Cilengitide in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) (ADVANTAGE)

Open-label, Randomized, Controlled Phase I/II Study of Cilengitide to Evaluate the Safety and Efficacy of the Combination of Different Regimens of Cilengitide Added to Cisplatin, 5-FU, and Cetuximab in Subjects With Recurrent/Metastatic Squamous Cell Cancer of the Head and Neck

The purpose of this open-label, randomized, controlled, Phase 1/2 study of the integrin inhibitor cilengitide is to evaluate the safety and efficacy of the combination of different regimens of cilengitide added to cisplatin, 5-fluorouracil (5-FU), and cetuximab in participants with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).

The Phase 1 part was conducted in dedicated study centers. In the Phase 2 part of this trial, cilengitide is administered at two different doses to two experimental groups. The third group will only receive cisplatin, 5-FU and cetuximab. In the Phase 1 part of this trial, the dose of cilengitide in combination with cisplatin, 5-FU and cetuximab was determined.

Cilengitide is an experimental anti-cancer substance interacting with so-called integrins. Integrins are protein molecules that are known to be present on the surface of certain cancer cells. Integrins are also found on certain cells that belong to growing blood vessels (endothelial cells). Integrins potentially facilitate the blood vessels' support of the tumor (angiogenesis) as well as the tumor's growth and further spread throughout the body (metastasis). By inhibiting integrins on the tumor cell surface, cilengitide potentially kills cancer cells, and potentially sensitizes cancer cells to other co-administered therapeutics. By inhibiting integrins on the endothelial cell surface, it potentially inhibits the ingrowth of additional blood vessels towards the tumor.

Cilengitide is given as an intravenous infusion (given by a drip in one vein of your arm). If any unacceptable side effect occurs, treatment with the study drug will be stopped.

Study Overview

• Status: Completed
• Conditions: Squamous Cell Cancer
• Intervention / Treatment: Drug: Cilengitide 2000 mg once weekly; Drug: Cetuximab; Drug: 5-fluorouracil (5-FU); Drug: Cisplatin; Drug: Cilengitide 2000 mg twice weekly

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria
    • Research Site
  • Wien, Austria
    • Research Site
• Belgium
  • Antwerp, Belgium
    • Research Site
  • Bruxelles, Belgium
    • Research Site
  • Edegem (Antwerp), Belgium
    • Research Site
  • Gent, Belgium
    • Research Site
  • Leuven, Belgium
    • Research Site
  • Namur, Belgium
    • Research Site
• France
  • Lille cedex, France
    • Research Site
  • Montpellier, France
    • Research Site
  • Nice, France
    • Research Site
  • Toulouse, France
    • Research Site
  • Tours, France
    • Research Site
  • Vandoeuvre les Nancy, France
    • Research Site
  • Villejuif, France
    • Research Site
• Germany
  • Aachen, Germany
    • Research Site
  • Berlin, Germany
    • Research Site
  • Essen, Germany
    • Research Site
  • Hamburg, Germany
    • Research Site
  • Heidelberg, Germany
    • Research Site
  • Jena, Germany
    • Research Site
  • Leipzig, Germany
    • Research Site
  • Rostock, Germany
    • Research Site
  • Stuttgart, Germany
    • Research Site
• Hungary
  • Budapest, Hungary
    • Research Site
  • Gyor, Hungary
    • Research Site
  • Nyiregyhaza, Hungary
    • Research Site
• Italy
  • La Spezia, Italy
    • Research Site
  • Milano, Italy
    • Research Site
  • Napoli, Italy
    • Research Site
• Poland
  • Gliwice, Poland
    • Research Site
  • Warsaw, Poland
    • Research Site
• Spain
  • L'Hospitalet de Llobregat, Spain
    • Research Site
  • Madrid, Spain
    • Research Site
  • Velencia, Spain
    • Research Site
• Switzerland
  • Basel, Switzerland
    • Research Site
  • Geneva, Switzerland
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of SCCHN
• At least one measurable lesion either by computerized tomography (CT) scan or magnetic resonance imaging (MRI)
• Karnofsky performance status (KPS) of greater than or equal to 70 or eastern cooperative oncology group performance status (ECOG PS) of 0-1 at trial entry

Exclusion Criteria:

