Squamous Cell Cancer
Conditions
Keywords
Randomized treatment, open-label, controlled, recurrent, metastatic, SCCHN, suitable, for local therapy
Brief summary
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.
Interventions
DRUGCilengitide 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.
DRUGCilengitide 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.
DRUGCetuximab
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.
DRUG5-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.
DRUGCisplatin
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Time: Investigator Read | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) Rate | 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) | 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). |
| Disease Control Rate | 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) | 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). |
| Overall Survival (OS) Time | Time from randomization to death, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011) | 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. |
| Duration of Response | 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) | 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. |
| Safety - Number of Participants Experiencing Any Adverse Event | 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) | Please refer to Adverse Events section for details of individual serious adverse events and other adverse events |
| Time to Treatment Failure (TTF) | 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) | 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. |
Countries
Austria, Belgium, France, Germany, Hungary, Italy, Poland, Spain, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin Cilengitide 500 milligram (mg) intravenous infusion over 60 minutes, daily from Day 1 to 4 of the first week of each 3-week cycle, subsequently followed by cilengitide 2000 mg once weekly along with cetuximab 250 milligram per square meter (mg/m\^2) intravenous infusion (initial starting dose of 400 mg/m\^2) once weekly, 5-fluorouracil (5-FU) 1000 mg/m\^2 intravenous continuous infusion daily from Day 1 to 4 and cisplatin 100 mg/m\^2 intravenous infusion over 60 minutes on Day 1, of each 3-week treatment cycle for a total of 6 cycles (18 weeks) or until progressive disease (PD), unacceptable toxicity or withdrawal for any other reason. After 6 cycles, participants received cilengitide 2000 mg once weekly along with cetuximab 250 mg/m\^2 intravenous infusion until PD, unacceptable toxicity or withdrawal for any other reason. | 62 |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin Cilengitide 2000 mg intravenous infusion over 60 minutes twice weekly along with cetuximab 250 mg/m\^2 intravenous infusion (initial starting dose of 400 mg/m\^2) once weekly, 5-fluorouracil (5-FU) 1000 mg/m\^2 intravenous continuous infusion daily from Day 1 to 4 and cisplatin 100 mg/m\^2 intravenous infusion over 60 minutes on Day 1, of each 3-week treatment 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 along with cetuximab 250 mg/m\^2 intravenous infusion until PD, unacceptable toxicity or withdrawal for any other reason. | 60 |
| Cetuximab+5-FU+Cisplatin Cetuximab 250 mg/m\^2 intravenous infusion (initial starting dose of 400 mg/m\^2) once weekly along with 5-fluorouracil (5-FU) 1000 mg/m\^2 intravenous continuous infusion daily from Day 1 to 4 and cisplatin 100 mg/m\^2 intravenous infusion over 60 minutes on Day 1, of each 3-week treatment 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 cetuximab 250 mg/m\^2 intravenous infusion until PD, unacceptable toxicity or withdrawal for any other reason. | 62 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 11 | 10 |
| Overall Study | Death | 5 | 7 | 5 |
| Overall Study | Other | 9 | 6 | 6 |
| Overall Study | Progressive Disease | 33 | 29 | 33 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Symptomatic Deterioration | 3 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 2 |
Baseline characteristics
| Characteristic | Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Cetuximab+5-FU+Cisplatin | Total |
|---|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 7.4 | 56.8 years STANDARD_DEVIATION 7.9 | 58.6 years STANDARD_DEVIATION 8.1 | 58.2 years STANDARD_DEVIATION 7.8 |
| Age, Customized Greater than or equal to (>=) 65 years | 15 participants | 12 participants | 15 participants | 42 participants |
| Age, Customized Less than (<) 65 years | 47 participants | 48 participants | 46 participants | 141 participants |
| Extent of disease at study entry Distant Metastasis | 32 participants | 28 participants | 31 participants | 91 participants |
| Extent of disease at study entry Recurrence | 30 participants | 32 participants | 31 participants | 93 participants |
| Karnofsky Performance Status < 80 (Karnofsky Score) | 7 participants | 6 participants | 5 participants | 18 participants |
| Karnofsky Performance Status >= 80 (Karnofsky Score) | 55 participants | 54 participants | 57 participants | 166 participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 6 Participants | 25 Participants |
| Sex: Female, Male Male | 54 Participants | 49 Participants | 56 Participants | 159 Participants |
| Site of origin of tumor Hypopharynx | 10 participants | 14 participants | 14 participants | 38 participants |
| Site of origin of tumor Larynx | 14 participants | 15 participants | 13 participants | 42 participants |
| Site of origin of tumor Oral cavity | 11 participants | 6 participants | 11 participants | 28 participants |
| Site of origin of tumor Oropharynx | 25 participants | 23 participants | 21 participants | 69 participants |
