Colorectal CancerNCT02175095

[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib

A study testing Regorafenib, [18F]FLT-PET and [18F]FDG-PET in people with Colorectal Cancer, run by Asan Medical Center at 1 site in South Korea.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 20 years and older
Conditions the study is for: Colorectal Cancer
What is being tested?: Regorafenib, [18F]FLT-PET and [18F]FDG-PET
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 68 participants
Where: 1 siteSouth Korea
Study dates: 18 Jul 2014to 30 Apr 2019
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 20 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
Progressed after 3 active cytotoxic chemotherapy including fluoropyrimidines, oxaliplatin and irinotecan during or within 6 months of their administrations with or without targeted agents (bevacizumab or cetuximab).
Extrahepatic measurable lesion(s) by RECIST 1.1.
Unresectable metastatic disease.
Age over 20 years old.
Have a life expectancy of at least 3 months.

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ECOG performance status of 1 or lower.
Adequate organ functions.
Be willing and able to comply with the protocol for the duration of the study.
Give written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw the study at any time, without prejudice.
Women of childbearing potential and men must agree to use adequate contraception since signing of the IC form until at least 8 weeks after the last study drug administration.

Who cannot join

Prior treatment of regorafenib.
Liver-limited metastasis.
Inability to perform [18F]FLT and [18F]FDG-PET imaging studies due to physical inability or claustrophobia.
Concurrent or previous history of another primary cancer within 3 years prior to randomisation except for curatively treated cervical cancer in situ, non-melanomatous skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without distant metastasis could be allowed with the agreement of the chief principal investigator.
Uncontrolled CNS metastases.
Prior radiation therapy would be permitted, but non-radiated evaluable lesions should be present at study entry.

Show all 23Show fewer

Uncontrolled hypertension (>150/90 mmHg) despite of optimal management; anti-hypertensive drugs for BP lowering before study entry would be permitted.
Congestive heart failure ≥ New York Heart Association (NYHA) class 2.
Unstable angina, new-onset angina within 3 months, or history of myocardial infarction within 6 months before the study entry.
Arterial or venous thromboembolism within 6 months.
Serious concurrent infections or non-malignant illness.
Liver cirrhosis ≥ Child-Pugh class B.
Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
Peripheral neuropathy of grade ≥ 2.
Major surgery or significant traumatic injury within 28 days prior to study treatment.
Non-healing wound, ulcer, or bone fracture.
Current evidence of significant gastrointestinal bleeding or (impending) obstruction.
Any hemorrhage or bleeding event of grade ≥ 3 within 4 weeks prior to the start of study medication.
Proteinuria ≥ 3+ in the routine urinalysis; in this case, the total protein in the 24-hour urine collection should be measured, and the accrual is permitted if total protein < 3.5 g/day.
Pregnant of breast-feeding subjects. Women of child-bearing potential must have pregnancy test within 7 days and a negative result must be documented before start of study treatment.
Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
Use of strong CYP3A4 inducers or inhibitors which are known to decrease the metabolism of regorafenib (ketoconazole, rifampin, phenytoin, carbamazepine, phenobarbital).
Known hypersensitivity to the study drug or any of its excipients.

Trial locations and contacts

1 site in 1 country.

South Korea1 site

Asan Medical Center
Seoul, Songpa, 138736

Other trials in South Korea

About this study

Official title: 3'-Deoxy-3'-18F-fluorothymidine Positron Emission Tomography ([18F] FLT-PET) for the Prediction of Response to Regorafenib in the Metastatic Colorectal Cancer Patients Who Progressed After All Standard Therapies

Regorafenib is approved in the treatment for metastatic colorectal cancer patients who have been progressed after standard therapies, however, there has not been a predictive biomarker. The investigators designed this study to investigate whether [18F]FLT-PET might paly a role as a predictive imaging biomarker of treatment responses to regorafenib.

