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

NCT02175095 | Completed Results

• 1 other identifier: FLT-PET-regorafenib
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Colorectal Cancer

Keywords

regorafenib; fluorothymidine; positron emission tomography; metastatic colorectal cancer

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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

  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.

Study Arms (1)

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).

Drug: Regorafenib; Diagnostic Test: [18F]FLT-PET; Diagnostic Test: [18F]FDG-PET

Interventions

Regorafenib DRUG

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.

Also known as: Stivarga

Regorafenib and FLT-PET

[18F]FLT-PET DIAGNOSTIC_TEST

\[18F\]FLT-PET scans before and on 21st day from the administration of regorafenib.

Regorafenib and FLT-PET

[18F]FDG-PET DIAGNOSTIC_TEST

\[18F\]FDG-PET will be performed before treatment and at 21 days after treatment.

Regorafenib and FLT-PET

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Asan Medical Center: lead

Study Sites (1)

Asan Medical Center

Seoul, Songpa, 138736, South Korea

Location

Related Publications (27)

• 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.

  PMID: 22949147 BACKGROUND

• 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.

  PMID: 23168366 BACKGROUND

• 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.

  PMID: 15175435 BACKGROUND

• 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.

  PMID: 18421054 BACKGROUND

• 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.

  PMID: 18946061 BACKGROUND

• 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.

  PMID: 19339720 BACKGROUND

• 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.

  PMID: 20921465 BACKGROUND

• 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.

  PMID: 20921462 BACKGROUND

• 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.

  PMID: 23177514 BACKGROUND

• 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.

  PMID: 23177515 BACKGROUND

• 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.

  PMID: 19001320 BACKGROUND

• 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.

  PMID: 18202412 BACKGROUND

• 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.

  PMID: 22418613 BACKGROUND

• 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.

  PMID: 21682675 BACKGROUND

• 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.

  PMID: 19136215 BACKGROUND

• Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007 Oct 20;25(30):4714-21. doi: 10.1200/JCO.2006.10.5825.

  PMID: 17947718 BACKGROUND

• Herrmann K, Wieder HA, Buck AK, Schoffel M, Krause BJ, Fend F, Schuster T, Meyer zum Buschenfelde C, Wester HJ, Duyster J, Peschel C, Schwaiger M, Dechow T. Early response assessment using 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin's lymphoma. Clin Cancer Res. 2007 Jun 15;13(12):3552-8. doi: 10.1158/1078-0432.CCR-06-3025.

  PMID: 17575218 BACKGROUND

• Kahraman D, Scheffler M, Zander T, Nogova L, Lammertsma AA, Boellaard R, Neumaier B, Ullrich RT, Holstein A, Dietlein M, Wolf J, Kobe C. Quantitative analysis of response to treatment with erlotinib in advanced non-small cell lung cancer using 18F-FDG and 3'-deoxy-3'-18F-fluorothymidine PET. J Nucl Med. 2011 Dec;52(12):1871-7. doi: 10.2967/jnumed.111.094458. Epub 2011 Nov 7.

  PMID: 22065872 BACKGROUND

• Kim SJ, Lee JS, Im KC, Kim SY, Park SA, Lee SJ, Oh SJ, Lee DS, Moon DH. Kinetic modeling of 3'-deoxy-3'-18F-fluorothymidine for quantitative cell proliferation imaging in subcutaneous tumor models in mice. J Nucl Med. 2008 Dec;49(12):2057-66. doi: 10.2967/jnumed.108.053215. Epub 2008 Nov 7.

  PMID: 18997037 BACKGROUND

• McKinley ET, Smith RA, Zhao P, Fu A, Saleh SA, Uddin MI, Washington MK, Coffey RJ, Manning HC. 3'-Deoxy-3'-18F-fluorothymidine PET predicts response to (V600E)BRAF-targeted therapy in preclinical models of colorectal cancer. J Nucl Med. 2013 Mar;54(3):424-30. doi: 10.2967/jnumed.112.108456. Epub 2013 Jan 22.

  PMID: 23341544 BACKGROUND

• Nakajo M, Nakajo M, Kajiya Y, Jinguji M, Nishimata N, Shimaoka S, Nihara T, Aridome K, Tanaka S, Fukukura Y, Tani A, Koriyama C. Diagnostic performance of (1)(8)F-fluorothymidine PET/CT for primary colorectal cancer and its lymph node metastasis: comparison with (1)(8)F-fluorodeoxyglucose PET/CT. Eur J Nucl Med Mol Imaging. 2013 Aug;40(8):1223-32. doi: 10.1007/s00259-013-2424-9. Epub 2013 May 8.

  PMID: 23653240 BACKGROUND

• Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, Lee DH, Suh C, Lee JS, Kim SW. [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res. 2008 Nov 15;14(22):7423-9. doi: 10.1158/1078-0432.CCR-08-0312.

  PMID: 19010859 BACKGROUND

• Hong YS, Kim HO, Kim KP, Lee JL, Kim HJ, Lee SJ, Lee SJ, Oh SJ, Kim JS, Ryu JS, Moon DH, Kim TW. 3'-Deoxy-3'-18F-fluorothymidine PET for the early prediction of response to leucovorin, 5-fluorouracil, and oxaliplatin therapy in patients with metastatic colorectal cancer. J Nucl Med. 2013 Aug;54(8):1209-16. doi: 10.2967/jnumed.112.117010. Epub 2013 Jun 26.

  PMID: 23804324 BACKGROUND

• Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, Unger C, Kratzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. doi: 10.1158/1078-0432.CCR-11-1900. Epub 2012 Mar 15.

  PMID: 22421192 BACKGROUND

• Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Buchert M, Christensen O, Jeffers M, Heinig R, Boix O, Mross K. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012 May 22;106(11):1722-7. doi: 10.1038/bjc.2012.153. Epub 2012 May 8.

  PMID: 22568966 BACKGROUND

• Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011 Jul 1;129(1):245-55. doi: 10.1002/ijc.25864. Epub 2011 Apr 22.

  PMID: 21170960 BACKGROUND

• George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, Morgan JA, Wagner AJ, Choy E, Tap WD, Yap JT, Van den Abbeele AD, Manola JB, Solomon SM, Fletcher JA, von Mehren M, Demetri GD. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol. 2012 Jul 1;30(19):2401-7. doi: 10.1200/JCO.2011.39.9394. Epub 2012 May 21.

  PMID: 22614970 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Results Point of Contact

• Title: Yong Sang Hong, M.D., Ph.D.
• Organization: Asan Medical Center

yshong@amc.seoul.kr

+82-2-3010-3227

Study Officials

• Yong Sang Hong, M.D., Ph.D.

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 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.

Study Record Dates

• First Submitted: June 23, 2014
• First Posted: June 26, 2014
• Study Start: July 18, 2014
• Primary Completion: August 10, 2016
• Study Completion: April 30, 2019
• Last Updated: October 4, 2024
• Results First Posted: October 4, 2024

Record last verified: 2024-06

Locations

KR (1)