Adenoid Cystic Carcinoma, Erbitux, and Particle Therapy (ACCEPT)

Study Description

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Brief Summary:

The ACCEPT (A(denoid) c(ystic) c(arcinoma), E(rbitux, and) p(article) t(herapy))-trial is a prospective, monocentric phase I/II feasibility trial evaluating toxicity and efficacy in the combined treatment of intensity-modulated radiation therapy (IMRT) and carbon ion (C12) boost with the epidermal growth factor receptor (EGFR) antibody cetuximab. The primary objective of the study is to explore the toxicity of the combined modality regimen consisting of heavy ion therapy / IMRT and EGFR antibody immunotherapy, by assessing the rate of patients with mucositis or any other toxicity of severity grade 3 or 4 according to NCI CTCAE V. 4. Secondary endpoints include local control, distant control, overall disease-free survival, overall survival

Condition or disease	Intervention/treatment	Phase
Adenoid Cystic Carcinoma	Drug: Cetuximab	Phase 1; Phase 2

Detailed Description:

Treatment with novel radiotherapeutic technologies could increase local control in adenoid cystic carcinoma of the head and neck. Especially combined treatment with intensity-modulated radiation therapy and heavy ion (C12) boost to the primary tumor or previous tumor bed could be established as the treatment of choice in this disease.

Unfortunately, therapeutic results in the treatment of adenoid cystic carcinoma are still hampered by the occurrence of distant metastases (predominantly in the lungs) which, though progressing comparatively slowly, still limit the patient's life expectancy. Most adenoid cystic carcinomas (> 80%) though, exhibit over-expression of EGFR receptors and hence provide an approach for systemic treatment. In this prospective phase II trial, the application of the EGFR antibody cetuximab will be evaluated in combination with the established treatment of intensity-modulated radiation therapy plus C12 heavy ion boost.

The trial aims at evaluation of toxicity and feasibility of the combined treatment, as primary endpoint, as well as local control and disease-free survival as secondary endpoints.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	49 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Combined Treatment of Adenoid Cystic Carcinoma With Cetuximab and IMRT Plus C12 Heavy Ion Boost - ACCEPT - (ACC, Erbitux, and Particle Therapy); Phase I/II Feasibility Study
Study Start Date :	June 2012
Estimated Primary Completion Date :	July 2015
Estimated Study Completion Date :	July 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cetuximab arm; patients receive weekly cetuximab in combination with IMRT and carbon ion boost	Drug: Cetuximab; cetuximab initial dose (7 days prior to RT treatment start): 400 mg/m² body surface cetuximab weekly doses (from RT treatment start throughout radiation treatment): 250 mg/m² body surface; Other Name: Cetuximab (Erbitux)

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants with acute adverse effects as a Measure of toxicity [ Time Frame: 6 weeks post completion of therapy ]

   The primary objective is to explore the toxicity of the combined treatment consisting of heavy ion therapy / IMRT and cetuximab by assessing the rate of patients with mucositis or any other toxicity of severity grade 3 or 4 according to NCI CTCAE V. 4.

   Acute treatment effects will be evaluated 6 weeks and late effects 3 years post completion of treatment

2. Number of Participants with late adverse effects as a Measure of toxicity [ Time Frame: 3 years post completion of treatment ]

   The primary objective is to explore the toxicity of the combined treatment consisting of heavy ion therapy / IMRT and cetuximab by assessing the rate of patients with mucositis or any other toxicity of severity grade 3 or 4 according to NCI CTCAE V. 4.

   Acute treatment effects will be evaluated 6 weeks and late effects 3 years post completion of treatment

Secondary Outcome Measures :

1. local relapse-free survival [ Time Frame: at 3 years post treatment ]
   Local relapse-free survival will be defined as the time from the initial dose of study therapy to the time of locoregional disease progression or relapse or death, or to the date of last assessment without any such event (censored observation)
2. distant relapse-free survival [ Time Frame: at 3 years post treatment ]
   Distant relapse-free survival will be defined as the time from the initial dose of study therapy to the time of distant metastasis detection or death, or to the date of last assessment without any such event (censored observation)
3. overall disease-free survival [ Time Frame: at 3 years post treatment ]
   Distant disease-free survival will be defined as the time from the initial dose of study therapy to the time of any detection of adenoid cystic carcinoma relapse or development of secondary cancer or death, or to the date of last assessment without any such event (censored observation)
4. overall survival [ Time Frame: at 3 years post treatment ]
   The duration of survival will be determined by measuring the time interval from initial dose of study therapy to the date of death of any cause or last observation (censored)

