Prospective Clinical Validation of Next Generation Sequencing (NGS) and Patient-Derived Tumor Organoids (PDO) Guided Therapy in Patients With Advanced/ Inoperable Solid Tumors

NCT06077591 | Recruiting DMC

• 1 other identifier: Prince of Wales Hospital
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Precision oncology aims to improve clinical outcome of patients by offering personalized treatment through identifying druggable genomic aberrations within their tumors. This is particularly valid when it comes to offering alternative treatment options for patients with advanced tumors that are chemo-refractory. Patient-derived organoids (PDOs) are 3 dimensional tumoroids that can be expanded ex vivo and are both pheno- and genotypically identical to patients' tumors. Observational studies have shown that PDO-based drug screens can predict treatment response with high sensitivity and specificity. Vlachogiannis G. reported a living biobank of patient-derived organoids (PDOs) from patients with advanced GI cancers enrolled in clinical trials. PDOs can recapitulate patients' clinical response to chemotherapeutic agents. In 19 tumor organoids, the group performed molecular profiling and drug screens and then compared ex vivo organoid responses to anticancer drugs. Drug response to PDO based orthotopic mouse tumor xenografts correlated to the drug response of the patient in clinical trials. Further to the study, there were other retrospective validation studies utilizing PDOs from patients enrolled in clinical trials such as the TUMOROID, CinClare to predict clinical response. Ooft studied PDOs from patients with metastatic colorectal cancers enrolled in the TUMOROID study to predict response to irinotecan-based therapies. Yao generated a organoid biobank of 80 locally advanced rectal cancers. These patients were derived from a phase III study (CinClare) that compared neoadjuvant chemo-radiation using either capecitabine or CAPIRI. Response to chemoradiation in patients matched to that of rectal cancer organoids (sensitivity 78% and specificity 91.9%). In a systematic analysis of 17 studies (9 on advanced GI and pancreatic cancers, one on renal cell cancer and others on miscellaneous cancers), the pooled sensitivity and specificity for discriminating patients with a clinical response through PDO-based drug screen was 0.81 (95%CI 0.69-0.89) and 0.74 (95%CI 0.64-0.82) respectively. Within 4-6 weeks, PDO-based drug screen creates a true personalised platform by predicting patient-specific drug response with high accuracy. Recent technical advancements in growing these PDO 'avatars' from biopsies have made it possible to test suitable anticancer drugs in patients with advanced inoperable tumors, and explore the new possibilities for treatment options that otherwise would be missed by standard conventional therapies. In 2019, our group embarked on PDO research; investigators obtained tissues from patients with advanced/ inoperable solid tumors, and performing drug screens on these PDOs ex vivo. In several patients, investigators were able to identified drugs not otherwise used through sequencing data, and observed remarkable clinical response in patients with PDO responsive tumors. Investigators illustrate with cases that underwent PDO culture and drug screens. \[ See appendix \] In the literature, the clinical utility of treatment based on PDO informed drug options has however not been fully established. Investigators therefore propose a phase 2 proof-of-concept clinical trial to evaluate efficacy of NGS/ PDO guided treatment in patients with inoperable or metastatic solid tumors..

Conditions

Hepatocellular Carcinoma; Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• tumor response

  tumor response, partial or complete (\>30% reduction in tumor size)

  6 months

Secondary Outcomes (5)

• rate of partial or complete response

  6 months

• rate of progression free survival survival

  6 months

• rate of overall survival

  6 months

• success rate in PDO culture and drug screen

  6 months

• rate of grade III/IV toxicities.

  6 months

Study Arms (1)

Patient-Derived Tumor Organoids (PDO) Guided Therapy

EXPERIMENTAL

Intervention in this study is to perform tissue sampling to patient's tumor which are then subjected to DNA extraction for whole exome sequencing, organoid culture, and drug screen. An MDT board will review the drug screen results and excluded drug choice of poor response. Then the referring oncologist has the final discretion on the choice of chemo- or targeted agent as usual.

Other: Patient-Derived Tumor Organoids

Interventions

Patient-Derived Tumor Organoids OTHER

Intervention in this study is to perform tissue sampling to patient's tumor which are then subjected to DNA extraction for whole exome sequencing, organoid culture, and drug screen. An MDT board will review the drug screen results and excluded drug choice of poor response. Then the referring oncologist has the final discretion on the choice of chemo- or targeted agent as usual.

Patient-Derived Tumor Organoids (PDO) Guided Therapy

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• patients with metastatic, inoperable or advanced solid tumors who are refractory to at least one standard chemo- or targeted drugs.
• The disease is accessible for a biopsy (radiologic or endoscopic) or resection of a metastatic site.
• These patients are seen at a multidisciplinary tumor board meeting prior to referrals.
• aged \>18 years, able to provide written consents to trial participation,
• with an Eastern cooperative oncology group performance status of 0 or 1,
• with measurable disease in accordance with response evaluation criteria in solid tumors (RECIST) version 1.1.
• deem suitable for standard chemo-therapy; i.e. with a normal neutrophil count, hemoglobin \> 9g/dl, serum creatinine, \<1.5 x upper limit of normal, bilirubin \< 1.5 x normal, Aspartate and alanine aminotransferases (\<3 x ULN or \<5x
• those with liver metastasis) and with an ejection Fraction \>50% of normal on echocardiography.

You may not qualify if:

• unable to provide informed consent

Sponsors & Collaborators

• Chinese University of Hong Kong: lead

Study Sites (1)

Endoscopy Centre, Prince of Wales Hospital

Hong Kong, N.T., 123, Hong Kong

RECRUITING

Related Publications (12)

• . De Souza, N. Organoids. Nat. Methods 15, 23 (2018).

