Biomarker Development for Response Prediction by DNA Mutational Analysis

NCT01855061 | Terminated DMC

• 1 other identifier: NL35198.041.11
• Study Type: observational
• Target: 79
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study is to determine whether it is possible to predict response to chemotherapy in patients with metastatic cancer who are treated with irinotecan by determining the mutational profile of the tumor.

Conditions

Neoplasm Metastasis

Keywords

Feasibility studies; Sequence analysis, DNA; Biological markers; Solid tumors; Neoplasm metastasis; Irinotecan; Pharmacokinetics SN-38; Carboxylesterase activity within metastasis

Outcome Measures

Primary Outcomes (1)

• Exploration of the correlation between the mutational profile and the percentage change in volumetric measurement of the index lesion after the first two cycles of chemotherapy.

  Change in radiological volume of the index lesion after the first 2 cycles of irinotecan. Radiological response (according to RECIST 1.1) after the first 2 cycles of irinotecan (i.e. after 2 x 3 weeks = 6 weeks)

Secondary Outcomes (9)

• Exploration of the correlation between the mutational profile and radiological response according to RECIST-criteria after the first two cycles of chemotherapy.

  Analysis 6 weeks after initiation of treatment

• Exploration of the correlation between the mutational profile and progression free survival and overall survival.

  Overall survival approximately after 2 years of first cycle of irinotecan. Progression free survival approximately 3 months after first irinotecan

• Exploration of the correlation between the mutational profile of the index lesion and patient's germline DNA background variation.

  Analysis after progressive disease, on average after 3 months.

• Differences in mutational profile of metastasis prior to and after exposure to treatment.

  Analysis after progressive disease and subsequent post-treatment biopsy, on average after 3 months of treatment

• Determine reliable and valid strategies for statistical analysis for biomarker discovery

  2 years

Study Arms (1)

Irinotecan

Patients will be subjected to a their metastatic solid tumor. Radiological response will be evaluated after each 2 cycles: 1. percentage change in radiological volume of the "index lesion" (radiological measurable lesion that underwent biopsy) after the first two cycles of irinotecan; 2. radiological response according to RECIST 1.1 after each 2 cycles. Patients are intended to receive irinotecan until progressive disease or unacceptable toxicity. Patients will be subjected to another biopsy of the index lesion at definitive discontinuation of irinotecan. Patients will also be subjected to blood draws for determining patient's genetic background variation. Side studies include: * pharmacogenetics * pharmacokinetics of SN-38 * carboxylesterase activity in the index lesion * midazolam clearance test (only in Rotterdam patients)

Procedure: Biopsy; Procedure: Blood samples; Procedure: Pharmacokinetics; Procedure: Midazolam clearance test

Interventions

Biopsy PROCEDURE

Histological biopsy of the "index lesion" (a radiological measurable lesion on which biopsy is performed) at baseline, as well as when showing progressive disease. Histological biopsies will be subjected to DNA sequencing to assess the mutational profile, as well as to analysis of carboxylesterase activity.

Also known as: Histological biopsy

Irinotecan

Blood samples PROCEDURE

Blood samples will be taken at baseline to determine patient's genetic background variation (germline DNA).

Also known as: Blood sampling

Irinotecan

Pharmacokinetics PROCEDURE

Blood samples will be taken for pharmacokinetic analysis of the active irinotecan metabolite (SN-38).

Also known as: PK, Pharmacokinetic analysis, Pharmacokinetic analyses

Irinotecan

Midazolam clearance test PROCEDURE

Patients who are being treated in Rotterdam will be subjected to blood draws for validation of the earlier developed midazolam phenotyping test (midazolam clearance test), which may be an indicator for pharmacokinetics of irinotecan.

Also known as: MCT

Irinotecan

Eligibility Criteria

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

Study Population

Patients with a metastatic solid tumor who are eligible for (standard of care) treatment with irinotecan.

You may qualify if:

• Patients with a metastatic solid tumor who have failed at least one line of palliative chemotherapy and are irinotecan naïve.
• Patients who are, as per local protocol, eligible for palliative treatment with (standard of care) irinotecan.
• Measurable metastatic lesion(s), according to RECIST 1.1 criteria.
• Radiological measurable metastatic lesion(s) of which a histological biopsy can safely be obtained:
• Patients with safely accessible metastases.
• Patients not known with bleeding disorders (such as hemophilia) or bleeding complications from biopsies, dental procedures or surgeries.
• Patients not using any anti-coagulant medication at the time of biopsy: all aspirin derivatives, NSAID's, coumarines, platelet function inhibitors, heparins (including LMWHs) and oral factor Xa inhibitors are not allowed, unless medication can either be safely stopped or counteracted.
• Adequate coagulation status on the day of biopsy as measured by:
• PTT \< 1.5 x ULN
• APTT \< 1.5 x ULN
• Platelet count 100 x 10\*9 / L or higher
• PT-INR \< 1.6
• HB \> 6
• Biopsies should be performed at least four weeks after last bevacizumab administration.
• Patients age 18 years or up, willing and able to comply with the protocol as judged by the investigator with a signed informed consent.

Sponsors & Collaborators

• P.O. Witteveen: lead
• Erasmus Medical Center: collaborator
• The Netherlands Cancer Institute: collaborator

Study Sites (3)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Erasmsus Medical Center - Daniël den Hoed clinic

Rotterdam, South Holland, 3075 EA, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Biospecimen

Retention: SAMPLES WITH DNA

Histological biopsies Blood samples

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Biopsy; Blood Specimen Collection; Pharmacokinetics

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Punctures; Metabolism; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Study Officials

• Marlies Langenberg, MD/PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Neeltje Steeghs, MD/PhD

  Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam

  PRINCIPAL INVESTIGATOR

• Ron Mathijssen, MD/PhD

  Erasmus Medical Center - Daniël den Hoed clinic, Rotterdam

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Investigator

Study Record Dates

• First Submitted: August 1, 2011
• First Posted: May 16, 2013
• Study Start: May 1, 2011
• Primary Completion: November 1, 2015
• Study Completion: August 1, 2016
• Last Updated: March 9, 2018

Record last verified: 2018-03

Locations

NL (3)