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria

• Histologically proven, or surgically resected adenoid-cystic carcinoma of the head and neck and
• macroscopic or microscopic residual tumor (R1/ R2) or
• Tumor stage >T3/T4 or
• perineural invasion and
• M0 stage
• Written informed consent
• Age between 18 and 70 years
• Karnofsky Index ≥ 70%
• Adequate bone-marrow, liver, and kidney function:
• neutrophils ≥ 1.5 x 109/L,
• thrombocytes ≥ 100 x 109/L,
• haemoglobin ≥ 10.0 g/dL
• bilirubin ≤ 2.0 g/dL
• SGOT, SGPT, AP, gamma-GT ≤ 3 x ULN
• serum creatinine ≤ 1.5 mg/dL
• effective contraception

Exclusion Criteria:

• Prior RT or chemotherapy for tumors of the head and neck
• R0 resection
• M1 (distant metastases)
• prior immunotherapy
• signs of active infection
• other serious illnesses
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias)
• Significant neurologic or psychiatric disorders including dementia or seizures
• Active disseminated intravascular coagulopathies
• Other serious underlying medical conditions prohibiting the patient's participation in the trial according to the judgement of the investigators
• Active participation in another clinical trial within the past 30 days
• Known allergic/ hypersensitivity reactions to non-human proteins
• Women: pregnant (Positive serum/ urine beta-HCG ) or breast-feeding,
• Known drug abuse,
• Other previous malignancy within the past 5 years, with exception of a history of a previous, adequately treated, basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix,
• Legal incapacity or limited legal capacity,
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Contacts and Locations

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Contacts

Contact: Alexandra D Jensen, MD MSc	+49-6221-56- ext 8202	alexandra.jensen@med.uni-heidelberg.de
Contact: Marc W Münter, MD	+49-6221-56- ext 8202	marc.muenter@med.uni-heidelberg.de

Locations

Germany
Dept. of Radiation Oncology	Recruiting
Heidelberg, Germany, 69120
Contact: Aleandra D Jensen, MD MSc +49-6221-56 ext 8202 alexandra.jensen@med.uni-heidelberg.de
Sub-Investigator: Alexandra D Jensen, MD MSc

Sponsors and Collaborators

Heidelberg University

Dept. of Radiation Oncology, INF 400, 69120 Heidelberg, Germany

University Hospital Heidelberg

Merck KGaA

Investigators

Principal Investigator:	Jürgen Debus, Prof. Dr. Dr.	Dept. of Radiation Oncology, INF 400, 69120 Heidelberg, Germany

More Information

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Publications:

Chen AM, Bucci MK, Weinberg V, Garcia J, Quivey JM, Schechter NR, Phillips TL, Fu KK, Eisele DW. Adenoid cystic carcinoma of the head and neck treated by surgery with or without postoperative radiation therapy: prognostic features of recurrence. Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):152-9.

Münter MW, Schulz-Ertner D, Hof H, Nikoghosyan A, Jensen A, Nill S, Huber P, Debus J. Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial clinical results and toxicity of treatment. Radiat Oncol. 2006 Jun 6;1:17.

Schulz-Ertner D, Nikoghosyan A, Didinger B, Münter M, Jäkel O, Karger CP, Debus J. Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques. Cancer. 2005 Jul 15;104(2):338-44.

Schulz-Ertner D, Nikoghosyan A, Thilmann C, Haberer T, Jäkel O, Karger C, Kraft G, Wannenmacher M, Debus J. Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):631-40.

Schulz-Ertner D, Nikoghosyan A, Jäkel O, Haberer T, Kraft G, Scholz M, Wannenmacher M, Debus J. Feasibility and toxicity of combined photon and carbon ion radiotherapy for locally advanced adenoid cystic carcinomas. Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):391-8.

Jäkel O, Krämer M, Schulz-Ertner D, Heeg P, Karger CP, Didinger B, Nikoghosyan A, Debus J. Treatment planning for carbon ion radiotherapy in Germany: review of clinical trials and treatment planning studies. Radiother Oncol. 2004 Dec;73 Suppl 2:S86-91.

Huber PE, Debus J, Latz D, Zierhut D, Bischof M, Wannenmacher M, Engenhart-Cabillic R. Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam? Radiother Oncol. 2001 May;59(2):161-7.

