Patient-derived Organoids Drug Screen in Metastatic Pancreatic Cancer
Study Details
Study Description
Brief Summary
In metastatic pancreatic cancer, few chemotherapeutic options exist. Moreover, there is a lack objective criteria for deciding which regimen is more beneficial for each specific patient.
This study investigates whether organoid generation from tumour samples of metastatic pancreatic cancer is a safe and feasible process for testing of multiple chemotherapy regimens in the laboratory.
By participating to this study, patients will undergo a laparoscopic surgical biopsy of part of the tumour tissue; the tissue retrieved will be sent to the laboratory for organoid generation and drug testing. At this stage of the study, the treatment that the patient will receive after surgery will not be affected by the results of the laboratory testing. In fact, all patients will receive the standard of care treatment based on the most recent oncologic guidelines and on the oncologist's clinical judgement. As part of the study, each patient will be followed for 90 days to assess possible surgical complications related to the surgical biopsy.
There are minimal risks in participating to this study, and they are solely related to the surgical laparoscopic biopsy. These include general surgical risk factors, which are common to every surgical procedure involving the abdomen (e.g. surgical site infection, bleeding, thrombosis, embolism, intraabdominal adhesions formation and incisional hernia) and procedure-specific surgical risk factors (e.g. damage to vessels, internal hollow or parenchymatous organs, bleeding at the site of surgical biopsy, abscess formation, bile leak).
This study will help to speed up the implementation of organoid generation in the clinical routine for the choice of the best treatment of patients affected by metastatic pancreatic cancer. Only in case of failure of the standard chemotherapeutic regimens, data from tissue samples can be exploited by the oncologist to propose alternative, nonstandard therapeutic options.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Organoid generation All patients will included in a single-arm. Participants will undergo biopsy of tumor tissue for subsequent organoid generation. |
Procedure: Laparoscopic surgical biopsy and organoid generation
All patients included in the study will undergo port-a-cath positioning and simultaneous explorative laparoscopy with tumoral excision biopsy. Intraoperative frozen section will confirm the presence of malignant cells in the retrieved sample. Part of the collected specimen will be sent for microbiological analysis at the Microbiology Laboratory and assessment of contamination by bacterial and/or fungal flora. The remaining part of tumour samples will be sent for patient-derived organoid (PDO) formation. Patients will also have two blood sample retrieved in ethylenediaminetetraacetic acid (EDTA) tubes that will be sent with the surgical specimen. All patients will then receive the standard of care (SOC) treatment according to the clinical judgement of the oncologist in charge, always within the framework of the international guidelines.
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Outcome Measures
Primary Outcome Measures
- Feasibility of the process [30 days after the last patient enrollment.]
To determine the proportion of patients (specifically, the percentage with respect to the total sample enrolled in the study) for which organoids can be successfully generated and in which an effective treatment can be identified by drug screens in these patient-derived organoids. Effective treatment is considered a treatment decreasing of 50% (or more) the viability of patient-derived organoids.
Secondary Outcome Measures
- Safety of surgical biopsy and post-operative surgical complications. [90 days post-operatively]
To evaluate safety of laparoscopic surgical biopsy for patient-derived organoids generation in patients with metastatic pancreatic cancer. Safety will be evaluated in terms of absolute and relative (%) number of postoperative complications. Severity will be graded according the Clavien-Dindo classification for surgical complications: complications equal to or greater than grade 3B will be considered as "severe". Management of each complication will be recorded for descriptive purposes.
- Concordance rate [60 days after the last patient enrollment.]
To evaluate the rate of concordance between patient-derived organoid-guided therapy and therapeutic regimens chosen based on guidelines and oncological clinical judgement.
- Serum and tissue tumoral biomarkers [60 days after the last patient enrollment.]
To assess whether increased levels of tumoral biomarkers in fresh tumour tissue and/or blood are predictive of response to specific therapies in patient-derived organoids. These can include known molecules (e.g. Carcinoembryonic antigen [CEA], Cancer antigen 19-9 [CA 19.9], CA 125) or further cellular markers potentially associated with treatment response. Association and its strength between markers and response will be assessed by means of appropriate statistic tests, according to the type and number of parameters taken into consideration (e.g. Chi-square test of association, logistic regression analysis...)
- Contamination rates [30 days after the last patient enrollment.]
To assess the rate of contaminated samples by endogenous bacterial and fungal flora and to highlight possible implications in patient-derived organoid testing response.
