Low-Dose Radiation Therapy to the Whole Liver With Gemcitabine and Cisplatin in IHC

NCT02254681 | Terminated Phase 2 Results DMC

• 1 other identifier: VPSR-1401
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The overall goal of this study is to determine the safety and efficacy of combination treatment of low-dose fractionated radiation therapy with gemcitabine-cisplatin chemotherapy for locally advanced mass forming intra-hepatic cholangiocarcinoma.

Conditions

Intrahepatic Cholangiocarcinoma

Keywords

low-dose radiotherapy; gemcitabine; cisplatin; cholangiocarcinoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Radiographic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

  16 weeks after treatment start

• Number of Participants With Adverse Events.

  Number of participants with adverse events during combined low-dose radiotherapy and gemcitabine-cisplatin treatment.

  up to 16 weeks after treatment start

Secondary Outcomes (5)

• Number of Participants With Post-operative Complications After Partial Hepatectomy After Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  up to 90 days after partial hepatectomy

• Number of Participants With Histologic Disease Response After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  16 weeks after start of first treatment

• Number of Participants With Injury to the Background Liver After Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  16 weeks after start of first treatment.

• Number of Participants With Intrahepatic Recurrence After Partial Hepatectomy With Antecedent Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  From date of partial hepatectomy until date of first documented recurrence or date of death from any cause, assessed up to 24 months.

• Number of Participants With Intrahepatic Disease Progression After Treatment With Combination Low-dose Radiotherapy and Gemcitabine-cisplatin.

  From date of first treatment until date of first documented progression or date of death from any cause, which ever comes first, assessed up to 24 months.

Study Arms (1)

Treatment

EXPERIMENTAL

Four three-week treatment cycles. Gemcitabine (1000 gm/m\^2) and cisplatin (25 mg/m\^2) administered on days one and eight of each cycle. Whole liver and portal lymph node basin low dose radiotherapy on days one, two, eight, and nine of each cycle.

Drug: Gemcitabine; Drug: Cisplatin; Radiation: low dose radiotherapy

Interventions

Gemcitabine DRUG

Also known as: Gemzar

Treatment

Cisplatin DRUG

Also known as: Platinol

Treatment

low dose radiotherapy RADIATION

Whole liver and portal lymph node basin low dose radiotherapy

Treatment

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic diagnosis of mass-forming IHC. OR
• Histologic diagnosis of adenocarcinoma of the liver in setting of negative colonoscopy, upper endoscopy, mammography (females), or cross-sectional imaging for primary disease.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm (≥1 cm) with spiral CT scan, MRI. See Section 8 for the evaluation of measurable disease.
• Locally advanced disease (portal lymph node disease, multifocal intrahepatic lesions, or major vascular invasion) AND no evidence of omental, peritoneal, or pelvic metastases.
• Other sites of metastatic disease (e.g. lung, distant lymph nodes, bone) are allowed.
• No prior chemotherapy, radiotherapy, or surgical therapy.
• ECOG performance status ≤ 1 (Karnofsky ≥70%). See Appendix A.
• Life expectancy of greater than six months.
• Patients must have normal organ and marrow function as defined below:
• leukocytes≥3,000/mcL
• absolute neutrophil count≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin≥9.0 g/dL
• total bilirubin≤2.0 mg/dL
• AST(SGOT)/ALT(SGPT)≤3 × institutional upper limit of normal

You may not qualify if:

• Prior chemotherapy, surgical therapy, or radiotherapy for IHC.
• Patients who are receiving any other investigational agents or have been treated with any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study.
• Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or cisplatin.
• Prior invasive malignancy (except for non-melanomatous skin cancer, low grade prostate cancer, and in situ cervical cancer) unless disease free for ≥ two years.
• Periductal infiltrating, intraductal, or poorly differentiated neuroendocrine (e.g. high grade, small, or large cell) tumor histology.
• Prior abdominal radiotherapy.
• Cirrhosis, primary sclerosing cholangitis, hepatitis viral infection (documented by positive serology and antigen serologic testing), or other background liver diseases.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; unstable angina and/or congestive heart failure within the last 6 months; transmural myocardial infarction within the last 6 months; New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registration; history of stroke, cerebral vascular accident or transient ischemic attack within 6 months; serious and inadequately controlled cardiac arrhythmia; significant vascular disease (e.g.;, high risk aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease; evidence of bleeding diathesis or coagulopathy; serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess, major surgical procedure or significant traumatic injury within 28 days prior to registration; bacterial or fungal infection requiring intravenous antibiotics at the time of registration; chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity; any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy; cognitive impairment that precludes a patient from acting as his or her own agent to provide informed consent.
• Pregnant or breast feeding women.
• Men and women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception.
• Acquired immune deficiency syndrome (AIDS) based upon current CDC definition. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol are significantly immunosuppressive.