• Prior systemic chemotherapy, except if given as part of a multimodal treatment for locally advanced disease, which was completed more than 6 months prior to trial entry
• Surgery (excluding prior diagnostic biopsy) or irradiation within 4 weeks before trial entry
• Nasopharyngeal Carcinoma
• Documented or symptomatic brain or leptomeningeal metastasis
• Previous treatment with epidermal growth factor receptor (EGFR) targeting therapy or signal transduction inhibitors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cilengitide 2000 mg once weekly+Cetuximab+5-FU+Cisplatin	Drug: Cilengitide 2000 mg once weekly; Cilengitide 500 milligram (mg) will be administered as an intravenous infusion over 60 minutes, daily from Day 1 to 4 of the first week of each 3-week cycle, subsequently followed by 2000 mg dose of cilengitide on Day 8 and 15 of every cycle for a total of 6 cycles (18 weeks) or until PD, unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants received cilengitide 2000 mg once weekly until PD, unacceptable toxicity or withdrawal for any other reason.; Drug: Cetuximab; Cetuximab will be administered as 250 milligram per square meter (mg/m^2) as infusion (initial starting dose of 400 mg/m^2) on Day 1, 8 and 15 of each 3-week treatment cycle. Cetuximab will be administered for a total of 6 cycles (18 weeks) or until PD, unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants received Cetuximab 250 mg/m^2 once weekly until PD, unacceptable toxicity or withdrawal for any other reason.; Other Names: Erbitux®; Drug: 5-fluorouracil (5-FU); 5-FU will be administered as an intravenous continuous infusion at a dose of 1000 mg/m^2 daily from Day 1 to 4 of each 3-week treatment cycle. 5-FU will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.; Drug: Cisplatin; Cisplatin will be administered as an intravenous infusion over 60 minutes, at a dose 100 mg/m^2 on Day 1 of each 3-week treatment cycle. Cisplatin will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.
Experimental: Cilengitide 2000 mg twice weekly+Cetuximab+5-FU+Cisplatin	Drug: Cetuximab; Cetuximab will be administered as 250 milligram per square meter (mg/m^2) as infusion (initial starting dose of 400 mg/m^2) on Day 1, 8 and 15 of each 3-week treatment cycle. Cetuximab will be administered for a total of 6 cycles (18 weeks) or until PD, unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants received Cetuximab 250 mg/m^2 once weekly until PD, unacceptable toxicity or withdrawal for any other reason.; Other Names: Erbitux®; Drug: 5-fluorouracil (5-FU); 5-FU will be administered as an intravenous continuous infusion at a dose of 1000 mg/m^2 daily from Day 1 to 4 of each 3-week treatment cycle. 5-FU will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.; Drug: Cisplatin; Cisplatin will be administered as an intravenous infusion over 60 minutes, at a dose 100 mg/m^2 on Day 1 of each 3-week treatment cycle. Cisplatin will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.; Drug: Cilengitide 2000 mg twice weekly; Cilengitide 2000 mg will be administered as an intravenous infusion over 60 minutes, twice weekly on Day 1, 4, 8, 11, 15, and 18 of each 3-week cycle for a total of 6 cycles (18 weeks) or until PD, unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants will receive cilengitide 2000 mg once weekly until PD, unacceptable toxicity or withdrawal for any other reason.
Active Comparator: Cetuximab+5-FU+Cisplatin	Drug: Cetuximab; Cetuximab will be administered as 250 milligram per square meter (mg/m^2) as infusion (initial starting dose of 400 mg/m^2) on Day 1, 8 and 15 of each 3-week treatment cycle. Cetuximab will be administered for a total of 6 cycles (18 weeks) or until PD, unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants received Cetuximab 250 mg/m^2 once weekly until PD, unacceptable toxicity or withdrawal for any other reason.; Other Names: Erbitux®; Drug: 5-fluorouracil (5-FU); 5-FU will be administered as an intravenous continuous infusion at a dose of 1000 mg/m^2 daily from Day 1 to 4 of each 3-week treatment cycle. 5-FU will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.; Drug: Cisplatin; Cisplatin will be administered as an intravenous infusion over 60 minutes, at a dose 100 mg/m^2 on Day 1 of each 3-week treatment cycle. Cisplatin will be administered for a total of 6 cycles (18 weeks), or until PD, unacceptable toxicity, or withdrawal for any other reason, whichever occur first.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Time: Investigator Read	The PFS is defined as the duration from randomization until radiological progression (based on response evaluation criteria in solid tumors [RECIST] Version 1.0) or death due to any cause. Only deaths within 84 days of last tumor assessment are considered. Participants without event are censored on the date of last tumor assessment. Investigator read is the assessment of all imaging by the treating physician at the local trial site.	Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Time	The OS time is defined as the time from randomization to death. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is earlier.	Time from randomization to death, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Best Overall Response (BOR) Rate	The BOR rate is defined as the percentage of the participants having achieved confirmed complete response (CR) or partial response (PR) as the best overall response according to radiological assessments (based on RECIST Version 1.0).	Evaluations will be performed every 6 weeks until progression reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Disease Control Rate	The disease control rate is defined as the percentage of participants having achieved confirmed CR, PR or stable disease (SD) as best overall response according to radiological assessments (based on RECIST Version 1.0).	Evaluations will be performed every 6 weeks until progression reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Time to Treatment Failure (TTF)	TTF is defined as the time from randomization to date of the first occurrence of; progression, discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death (within 84 days of last tumor assessment). Participants without event are censored on the date of last tumor assessment.	Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Duration of Response	Duration of response is defined as the time from the first assessment of CR or PR until the date of the first occurrence of progressive disease (PD), or until the date of death.	Time from first assessment of CR or PR until PD, death or last tumor assessment, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Safety - Number of Participants Experiencing Any Adverse Event	Please refer to Adverse Events section for details of individual serious adverse events and other adverse events	Time from first assessment of CR or PR until PD, death or last tumor assessment, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Principal Investigator: Jan Vermorken, MD, PhD, University Hospital, Antwerp

Publications and helpful links

General Publications

• Vermorken JB, Peyrade F, Krauss J, Mesia R, Remenar E, Gauler TC, Keilholz U, Delord JP, Schafhausen P, Erfan J, Brummendorf TH, Iglesias L, Bethe U, Hicking C, Clement PM. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol. 2014 Mar;25(3):682-688. doi: 10.1093/annonc/mdu003.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: June 24, 2008
• First Submitted That Met QC Criteria: June 24, 2008
• First Posted (Estimate): June 25, 2008

Study Record Updates

• Last Update Posted (Estimate): April 30, 2014
• Last Update Submitted That Met QC Criteria: March 28, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: open-label; metastatic; recurrent; SCCHN; controlled; Randomized treatment; suitable; for local therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Squamous Cell; Neoplasms, Squamous Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Cisplatin; Fluorouracil; Cetuximab
• Other Study ID Numbers: EMR 200052-013; 2008-000615-15 (EudraCT Number)