Eligibility Criteria
Criteria
Inclusion criteria:
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Written informed consent provided
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Patients older than 18 years
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Histologically- or cytologically-proven pancreatic ductal adenocarcinoma (PDAC)
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Patients with treatment naïve metastatic PDAC (stage IV) or at least 3 months after having received the last cycle of adjuvant chemotherapy
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Tumour lesion amenable for laparoscopic, surgical biopsy
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Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0-2
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Willingness to comply with scheduled visits
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Pancreatic cancer organoids were cultured successfully
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Radiologically measurable disease
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Life expectancy > 3 months
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Absolute neutrophile count >1500/microL, platelets >100'000/microL
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Serum creatinine <1.5 times of the upper limit of normal or Clearance >50ml/min (according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula)
Exclusion criteria:
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Concomitant need for full anticoagulation that cannot be interrupted or bridged prior to tissue biopsy
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ECOG PS >2
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Heart failure (NYHA class III-IV)
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Severe or uncontrolled concurrent illness
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Myocardial infarction within the previous 6 months
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Patients who are pregnant or breastfeeding
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Prof. Dr. med. Dres. h.c. Jan Schmidt, MME
Investigators
- Study Chair: Daniel Helbling, Dr. Med., Onkozentrum Zürich
- Study Chair: Marianna Kruithof-De Julio, Prof. Dr. phil., University of Bern
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Aung KL, Fischer SE, Denroche RE, Jang GH, Dodd A, Creighton S, Southwood B, Liang SB, Chadwick D, Zhang A, O'Kane GM, Albaba H, Moura S, Grant RC, Miller JK, Mbabaali F, Pasternack D, Lungu IM, Bartlett JMS, Ghai S, Lemire M, Holter S, Connor AA, Moffitt RA, Yeh JJ, Timms L, Krzyzanowski PM, Dhani N, Hedley D, Notta F, Wilson JM, Moore MJ, Gallinger S, Knox JJ. Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. Clin Cancer Res. 2018 Mar 15;24(6):1344-1354. doi: 10.1158/1078-0432.CCR-17-2994. Epub 2017 Dec 29.
- Clevers H. Modeling Development and Disease with Organoids. Cell. 2016 Jun 16;165(7):1586-1597. doi: 10.1016/j.cell.2016.05.082. Review.
- Dancey JE, Dodd LE, Ford R, Kaplan R, Mooney M, Rubinstein L, Schwartz LH, Shankar L, Therasse P. Recommendations for the assessment of progression in randomised cancer treatment trials. Eur J Cancer. 2009 Jan;45(2):281-9. doi: 10.1016/j.ejca.2008.10.042.
- Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13.
- Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2.
- Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist. 2008;13 Suppl 2:19-21. doi: 10.1634/theoncologist.13-S2-19. Review.
- Tiriac H, Belleau P, Engle DD, Plenker D, Deschênes A, Somerville TDD, Froeling FEM, Burkhart RA, Denroche RE, Jang GH, Miyabayashi K, Young CM, Patel H, Ma M, LaComb JF, Palmaira RLD, Javed AA, Huynh JC, Johnson M, Arora K, Robine N, Shah M, Sanghvi R, Goetz AB, Lowder CY, Martello L, Driehuis E, LeComte N, Askan G, Iacobuzio-Donahue CA, Clevers H, Wood LD, Hruban RH, Thompson E, Aguirre AJ, Wolpin BM, Sasson A, Kim J, Wu M, Bucobo JC, Allen P, Sejpal DV, Nealon W, Sullivan JD, Winter JM, Gimotty PA, Grem JL, DiMaio DJ, Buscaglia JM, Grandgenett PM, Brody JR, Hollingsworth MA, O'Kane GM, Notta F, Kim E, Crawford JM, Devoe C, Ocean A, Wolfgang CL, Yu KH, Li E, Vakoc CR, Hubert B, Fischer SE, Wilson JM, Moffitt R, Knox J, Krasnitz A, Gallinger S, Tuveson DA. Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov. 2018 Sep;8(9):1112-1129. doi: 10.1158/2159-8290.CD-18-0349. Epub 2018 May 31.
- Tiriac H, Bucobo JC, Tzimas D, Grewel S, Lacomb JF, Rowehl LM, Nagula S, Wu M, Kim J, Sasson A, Vignesh S, Martello L, Munoz-Sagastibelza M, Somma J, Tuveson DA, Li E, Buscaglia JM. Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy sampling for personalized cancer treatment. Gastrointest Endosc. 2018 Jun;87(6):1474-1480. doi: 10.1016/j.gie.2017.12.032. Epub 2018 Jan 9.
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