticipated response rates were missed.

At least four different drugs have been used in daily routine and/or clinical trials for instillation therapies in NMIBC. Namely, Epirubicin, Mitomycin C, Gemcitabine and Docetaxel have been investigated and administered.

The molecular landscape of NMIBC is heterogeneous. Not only the mutational pattern but also the transcriptomic characteristics vary between different NMIBC. Although different agents are used on a routine daily bases and in clinical trials, they have not been administered based on the molecular landscape or biological likelihood of response.

The investigators recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In brief: The bladder cancer is sampled during TURBT. Generation of organoids has been carefully optimized in order to yield high viability from each sample. Beside confirmation of similarities of the molecular landscape between parental NMIBC and subsequent PDO (in approx. 30 samples), the investigators established a standardized protocol to perform drug screens on these PDOs.

In this trial (POLO Trial) the investigators aim to generate PDOs from bladder cancer biopsies that are harvested in the outpatient clinic. Subsequent drug screen in PDOs for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel will identify the most effective agent in this given patient. Prior TURBT, patient will receive 6 intravesical instillations with the identified agent as neoadjuvant treatment in order to perform chemoresection of the tumor. Three months after initial diagnosis, TURBT will be performed as the standard treatment and to confirm response rate of precise chemoresection.

Phase II, all 28 patients will follow the same treatment. Only, selection of the use drug is performed using drug screens in patient derived organoids and is specific for each patient

Precise Neoadjuvant Chemoresection of Low Grade NMIBC

Precise Neoadjuvant Chemoresection of Low Grade NMIBC Guided by Drug Screens in Patient Derived Organoidst: A Single Center, Open-label, Phase II Trial

After completion of the trial for the primary endpoint, deidentified data will be shared to other researches upon request.

Rate of patients that show complete pathological response to neoadjuvant chemoresection

Recurrence after neoadjuvant chemoresection and transurethral resection of the bladder tumor

Composite endpoint determined by standardized questionnaires (EORTC QLQ-C30, QLQ-NMIBC24 and IPSS)

Rate of patients in which drug screen in patient derived organoids was successful

Spitalzentrum Biel

University of Bern

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Estrogens

Progesterone

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

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.

QPOP

Soo Chin Lee

Soo Chin Lee, MBBS, MRCP

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.

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".

This is a single-centre study based on the Simon 2-stage optimal design: 9 patients will be enrolled initially. The study will be expanded to a further 14 patients (Stage II) if 2 or more patients enrolled in stage I of the study achieve an objective response (of \>35% ) with the chemotherapeutic agent selected by the drug screen assay. Accounting for 10% attrition rate, a total of 26 evaluable patients will be included in both stages of study.

QPOP-based drug screen assay will be used as a clinical decision platform to identify patient-specific drug combinations across a range of breast cancer patients.

Breast cancer study - 99.9% breast cancer patients are female. Male breast cancer is extremely rare and we do not intend to include this rare population

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Precise Neoadjuvant Chemoresection of Low Grade NMIBC	NCT06227065	Bladder Cancer Non-muscle Inva... Low-risk	Epirubicin Mitomycin Gemcitabine Docetaxel	18 Years -	University of Bern
Quadratic Phenotypic Optimisation Platform (QPOP) Utilisation to Enhance Selection of Patient Therapy Through Patient Derived Organoids in Breast Cancer	NCT05177432	Breast Cancer	QPOP	21 Years - 99 Years	National University Hospital, Singapore

Spots Global Cancer Trial Database for patient derived organoids