Sponsors & Collaborators

• Allina Health System: lead

Study Sites (1)

Virginia Piper Cancer Institute

Minneapolis, Minnesota, 55407, United States

Location

Related Publications (33)

• Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun;60(6):1268-89. doi: 10.1016/j.jhep.2014.01.021. Epub 2014 Mar 27. No abstract available.

  PMID: 24681130 BACKGROUND

• Ilyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013 Dec;145(6):1215-29. doi: 10.1053/j.gastro.2013.10.013. Epub 2013 Oct 15.

  PMID: 24140396 BACKGROUND

• de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Gamblin TC, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Schulick RD, Choti MA, Gigot JF, Mentha G, Pawlik TM. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011 Aug 10;29(23):3140-5. doi: 10.1200/JCO.2011.35.6519. Epub 2011 Jul 5.

  PMID: 21730269 BACKGROUND

• Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O'Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi: 10.1097/SLA.0b013e318176c4d3.

  PMID: 18580211 BACKGROUND

• Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, Zopf T, Trarbach T, Malago M, Baba HA, Broelsch CE. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg. 2009 Feb;208(2):218-28. doi: 10.1016/j.jamcollsurg.2008.10.017.

  PMID: 19228533 BACKGROUND

• Choi SB, Kim KS, Choi JY, Park SW, Choi JS, Lee WJ, Chung JB. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann Surg Oncol. 2009 Nov;16(11):3048-56. doi: 10.1245/s10434-009-0631-1. Epub 2009 Jul 22.

  PMID: 19626372 BACKGROUND

• Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol. 2008 May;23(5):766-70. doi: 10.1111/j.1440-1746.2007.05040.x. Epub 2007 Sep 12.

  PMID: 17868336 BACKGROUND

• Nakagohri T, Kinoshita T, Konishi M, Takahashi S, Gotohda N. Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma. World J Surg. 2008 Dec;32(12):2675-80. doi: 10.1007/s00268-008-9778-3.

  PMID: 18843437 BACKGROUND

• Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008 Oct;15(10):2787-94. doi: 10.1245/s10434-008-0081-1. Epub 2008 Aug 7.

  PMID: 18685896 BACKGROUND

• Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.

  PMID: 20375404 BACKGROUND

• Woo SM, Lee WJ, Kim JH, Kim DH, Han SS, Park SJ, Kim TH, Lee JH, Koh YH, Hong EK. Gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective cohort study. Chemotherapy. 2013;59(3):232-8. doi: 10.1159/000354539. Epub 2013 Dec 13.

  PMID: 24356333 BACKGROUND

• Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, Finch TR, Levitt R, Windschitl HE, Knost JA, Tschetter LK. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer. 2005 Jan 1;103(1):111-8. doi: 10.1002/cncr.20753.

  PMID: 15558814 BACKGROUND

• Jensen LH, Lindebjerg J, Ploen J, Hansen TF, Jakobsen A. Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer. Ann Oncol. 2012 Sep;23(9):2341-2346. doi: 10.1093/annonc/mds008. Epub 2012 Feb 23.

  PMID: 22367707 BACKGROUND

• Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. doi: 10.1200/JCO.2010.28.4075. Epub 2010 Jun 7.

  PMID: 20530271 BACKGROUND

• Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, Botha JF, Mezrich JD, Chapman WC, Schwartz JJ, Hong JC, Emond JC, Jeon H, Rosen CB, Gores GJ, Heimbach JK. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012 Jul;143(1):88-98.e3; quiz e14. doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.

  PMID: 22504095 BACKGROUND

• Kim YI, Park JW, Kim BH, Woo SM, Kim TH, Koh YH, Lee WJ, Kim CM. Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma. Radiat Oncol. 2013 Dec 21;8:292. doi: 10.1186/1748-717X-8-292.

  PMID: 24359879 BACKGROUND

• Ben-Josef E, Normolle D, Ensminger WD, Walker S, Tatro D, Ten Haken RK, Knol J, Dawson LA, Pan C, Lawrence TS. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 2005 Dec 1;23(34):8739-47. doi: 10.1200/JCO.2005.01.5354.

  PMID: 16314634 BACKGROUND

• Servajean C, Gilabert M, Piana G, Monges G, Delpero JR, Brenot I, Raoul JL. One case of intrahepatic cholangiocarcinoma amenable to resection after radioembolization. World J Gastroenterol. 2014 May 7;20(17):5131-4. doi: 10.3748/wjg.v20.i17.5131.

