Biomarker Development for Response Prediction by DNA Mutational Analysis

Terminated

• Conditions: Neoplasm Metastasis
• Interventions: Procedure: Biopsy; Procedure: Blood samples; Procedure: Pharmacokinetics; Procedure: Midazolam clearance test

• Registration Number: NCT01855061
• Lead Sponsor: P.O. Witteveen

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2011-05
• Study First Submitted: 2011-08-01
• Study First Submitted QC: 2013-05-13
• Study First Posted: 2013-05-16
• Primary Completion: 2015-11
• Study Completion: 2016-08
• Status Verified: 2018-03
• Last Update Submitted: 2018-03-07
• Last Update Posted: 2018-03-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 79

Inclusion Criteria

1. Patients with a metastatic solid tumor who have failed at least one line of palliative chemotherapy and are irinotecan naïve.

2. Patients who are, as per local protocol, eligible for palliative treatment with (standard of care) irinotecan.

3. Measurable metastatic lesion(s), according to RECIST 1.1 criteria.

4. Radiological measurable metastatic lesion(s) of which a histological biopsy can safely be obtained:

   1. Patients with safely accessible metastases.

   2. Patients not known with bleeding disorders (such as hemophilia) or bleeding complications from biopsies, dental procedures or surgeries.

   3. 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.

   4. 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

   5. Biopsies should be performed at least four weeks after last bevacizumab administration.

5. Patients age 18 years or up, willing and able to comply with the protocol as judged by the investigator with a signed informed consent.

Exclusion Criteria

Patients not meeting all of the above inclusion criteria.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Irinotecan	Biopsy	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)
Irinotecan	Pharmacokinetics	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)
Irinotecan	Midazolam clearance test	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)
Irinotecan	Blood samples	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)

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
Correlate response to pharmacokinetics of SN-38	After progressive disease and subsequent post-treatment biopsy, in general after 3 months of treatment
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
Determine carboxylesterase activity in metastatic tumor material (pre- and posttreatment) and correlate intra-tumoral carboxylesterase activity to systemic SN-38 pharmacokinetics and to irinotecan response	After progressive disease and subsequent post-treatment biopsy, in general after 3 months of treatment
Determine clinical applicability of the midazolam phenotyping probe	After first cycle of irinotecan, at three weeks
Number and nature of all (serious) adverse events of study related procedures	14 days after baseline biopsy and 14 days after post-treatment biopsy (approximately after 3 months of treatment)

Trial Locations

Locations (3)

Erasmsus Medical Center - Daniël den Hoed clinic; 🇳🇱 Rotterdam, South Holland, Netherlands

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital; 🇳🇱 Amsterdam, North Holland, Netherlands

University Medical Center Utrecht; 🇳🇱 Utrecht, Netherlands