Read the detailed description

Recent advances have been made in the treatments for the patients with metastatic colorectal cancer (mCRC) owing to the introductions of targeted agents, which included bevacizumab, cetuximab, panitumumab, and aflibercept. And in addition, regorafenib, a newer tyrosine kinase inhibitor (TKI), has been approved in the treatment for the mCRC patients.

Regorafenib (BAY 73-4506) is an orally available multikinase inhibitor with activity against multiple targets, including tumor angiogenesis (VEGFR-1, -2, -3 and TIE-2), oncogenesis (KIT, RET, RAF-1, BRAF, and BRAFV600E), and tumor microenvironment (PDGF and FGFR). Regorafenib has shown antitumor activities in multiple solid tumors, and demonstrated significant efficacy outcomes in patients with advanced gastrointestinal stromal tumors and colorectal cancers.

The CORRECT study, which compared regorafenib vs placebo in mCRC patients who have been treated with all standard treatment, showed survival improvements with statistical significances; median OS 6.4 vs 5.0 months, HR 0.77, p=0.0052; median PFS 1.9 vs 1.7 months, HR 0.49, p<0.000001. Above these results, regorafenib monotherapy has been recently approved for the treatment of mCRC patients who have been refractory to all of standard therapies.

However, there are still only a few biomarkers which have been established as predictive of treatment responses in the fields of treatments for mCRC patients; KRAS or BRAF mutations for the lack of responses to anti-EGFR agents, cetuximab or panitumumab. There still has not been any biomarker which would be predictive of treatment responses to bevacizumab, aflibercept or regorafenib. The difficulties in search for biomarkers for these agents might come from the facts as following; either bevacizumab or aflibercept does not act directly against tumor itself and should be combined with cytotoxic agents to show efficacy; regorafenib is a multikinase inhibitor which has too many potential targets.

Above these reasons, imaging modalities can be fascinating and alternative candidates for predictive biomarkers of treatment responses. Conventional anatomic imaging studies such as computed tomography (CT) scans can hardly predict the treatment responses earlier, and the RECIST using CT scans, which is widely used for measurement of treatment responses, might have several limitations for measurement of efficacy from targeted agents such as cystic necrosis without tumor shrinkage. In the CORRECT study, overall response rate by RECIST was only 1%, although the rates for disease stabilization was up to 40%, which might be a good example for the limitations of the RECIST using conventional anatomical imaging studies for the response evaluation of regorafenib.

Among imaging studies, PET scans are useful tools for the noninvasive measurement of functional changes after treatment with targeted agents, and [18F]FLT-PET is potentially useful tool for earlier prediction of treatment responses because it can detect earlier changes of cellular proliferation using [18F]FLT (fluorothymidine), a radiotraceable substitute for thymidine which is essential for DNA synthesis. Several studies have been reported that [18F]FLT-PET may allow an early assessment of the response to chemotherapy including targeted agents. There also has been a report that [18F]FLT-PET could predict treatment responses of BRAF inhibitors in the colorectal cancer xenograft model; regorafenib also has an inhibitory effect on BRAF.

Therefore, the investigators have planned this study with hypothesis that [18F]FLT-PET could be useful for identifying a subgroup of mCRC patients with clinical responsiveness to regorafenib.

Conditions: Colorectal Cancer
Being tested: Regorafenib, [18F]FLT-PET, [18F]FDG-PET
Keywords: regorafenib, fluorothymidine, positron emission tomography, metastatic colorectal cancer
Medical subject headings: Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RegorafenibDrug
Also called Stivarga
Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal.
[18F]FLT-PETDiagnostic test
[18F]FLT-PET scans before and on 21st day from the administration of regorafenib.
[18F]FDG-PETDiagnostic test
[18F]FDG-PET will be performed before treatment and at 21 days after treatment.