Douglas JG, Koh WJ, Austin-Seymour M, Laramore GE. Treatment of salivary gland neoplasms with fast neutron radiotherapy. Arch Otolaryngol Head Neck Surg. 2003 Sep;129(9):944-8.

Pommier P, Liebsch NJ, Deschler DG, Lin DT, McIntyre JF, Barker FG 2nd, Adams JA, Lopes VV, Varvares M, Loeffler JS, Chan AW. Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch Otolaryngol Head Neck Surg. 2006 Nov;132(11):1242-9.

Mizoe JE, Tsujii H, Kamada T, Matsuoka Y, Tsuji H, Osaka Y, Hasegawa A, Yamamoto N, Ebihara S, Konno A; Organizing Committee for the Working Group for Head-And-Neck Cancer. Dose escalation study of carbon ion radiotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):358-64.

de Haan LD, De Mulder PH, Vermorken JB, Schornagel JH, Vermey A, Verweij J. Cisplatin-based chemotherapy in advanced adenoid cystic carcinoma of the head and neck. Head Neck. 1992 Jul-Aug;14(4):273-7.

Kaplan MJ, Johns ME, Cantrell RW. Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg. 1986 Sep;95(2):165-70.

Suen JY, Johns ME. Chemotherapy for salivary gland cancer. Laryngoscope. 1982 Mar;92(3):235-9.

Creagan ET, Woods JE, Rubin J, Schaid DJ. Cisplatin-based chemotherapy for neoplasms arising from salivary glands and contiguous structures in the head and neck. Cancer. 1988 Dec 1;62(11):2313-9.

Dreyfuss AI, Clark JR, Fallon BG, Posner MR, Norris CM Jr, Miller D. Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin. Cancer. 1987 Dec 15;60(12):2869-72.

Venook AP, Tseng A Jr, Meyers FJ, Silverberg I, Boles R, Fu KK, Jacobs CD. Cisplatin, doxorubicin, and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group. J Clin Oncol. 1987 Jun;5(6):951-5.

Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006 Jun 10;24(17):2673-8. Review.

Dodd RL, Slevin NJ. Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. Oral Oncol. 2006 Sep;42(8):759-69. Epub 2006 Jun 6. Review.

Airoldi M, Gabriele AM, Gabriele P, Pedani F, Marchionatti S, Succo G, Beatrice F, Bumma C. Concomitant chemoradiotherapy followed by adjuvant chemotherapy in parotid gland undifferentiated carcinoma. Tumori. 2001 Jan-Feb;87(1):14-7.

Haddad RI, Posner MR, Busse PM, Norris CM Jr, Goguen LA, Wirth LJ, Blinder R, Krane JF, Tishler RB. Chemoradiotherapy for adenoid cystic carcinoma: preliminary results of an organ sparing approach. Am J Clin Oncol. 2006 Apr;29(2):153-7.

Younes MN, Park YW, Yazici YD, Gu M, Santillan AA, Nong X, Kim S, Jasser SA, El-Naggar AK, Myers JN. Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model. Mol Cancer Ther. 2006 Nov;5(11):2696-705.

Vered M, Braunstein E, Buchner A. Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin. Head Neck. 2002 Jul;24(7):632-6.

Hotte SJ, Winquist EW, Lamont E, MacKenzie M, Vokes E, Chen EX, Brown S, Pond GR, Murgo A, Siu LL. Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study. J Clin Oncol. 2005 Jan 20;23(3):585-90.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78.

Alcedo JC, Fábrega JM, Arosemena JR, Urrutia A. Imatinib mesylate as treatment for adenoid cystic carcinoma of the salivary glands: report of two successfully treated cases. Head Neck. 2004 Sep;26(9):829-31.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jensen AD, Nikoghosyan A, Hinke A, Debus J, Münter MW. Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux® and particle therapy]. BMC Cancer. 2011 Feb 15;11:70. doi: 10.1186/1471-2407-11-70.

Responsible Party:	Prof. Dr. Dr. J. Debus, Dept. of Radiation Oncology, INF 400, 69120 Heidelberg, Germany
ClinicalTrials.gov Identifier:	NCT01192087 History of Changes
Other Study ID Numbers:	ACCEPT
First Posted:	August 31, 2010
Last Update Posted:	April 24, 2013
Last Verified:	April 2013

Keywords provided by Heidelberg University:

adenoid cystic carcinoma; carbon ion therapy; IMRT (intensity-modulated therapy); radioimmunotherapy; Cetuximab

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Adenoid Cystic; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type	Neoplasms; Adenocarcinoma; Cetuximab; Antineoplastic Agents