| Site of origin of tumor Other, including non-classifiable | 2 participants | 2 participants | 3 participants | 7 participants |
| Tumor Grade Poorly differentiated | 11 participants | 19 participants | 22 participants | 52 participants |
| Tumor Grade Well or moderately differentiated | 46 participants | 39 participants | 35 participants | 120 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 61 / 61 | 57 / 59 | 61 / 62 |
| serious Total, serious adverse events | 41 / 61 | 45 / 59 | 44 / 62 |
Outcome results
Primary
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 frame: 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)
Population: Intention-to-treat (ITT) population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Progression-free Survival (PFS) Time: Investigator Read | 6.4 months |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Progression-free Survival (PFS) Time: Investigator Read | 5.6 months |
| Cetuximab+5-FU+Cisplatin | Progression-free Survival (PFS) Time: Investigator Read | 5.7 months |
Comparison: Sample size of 177 subjects was estimated such that the treatment group with the best PFS result had a 90% probability of emerging as the one with the smaller observed log Hazard ratio (HR), if there was an underlying difference of 2.2 months between the arms in the median PFS (7.8 months in the best group and 5.6 months in the other 2 groups). It was assumed that the accrual and follow-up time would take 1 year each, and that the drop-out rate was 8%.p-value: 0.88595% CI: [0.67, 1.59]Cox proportional hazards model
Comparison: Sample size of 177 subjects was estimated such that the treatment group with the best PFS result had a 90% probability of emerging as the one with the smaller observed log HR, if there was an underlying difference of 2.2 months between the arms in the median PFS (7.8 months in the best group and 5.6 months in the other 2 groups). It was assumed that the accrual and follow-up time would take 1 year each, and that the drop-out rate was 8%.p-value: 0.05495% CI: [0.99, 2.43]Cox proportional hazards model
Secondary
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).
Time frame: 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)
Population: ITT population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Best Overall Response (BOR) Rate | 46.8 percentage of participants |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Best Overall Response (BOR) Rate | 26.7 percentage of participants |
| Cetuximab+5-FU+Cisplatin | Best Overall Response (BOR) Rate | 35.5 percentage of participants |
p-value: 0.20595% CI: [0.776, 3.276]Cochran-Mantel-Haenszel
p-value: 0.31795% CI: [0.307, 1.465]Cochran-Mantel-Haenszel
Secondary
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).
Time frame: 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)
Population: ITT population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Disease Control Rate | 85.5 percentage of participants |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Disease Control Rate | 73.3 percentage of participants |
| Cetuximab+5-FU+Cisplatin | Disease Control Rate | 80.6 percentage of participants |
p-value: 0.47695% CI: [0.551, 3.539]Cochran-Mantel-Haenszel
p-value: 0.34795% CI: [0.287, 1.555]Cochran-Mantel-Haenszel
Secondary
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 frame: 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)
Population: ITT population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Duration of Response | 5.8 months |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Duration of Response | 4.1 months |
| Cetuximab+5-FU+Cisplatin | Duration of Response | 6.4 months |
p-value: 0.39195% CI: [0.71, 2.39]Cox proportional hazards model
p-value: 0.00795% CI: [1.3, 5.21]Cox proportional hazards model
Secondary
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 frame: Time from randomization to death, reported between day of first participant randomized, 03 July 2009, until cut-off date (03 September 2011)
Population: ITT population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Overall Survival (OS) Time | 12.4 months |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Overall Survival (OS) Time | 10.6 months |
| Cetuximab+5-FU+Cisplatin | Overall Survival (OS) Time | 11.6 months |
p-value: 0.895% CI: [0.61, 1.47]Cox proportional hazards model
p-value: 0.87895% CI: [0.66, 1.63]Cox proportional hazards model
Secondary
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 frame: 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)
Population: Safety population included all participants who were administered any dose of the trial medication, that is, cilengitide, cisplatin, 5-FU, or cetuximab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Safety - Number of Participants Experiencing Any Adverse Event | 61 participants |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Safety - Number of Participants Experiencing Any Adverse Event | 59 participants |
| Cetuximab+5-FU+Cisplatin | Safety - Number of Participants Experiencing Any Adverse Event | 61 participants |
Secondary
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 frame: 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)
Population: ITT population included all participants who were randomized to trial treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilengitide 2000 mg Once Weekly+Cetuximab+5-FU+Cisplatin | Time to Treatment Failure (TTF) | 5.6 months |
| Cilengitide 2000 mg Twice Weekly+Cetuximab+5-FU+Cisplatin | Time to Treatment Failure (TTF) | 4.5 months |
| Cetuximab+5-FU+Cisplatin | Time to Treatment Failure (TTF) | 4.3 months |
p-value: 0.29495% CI: [0.84, 1.81]Cox proportional hazards model
p-value: 0.00795% CI: [1.16, 2.57]Cox proportional hazards model