Study groups in NCT02175095
Study group	Role	What they receive
Regorafenib and FLT-PET	Experimental	After checking the eligibility for the study entry, patients will be scheduled to perform [18F]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional [18F]FDG-PET will be performed before treatment and at 8 weeks (just once at the point of first response evaluation). Receives: Drug: Regorafenib; Diagnostic Test: [18F]FLT-PET; Diagnostic Test: [18F]FDG-PET

What is being measured

The primary outcome is the main question the study is designed to answer.

Assessment of Early Response by 18F-Fluorodeoxyglucose(18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks
Response assessment using 18F-FDG PET/CT was based on the PERCIST 1.0. The peak SUV value corrected for lean body mass (SULpeak) was measured from the single hottest tumour at each time point. For a tumour to be measurable at baseline, the SULpeak in the target lesion was greater than or equal to 1.5 times the mean SUL in the 3-cm-diameter spherical volume of interest plus two times its standard deviation of the liver. The percentage of change in SULpeak in the measurable target lesion was computed as follows: 100×(SULpeak day 21-SULpeak baseline)/SULpeak baseline. When a non-target lesion showed different responses from the measurable target lesion, we used the overall response considering both the target and non-target responses as previously described.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) by CT scans at 8 weeks.
Measured: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.
Assessment of Early Response by Using 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks
PET response of 18F-FLT was assessed using the SUVmax. The percentage of change of SUVmax in the target lesion was calculated as follows: 100 ×(SUVmax day 21-SUVmax baseline)/SUVmax baseline. The non responders on 18F-FLT PET/CT were defined as those with decreased SUVmax <10.6% or new lesions on a follow-up scan.
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) by CT scans at 8 weeks.
Measured: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.
Survival Outcomes According to 18F-FLT and 18F-FDG PET/CT Response on Day 21 of Regorafenib and RECIST on CT at 8 Weeks of Regorafenib
Measured: Regardless of the reason for discontinuation, all subjects will be followed for survival until death is documented, except for those who specifically withdraw consent to follow-up.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

18 Jul 201430 Apr 2019

First posted26 Jun 2014 (estimated)
Study start18 Jul 2014
Primary completion10 Aug 2016
Study completion30 Apr 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (27)Papers the sponsor has linked to this study.
Other trials for Colorectal CancerStudies of the same condition, open and under way.
More trials run by Asan Medical CenterThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Diagnosis
Allocation: Not applicable
Intervention model: Single group
Model description: This is a imaging biomarker study to evaluate feasibility of \[18F\]FLT-PET as a potential candidate for predictive imaging biomarker of regorafenib treatment in mCRC patients who progressed after prior standard therapies. The mCRC patients who failed to all 3 active cytotoxic chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) with or without targeted agents will be accrued. Patients will be scheduled to perform \[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional \[ 18F\]FDG-PET will be performed before treatment and at 21 days after treatment.
Masking: None (open label)
Enrolment: 68 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02175095
Sponsor's protocol ID: FLT-PET-regorafenib
Status last verified: Jun 2024
First submitted: 23 Jun 2014
Last updated: 4 Oct 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Publications

Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 1;30(28):3499-506. doi: 10.1200/JCO.2012.42.8201. Epub 2012 Sep 4.
PubMed 22949147
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, Bendahmane B, Andre T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. doi: 10.1016/S1470-2045(12)70477-1. Epub 2012 Nov 16.
PubMed 23168366
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
PubMed 15175435
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930.
PubMed 18421054
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. doi: 10.1056/NEJMoa0804385.
PubMed 18946061
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
PubMed 19339720
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. doi: 10.1200/JCO.2009.27.4860. Epub 2010 Oct 4.
PubMed 20921465
Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. doi: 10.1200/JCO.2009.27.6055. Epub 2010 Oct 4.
PubMed 20921462
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.
PubMed 23177514
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schoffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.
PubMed 23177515
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008 Dec 10;26(35):5705-12. doi: 10.1200/JCO.2008.18.0786. Epub 2008 Nov 10.
PubMed 19001320
Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, Andre T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008 Jan 20;26(3):374-9. doi: 10.1200/JCO.2007.12.5906.
PubMed 18202412
Cousin S, Taieb S, Penel N. A paradigm shift in tumour response evaluation of targeted therapy: the assessment of novel drugs in exploratory clinical trials. Curr Opin Oncol. 2012 May;24(3):338-44. doi: 10.1097/CCO.0b013e3283528b73.
PubMed 22418613
Milano A, Perri F, Ciarmiello A, Caponigro F. Targeted-therapy and imaging response: a new paradigm for clinical evaluation? Rev Recent Clin Trials. 2011 Sep;6(3):259-65. doi: 10.2174/157488711796575540.
PubMed 21682675
Desar IM, van Herpen CM, van Laarhoven HW, Barentsz JO, Oyen WJ, van der Graaf WT. Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy. Cancer Treat Rev. 2009 Jun;35(4):309-21. doi: 10.1016/j.ctrv.2008.12.001. Epub 2009 Jan 10.
PubMed 19136215