  PMID: 24803830 BACKGROUND

• Vouche M, Lewandowski RJ, Atassi R, Memon K, Gates VL, Ryu RK, Gaba RC, Mulcahy MF, Baker T, Sato K, Hickey R, Ganger D, Riaz A, Fryer J, Caicedo JC, Abecassis M, Kulik L, Salem R. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol. 2013 Nov;59(5):1029-36. doi: 10.1016/j.jhep.2013.06.015. Epub 2013 Jun 25.

  PMID: 23811303 BACKGROUND

• Inarrairaegui M, Pardo F, Bilbao JI, Rotellar F, Benito A, D'Avola D, Herrero JI, Rodriguez M, Marti P, Zozaya G, Dominguez I, Quiroga J, Sangro B. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol. 2012 Jul;38(7):594-601. doi: 10.1016/j.ejso.2012.02.189. Epub 2012 Mar 21.

  PMID: 22440743 BACKGROUND

• Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, Abdalla EK, Curley SA, Capussotti L, Clary BM, Vauthey JN. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg. 2007 May;204(5):854-62; discussion 862-4. doi: 10.1016/j.jamcollsurg.2006.12.032. Epub 2007 Feb 15.

  PMID: 17481498 BACKGROUND

• Marples B, Wouters BG, Collis SJ, Chalmers AJ, Joiner MC. Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. Radiat Res. 2004 Mar;161(3):247-55. doi: 10.1667/rr3130.

  PMID: 14982490 BACKGROUND

• Short SC, Woodcock M, Marples B, Joiner MC. Effects of cell cycle phase on low-dose hyper-radiosensitivity. Int J Radiat Biol. 2003 Feb;79(2):99-105.

  PMID: 12569013 BACKGROUND

• Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):379-89. doi: 10.1016/s0360-3016(00)01471-1.

  PMID: 11173131 BACKGROUND

• Kunos CA, Sill MW, Buekers TE, Walker JL, Schilder JM, Yamada SD, Waggoner SE, Mohiuddin M, Fracasso PM. Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group. Gynecol Oncol. 2011 Feb;120(2):224-8. doi: 10.1016/j.ygyno.2010.10.018.

  PMID: 21075438 BACKGROUND

• Arnold SM, Regine WF, Ahmed MM, Valentino J, Spring P, Kudrimoti M, Kenady D, Desimone P, Mohiuddin M. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1411-7. doi: 10.1016/j.ijrobp.2003.09.019.

  PMID: 15050317 BACKGROUND

• Harney J, Short SC, Shah N, Joiner M, Saunders MI. Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1190-5. doi: 10.1016/j.ijrobp.2003.12.029.

  PMID: 15234055 BACKGROUND

• Joiner MC, Denekamp J. The effect of small radiation doses on mouse skin. Br J Cancer Suppl. 1986;7:63-6. No abstract available.

  PMID: 3459542 BACKGROUND

• Krueger SA, Wilson GD, Piasentin E, Joiner MC, Marples B. The effects of G2-phase enrichment and checkpoint abrogation on low-dose hyper-radiosensitivity. Int J Radiat Oncol Biol Phys. 2010 Aug 1;77(5):1509-17. doi: 10.1016/j.ijrobp.2010.01.028.

  PMID: 20637979 BACKGROUND

• Marples B, Wouters BG, Joiner MC. An association between the radiation-induced arrest of G2-phase cells and low-dose hyper-radiosensitivity: a plausible underlying mechanism? Radiat Res. 2003 Jul;160(1):38-45. doi: 10.1667/rr3013.

  PMID: 12816521 BACKGROUND

• Regine WF, Hanna N, Garofalo MC, Doyle A, Arnold S, Kataria R, Sims J, Tan M, Mohiuddin M. Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):172-7. doi: 10.1016/j.ijrobp.2006.11.045. Epub 2007 Feb 2.

  PMID: 17276612 BACKGROUND

• Wrenn DC, Saigal K, Lucci JA 3rd, Pearson MJ, Simpkins F, Schuman S, Twiggs LB, Walker GR, Wolfson AH. A Phase I Study using low-dose fractionated whole abdominal radiotherapy as a chemopotentiator to full-dose cisplatin for optimally debulked stage III/IV carcinoma of the endometrium. Gynecol Oncol. 2011 Jul;122(1):59-62. doi: 10.1016/j.ygyno.2011.03.007. Epub 2011 Apr 6.

  PMID: 21474169 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

MeSH Terms

Conditions

Cholangiocarcinoma

Interventions

Gemcitabine; Cisplatin; Radiotherapy

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Therapeutics

Results Point of Contact

• Title: Srinevas K. Reddy
• Organization: Allina Health

laura.rockwell@allina.com

612-863-8716

Study Officials

• Srinevas K Reddy, MD

  Allina Health System

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2014
• First Posted: October 2, 2014
• Study Start: September 1, 2014
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: October 3, 2018
• Results First Posted: October 3, 2018

Record last verified: 2018-10

Locations

US (1)