Prospective Translational Study Investigating Molecular Predictors of Resistance and Response to Regorafenib Monotherapy

NCT ID: NCT03010722

Last Updated: 2021-05-03

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 49 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2017-07-31

Brief Summary

This is a single centre prospective biological translational research study involving the collection of tumour tissue, blood samples and clinical data from patients being treated with regorafenib for metastatic Colorectal Cancer (mCRC) at the Royal Marsden Hospital. Patients will be eligible for the study if they have a histological diagnosis of CRC, are refractory to standard available therapies with palliative intent for mCRC, have received prior treatment with at least one anti-VEGF antibody and chemotherapy drugs including fluorouracil (5FU) or capecitabine, oxaliplatin and irinotecan, and patients have RAS mutant tumours.

Detailed Description

This is an exploratory translational research study to obtain research biopsies of RAS mutant metastatic colorectal cancer (mCRC) tumour tissue prior to commencement of regorafenib multi-tyrosine kinase inhibitor (MKI) treatment targeting vascular endothelial growth factor receptor (VEGFR), tumour microenvironment and oncogenic driver alterations, and again at development of resistance. Candidate markers of resistance will be identified in tissue biopsies through genetic and other molecular analysis and parallel collection of serial blood specimens will facilitate the identification of resistance markers and the tracking of resistance evolution in circulating nucleic acids. Early dynamic contrast enhanced MRI (DCE-MRI) along with diffusion weighted (DW)-MRI imaging at the beginning, and on day 15+/-7 post treatment will be performed. Additionally, dual contrast enhanced CT (DECT) will be performed according to routine clinical evaluation time points before drug administration and at 8 weeks after drug administration. Disease will be monitored with serial CT scans of the chest abdomen and pelvis (CT-CAP) every eight weeks, until progression. The aim of the study is to identify novel predictive biomarkers of resistance and response to this targeted therapy in mCRC previously treated with oxaliplatin, fluoropyrimidines and irinotecan, using genetic, epigenetic, transcriptomics, proteomic and live tissue culture methods. These molecular analyses will be performed on metastatic tumour tissue samples taken firstly before commencement of regorafenib, and secondly on progression of disease, and thirdly from archival primary or metastatic tumour tissue. There is an additional biopsy at 8 weeks in patients with response or stable disease, as determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria.

Conditions

Metastatic Colorectal Cancer

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Regorafenib

160 mg orally (po) od for 3 weeks of every 4-week cycle

All patients will be required to have pre-treatment dynamic contrast enhance computed tomography (DECT) scan pre-treatment and at 8 weeks. Suitable patients will also be required to have dynamic contrast enhanced magnetic resonance imaging (DEC-MRI) and diffusion weighted (DW)-MRI, pre-treatment and at 2 weeks. All patients will also be required to have an Ultrasound (USS) or CT-guided biopsy of suitable metastatic lesion.

Regorafenib

Intervention Type: DRUG

Patients meeting all of the inclusion criteria and none of the exclusion criteria will receive regorafenib 160 mg orally (po) od for 3 weeks of every 4-week cycle. Each cycle will comprise 3 weeks of treatment followed by 1 week without treatment, hereafter described as "3 weeks on/1 week off". Each 160-mg dose will include four regorafenib 40-mg tablets.

Interventions

Regorafenib

Patients meeting all of the inclusion criteria and none of the exclusion criteria will receive regorafenib 160 mg orally (po) od for 3 weeks of every 4-week cycle. Each cycle will comprise 3 weeks of treatment followed by 1 week without treatment, hereafter described as "3 weeks on/1 week off". Each 160-mg dose will include four regorafenib 40-mg tablets.

Intervention Type: DRUG

Other Intervention Names

Stivarga

Eligibility Criteria

Inclusion Criteria

1. Patients with RAS mutant (MT) metastatic colorectal cancer (mCRC) who have been at least once treated with available therapies including fluoropyrimidine-based chemotherapy, oxaliplatin, irinotecan and an anti-angiogenic agent, except for patients who have not been treated with oxaliplatin due to previous documented peripheral neuropathy in an adjuvant setting or in those patients where disease has progressed within a short time from receiving adjuvant treatment (<12 months).

2. Eligible to receive regorafenib within the context of PROSPECT-R trial at the Royal Marsden Hospital

Exclusion Criteria

A patient must NOT

1. have had prior treatment with regorafenib or any other VEGF-targeting kinase inhibitor

2. have had previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Noninvasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].

3. Patients that are participating in another clinical trial involving an investigational medicinal product, unless it is more than 14 days after they have ceased the investigational medicinal product

4. Patients that are participating in another research study involving tumour tissue biopsies planned to take place during the time that the patient is participating in this study

5. Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment

6. If female and of childbearing potential, be engaged in breast feeding

7. Be unable to swallow oral tablets (crushing of study treatment tablets is not allowed)

8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 month before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)

9. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.

10. Ongoing infection > Grade 2 NCI Common Toxicity Criterial for Adverse Effects (CTCAE).

11. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management

12. Have congestive heart failure classified as New York Heart Association Class 2 or higher

13. Have had unstable angina (angina symptoms at rest) or new-onset angina < 3 months prior to screening

14. Have had a myocardial infarction < 6 months prior to initiation of study treatment

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

The Royal Marsden NHS Foundation Trust London and Surrey

Carshalton, Surrey, United Kingdom

Countries

United Kingdom

References

Rata M, Khan K, Collins DJ, Koh DM, Tunariu N, Bali MA, d'Arcy J, Winfield JM, Picchia S, Valeri N, Chau I, Cunningham D, Fassan M, Leach MO, Orton MR. DCE-MRI is more sensitive than IVIM-DWI for assessing anti-angiogenic treatment-induced changes in colorectal liver metastases. Cancer Imaging. 2021 Dec 19;21(1):67. doi: 10.1186/s40644-021-00436-0.

Reference Type: DERIVED

PMID: 34924031 (View on PubMed)

Other Identifiers

4164

Identifier Type: -

Identifier Source: org_study_id