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The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

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Can I keep seeing my own doctor during the study?
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Study at a glance

From the registry record, last updated by the sponsor on 4 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 3'-Deoxy-3'-18F-fluorothymidine Positron Emission Tomography ([18F] FLT-PET) for the Prediction of Response to Regorafenib in the Metastatic Colorectal Cancer Patients Who Progressed After All Standard Therapies
ClinicalTrials.gov ID: NCT02175095
Acronym / sponsor ID: FLT-PET-regorafenib
Conditions: Colorectal Cancer
Keywords: regorafenib, fluorothymidine, positron emission tomography, metastatic colorectal cancer
Study type: Interventional
Recruitment status: Completed
Enrolment: 68 participants (actual)
Lead sponsor: Asan Medical CenterUniversity, hospital or other
Study start: 18 Jul 2014 (actual)
Primary completion: 10 Aug 2016 (actual)
Study completion: 30 Apr 2019 (actual)
First posted: 26 Jun 2014 (estimated)
Results: Posted 4 Oct 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Therefore, the investigators have planned this study with hypothesis that [18F]FLT-PET could be useful for identifying a subgroup of mCRC patients with clinical responsiveness to regorafenib.

Study design

Primary purpose: Diagnosis
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1
Model description: This is a imaging biomarker study to evaluate feasibility of [18F]FLT-PET as a potential candidate for predictive imaging biomarker of regorafenib treatment in mCRC patients who progressed after prior standard therapies. The mCRC patients who failed to all 3 active cytotoxic chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) with or without targeted agents will be accrued. Patients will be scheduled to perform [18F]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional [ 18F]FDG-PET will be performed before treatment and at 21 days after treatment.

Arm	Type	Receives
Regorafenib and FLT-PET	Experimental	Drug: Regorafenib, Diagnostic Test: [18F]FLT-PET, Diagnostic Test: [18F]FDG-PETAfter checking the eligibility for the study entry, patients will be scheduled to perform [18F]FLT-PET scans before and on 21st day from the administration of regorafenib. Regorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal. Standard anatomical response evaluation will be performed every 8 weeks (without regard to the cycles or schedules of chemotherapy). Additional [18F]FDG-PET will be performed before treatment and at 8 weeks (just once at the point of first response evaluation).

Who may qualify

Ages: 20 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (11 listed)

Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
Progressed after 3 active cytotoxic chemotherapy including fluoropyrimidines, oxaliplatin and irinotecan during or within 6 months of their administrations with or without targeted agents (bevacizumab or cetuximab).
Extrahepatic measurable lesion(s) by RECIST 1.1.
Unresectable metastatic disease.
Age over 20 years old.