  BACKGROUND

• Li M, Izpisua Belmonte JC. Organoids - Preclinical Models of Human Disease. N Engl J Med. 2019 Feb 7;380(6):569-579. doi: 10.1056/NEJMra1806175. No abstract available.

  PMID: 30726695 BACKGROUND

• van der Velden DL, Hoes LR, van der Wijngaart H, van Berge Henegouwen JM, van Werkhoven E, Roepman P, Schilsky RL, de Leng WWJ, Huitema ADR, Nuijen B, Nederlof PM, van Herpen CML, de Groot DJA, Devriese LA, Hoeben A, de Jonge MJA, Chalabi M, Smit EF, de Langen AJ, Mehra N, Labots M, Kapiteijn E, Sleijfer S, Cuppen E, Verheul HMW, Gelderblom H, Voest EE. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature. 2019 Oct;574(7776):127-131. doi: 10.1038/s41586-019-1600-x. Epub 2019 Sep 30.

  PMID: 31570881 RESULT

• Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, Van Houdt WJ, Pronk A, Van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology. 2011 Nov;141(5):1762-72. doi: 10.1053/j.gastro.2011.07.050. Epub 2011 Sep 2.

  PMID: 21889923 RESULT

• van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, van Houdt W, van Gorp J, Taylor-Weiner A, Kester L, McLaren-Douglas A, Blokker J, Jaksani S, Bartfeld S, Volckman R, van Sluis P, Li VS, Seepo S, Sekhar Pedamallu C, Cibulskis K, Carter SL, McKenna A, Lawrence MS, Lichtenstein L, Stewart C, Koster J, Versteeg R, van Oudenaarden A, Saez-Rodriguez J, Vries RG, Getz G, Wessels L, Stratton MR, McDermott U, Meyerson M, Garnett MJ, Clevers H. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015 May 7;161(4):933-45. doi: 10.1016/j.cell.2015.03.053.

  PMID: 25957691 RESULT

• Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernandez-Mateos J, Khan K, Lampis A, Eason K, Huntingford I, Burke R, Rata M, Koh DM, Tunariu N, Collins D, Hulkki-Wilson S, Ragulan C, Spiteri I, Moorcraft SY, Chau I, Rao S, Watkins D, Fotiadis N, Bali M, Darvish-Damavandi M, Lote H, Eltahir Z, Smyth EC, Begum R, Clarke PA, Hahne JC, Dowsett M, de Bono J, Workman P, Sadanandam A, Fassan M, Sansom OJ, Eccles S, Starling N, Braconi C, Sottoriva A, Robinson SP, Cunningham D, Valeri N. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018 Feb 23;359(6378):920-926. doi: 10.1126/science.aao2774.

  PMID: 29472484 RESULT

• Ooft SN, Weeber F, Dijkstra KK, McLean CM, Kaing S, van Werkhoven E, Schipper L, Hoes L, Vis DJ, van de Haar J, Prevoo W, Snaebjornsson P, van der Velden D, Klein M, Chalabi M, Boot H, van Leerdam M, Bloemendal HJ, Beerepoot LV, Wessels L, Cuppen E, Clevers H, Voest EE. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci Transl Med. 2019 Oct 9;11(513):eaay2574. doi: 10.1126/scitranslmed.aay2574.

  PMID: 31597751 RESULT

• Yao Y, Xu X, Yang L, Zhu J, Wan J, Shen L, Xia F, Fu G, Deng Y, Pan M, Guo Q, Gao X, Li Y, Rao X, Zhou Y, Liang L, Wang Y, Zhang J, Zhang H, Li G, Zhang L, Peng J, Cai S, Hu C, Gao J, Clevers H, Zhang Z, Hua G. Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer. Cell Stem Cell. 2020 Jan 2;26(1):17-26.e6. doi: 10.1016/j.stem.2019.10.010. Epub 2019 Nov 21.

  PMID: 31761724 RESULT

• Wensink GE, Elias SG, Mullenders J, Koopman M, Boj SF, Kranenburg OW, Roodhart JML. Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. NPJ Precis Oncol. 2021 Apr 12;5(1):30. doi: 10.1038/s41698-021-00168-1.

  PMID: 33846504 RESULT

• Loong HH, Wong AM, Chan DT, Cheung MS, Chow C, Ding X, Chan AK, Johnston PA, Lau JY, Poon WS, Wong N. Patient-derived tumor organoid predicts drugs response in glioblastoma: A step forward in personalized cancer therapy? J Clin Neurosci. 2020 Aug;78:400-402. doi: 10.1016/j.jocn.2020.04.107. Epub 2020 Apr 24.

  PMID: 32340843 RESULT

• Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat Protoc. 2020 Oct;15(10):3380-3409. doi: 10.1038/s41596-020-0379-4. Epub 2020 Sep 14.

  PMID: 32929210 RESULT

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.

  PMID: 2702835 RESULT

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• James Lau

  Prince of Wales Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

James Lau, MD

CONTACT

35051445; laujyw@surgery.cuhk.edu.hk

Bing Yee SUEN, BHSc

CONTACT

35052640; suenbingyee@cuhk.edu.hk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Intervention in this study is to perform tissue sampling to patient's tumor which are then subjected to DNA extraction for whole exome sequencing, organoid culture, and drug screen. This takes between 2- 4 weeks. In the interim period, the patient is allowed to receive a chemotherapy agent, a target agent or hormone therapy between the time of the biopsy and the availability of drug screen results. An MDT board will review the drug screen results and excluded drug choice of poor response. Then the referring oncologist has the final discretion on the choice of chemo- or targeted agent as usual.

Study Record Dates

• First Submitted: October 5, 2023
• First Posted: October 11, 2023
• Study Start: October 18, 2024
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2028
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)