Key exclusion criteria (23 listed)

Prior treatment of regorafenib.
Liver-limited metastasis.
Inability to perform [18F]FLT and [18F]FDG-PET imaging studies due to physical inability or claustrophobia.
Concurrent or previous history of another primary cancer within 3 years prior to randomisation except for curatively treated cervical cancer in situ, non-melanomatous skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without distant metastasis could be allowed with the agreement of the chief principal investigator.
Uncontrolled CNS metastases.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RegorafenibAlso: StivargaRegorafenib will be administered 160 mg/day given orally on day 1 to days 21 following 7 days break, which consists of 4 weeks as 1 cycle. Treatment will be repeated every 4 weeks and continued until disease progression, unacceptable toxicity or the patient's refusal.	Drug	Regorafenib and FLT-PET
[18F]FLT-PET[18F]FLT-PET scans before and on 21st day from the administration of regorafenib.	Diagnostic test	Regorafenib and FLT-PET
[18F]FDG-PET[18F]FDG-PET will be performed before treatment and at 21 days after treatment.	Diagnostic test	Regorafenib and FLT-PET

Primary outcome

Assessment of Early Response by 18F-Fluorodeoxyglucose(18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks
Time frame: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.
Response assessment using 18F-FDG PET/CT was based on the PERCIST 1.0. The peak SUV value corrected for lean body mass (SULpeak) was measured from the single hottest tumour at each time point. For a tumour to be measurable at baseline, the SULpeak in the target lesion was greater than or equal to 1.5 times the mean SUL in the 3-cm-diameter spherical volume of interest plus two times its standard deviation of the liver. The percentage of change in SULpeak in the measurable target lesion was computed as follows: 100×(SULpeak day 21-SULpeak baseline)/SULpeak baseline. When a non-target lesion showed different responses from the measurable target lesion, we used the overall response considering both the target and non-target responses as previously described. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) by CT scans at 8 weeks.
Assessment of Early Response by Using 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks
Time frame: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.
PET response of 18F-FLT was assessed using the SUVmax. The percentage of change of SUVmax in the target lesion was calculated as follows: 100 ×(SUVmax day 21-SUVmax baseline)/SUVmax baseline. The non responders on 18F-FLT PET/CT were defined as those with decreased SUVmax <10.6% or new lesions on a follow-up scan. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) by CT scans at 8 weeks.
Survival Outcomes According to 18F-FLT and 18F-FDG PET/CT Response on Day 21 of Regorafenib and RECIST on CT at 8 Weeks of Regorafenib
Time frame: Regardless of the reason for discontinuation, all subjects will be followed for survival until death is documented, except for those who specifically withdraw consent to follow-up.

Results and safety

Results posted to the registry on 4 Oct 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Regorafenib and FLT-PET	68	65

Primary outcome: Assessment of Early Response by 18F-Fluorodeoxyglucose(18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks

Time frame: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.. Count of participants. Unit: Participants

Measure	Response Evaluation Criteria In Solid Tumors Criteria (RECIST) n = 61	PET Response Criteria in Solid Tumours (PERCIST) n = 61
Partial response; Partial metabolic response	5	28
Stable disease; Stable metabolic disease	41	24
Progressive disease; Progressive metabolic disease	15	9

Population analysed: Both 18F-FLT and 18F-FDG PET/CT scans were performed in 64 patients; among the remaining four patients, one withdrew consent and three discontinued Regorafenib treatment during the first cycle because of toxicities. With the exception of three patients who had no follow-up CT (n = 2) or no uptake of 18F-FLT (n = 1), 61 were evaluable for the treatment response on both CT and PET/CT in final.

Primary outcome: Assessment of Early Response by Using 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks

Measure	Responders and Non-responders on CT and 18F-FLT PET/CT n = 61
Responders on 18F-FLT PET/CT and Responders on RECIST	5
Responders on 18F-FLT PET/CT and Non-Responders on RECIST	43
Non-Responders on 18F-FLT PET/CT and Responders on RECIST	0
Non-Responders on 18F-FLT PET/CT and Non-Responders on RECIST	13

Primary outcome: Survival Outcomes According to 18F-FLT and 18F-FDG PET/CT Response on Day 21 of Regorafenib and RECIST on CT at 8 Weeks of Regorafenib

Time frame: Regardless of the reason for discontinuation, all subjects will be followed for survival until death is documented, except for those who specifically withdraw consent to follow-up.. Median (95% Confidence Interval). Unit: months

Measure	Partial Metabolic Response Group (PMR Group) n = 28	Non-Partial Metabolic Response Group(Non-PMR Group) n = 33	Non-progressive Metabolic Disease Group (Non-PMD Group) n = 52	Progressive Metabolic Disease Group (PMD Group) n = 9	Responders on 18F-FLT PET/CT n = 48	Non-Responders on 18F-FLT PET/CT n = 13	Concordant Pairs of Responders on Day 21 18F-FLT PET/CT and 8 Weeks CT n = 5	Concordant Pairs of Non-responders on Day 21 18F-FLT PET/CT and 8 Weeks CT n = 13	Partial Response Group (PR Group) n = 5	Non-Partial Response Group (Non-PR Group) n = 56	Non-Progressive Disease Group (Non-PD Group) n = 46	Progressive Disease Group (PD Group) n = 15
Progression-free survival(PFS)	3.9 (1.60 to 6.27)	3.5 (3.26 to 3.76)	1.8 (0.00 to 3.79)	3.6 (3.18 to 4.02)	3.9 (1.93 to 5.87)	3.4 (2.72 to 4.16)	9.0 (2.44 to 15.53)	3.4 (2.72 to 4.16)	8.9 (2.43 to 15.53)	3.5 (3.45 to 3.63)	5.3 (3.36 to 7.33)	1.6 (1.33 to 1.88)
Overall survival (OS)	11.8 (7.54 to 16.13)	7.9 (5.25 to 10.62)	3.9 (2.22 to 6.18)	10.5 (8.07 to 12.83)	11.6 (7.33 to 13.85)	7.0 (4.45 to 9.45)	10.6 (7.33 to 13.85)	7.0 (4.45 to 9.45)	22.5 (0.00 to 45.64)	9.2 (7.47 to 11.01)	10.7 (8.00 to 13.37)	4.6 (1.83 to 7.48)

Adverse events

Other adverse events reported at 1% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Regorafenib and FLT-PET	0 of 68 (0%)	3 of 68 (4.4%)	0 of 68

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 4 Oct 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Background: PubMed 23168366Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, von Moos R, Vieitez JM, Bouche O, Borg C, Steffens CC, Alonso-Orduna V, Schlichting C, Reyes-Rivera I, Bendahmane B, Andre T, Kubicka S; ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan;14(1):29-37. doi: 10.1016/S1470-2045(12)70477-1. Epub 2012 Nov 16.
Background: PubMed 15175435Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
Background: PubMed 18421054Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930.
Background: PubMed 18946061Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. doi: 10.1056/NEJMoa0804385.
Background: PubMed 19339720Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.
Background: PubMed 20921465Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. doi: 10.1200/JCO.2009.27.4860. Epub 2010 Oct 4.
Background: PubMed 20921462Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. doi: 10.1200/JCO.2009.27.6055. Epub 2010 Oct 4.
Background: PubMed 23177514Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.
Background: PubMed 23177515Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schoffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22.
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Yong Sang Hong, M.D., Ph.D. principal investigator

Asan Medical Center

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing Regorafenib, [18F]FLT-PET and [18F]FDG-PET in people with Colorectal Cancer, run by Asan Medical Center at 1 site in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 4 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Assessment of Early Response by 18F-Fluorodeoxyglucose(18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) on Day 21 of Regorafenib Compared With the Response Rate of CT RECIST at 8 Weeks (time frame: Regorafenib was administered orally at a dose of 160 mg/day on days 1 to 21 following a 7-day break, with each cycle lasting 4 weeks. Treatment was repeated every 4 weeks and continued until disease progression, unacceptable toxicity, or patient refusal.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02175095, which also lists 27 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Oct 2024.