Study of Radiation (RT) Concurrent With Cetuximab in Patients With Advanced Head and Neck Squamous Cell Carcinoma (SCC)

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00904345
• Collaborator: (none)
• Enrollment: 23
• Locations: 2
• Arm: 1
• Duration (Months): 140
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a single-arm, phase II trial to characterize the clinical outcome of standard of care, cetuximab concurrent with radiation, in a special population (head and neck cancer patients who cannot tolerate concurrent chemoradiotherapy due to advanced age, poor performance status or concurrent illness), and to determine if biomarker response to a loading dose of cetuximab is predictive of that outcome.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer	Drug: Cetuximab; Radiation: 50-60 Gy and 70 Gy	Phase 2

Detailed Description

Primary Objective 1: Determine changes in tumor EGFR, pEGFR, downstream signaling and novel phosphoproteins following a loading dose of cetuximab in patients who are poor candidates for chemoradiation (age =70 years or with significant co-morbidities) and are therefore treated with cetuximab with radiation.

Primary Objective 2: Characterize clinical outcomes, including local recurrence, progression-free survival and overall survival in these patients, and correlate these clinical outcomes with the changes in tumor EGFR, pEGFR, downstream signaling, and novel phosphoproteins.

Primary Objective 3: Describe the toxicity, in particular mucositis/dysphagia, of this regimen.

Secondary Objective 1: Conduct normal mucosa EGFR assessment for comparison with tumor sample.

Secondary Objective 2: Correlate HPV presence and titer with p53 status and clinical outcome.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of RT Concurrent w/ Cetuximab in Patients w/ Locally Advanced Head & Neck SCC Who Do Not Qualify For Standard Chemotherapy Due To Age >70 Or Co-Morbidities
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment

Drug: Cetuximab; Patients will receive a single dose of cetuximab 400 mg/m (Day 0). On day 7 (+/- 1 day), a repeat biopsy will be performed. Radiation concurrent with weekly cetuximab 250 mg/m.; Radiation: 50-60 Gy and 70 Gy; Within approximately 4 days (after single dose of Cetuximab), definitive radiation will begin (70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes) concurrent with weekly cetuximab 250 mg/m.

Outcome Measures

Primary Outcome Measures

1. Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR) [At baseline (pre-loading dose) and day 7 post-loading dose]

   The ratio (fold change) of tumor EGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.

2. Mean Change in Tumor Phosphorylated EGFR (pEGFR) [At baseline (pre-loading dose) and day 7 post-loading dose]

   The ratio (fold change) of tumor pEGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.

3. Progression Free Survival Rate [At 1 and 2 years]

   Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years.

4. Overall Survival Rate [At 1 and 2 Years]

   Percentage of participants alive at 1 and 2 years after enrollment.

5. Number of Participants With Treatment Related Toxicities [3 years]

   Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the total number of incidents outnumbers the number of participants. Toxicities are graded according to the CTCAE v4.

Secondary Outcome Measures

1. Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa [At baseline (pre-loading dose) and day 7 post-loading dose]

   Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level at post-loading dose/pre-loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.

2. Change in Tumor pEGFR Level Relative to pEGFR in Normal Mucosa [At baseline (pre-loading dose) and day 7 post-loading dose]

   Normal mucosa pEGFR was assessed for comparison with pEGFR in tumor sample. The fold change in tumor pEGFR level post-loading dose/pre loading dose of cetuximab, relative to fold change in normal mucosa pEGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal pEGFR.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have pathologically-confirmed, previously untreated, clinically accessible (without general anesthesia) locally advanced squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or nonresectable head and neck squamous cell carcinomas of the skin.

• Patients will be limited to:

• ≥ 70 years of age, OR

• with co-morbidities that preclude treatment with standard platinum-based chemotherapy, as determined by the treating physician, OR

• KPS ≤ 80, OR

• Creatinine clearance < 30 cc/min

• Laboratory criteria:

• WBC > 3500/ul

• Granulocyte > 1500/ul

• Platelet count > 100,000/ul

• Total Bilirubin < 1.5 X ULN

• AST and ALT < 2.5 X ULN

• Patients must give documented informed consent to participate in this study.

Exclusion Criteria:

• Prior head and neck malignancy, or history of other prior non-head and neck malignancy within the past 3 years (excluding skin cancer and early stage treated prostate cancer).

• Prior head and neck radiation or chemotherapy.

• Documented evidence of distant metastases.

• Patients with nasopharyngeal carcinoma.

• Any medical or psychiatric illness, which, in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment.

• Patients with psychiatric/social situations that would limit compliance with study requirements are not eligible.

• Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or small molecule).

• Patients residing in prison.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
2	University of Michigan Veterans Administration Hospital	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Shruti Jolly, MD, University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 3, 2018

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT00904345
• Other Study ID Numbers: UMCC 2009.009; HUM 27253; NCT01250522
• First Posted: May 19, 2009
• Last Update Posted: Feb 24, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by University of Michigan Rogel Cancer Center: SCC Head and Neck Cancer
• Additional relevant MeSH terms: Head and Neck Neoplasms; Cetuximab

Study Results

Participant Flow

Pre-assignment Detail	2 participants withdrew before receiving treatment

Arm/Group Title	Treatment With Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab 400 mg/m (Day 0), then weekly cetuximab 250 mg/m concurrent with radiation. Within approximately 4 days after first (loading) dose of cetuximab, patients received radiation administered as 70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes.
Period Title: Overall Study
STARTED	21
Stopped or Modified Treatment Due to Toxicity	3
COMPLETED	18
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Overall Participants	21
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65.6
Sex: Female, Male (Count of Participants)
Female	4 19%
Male	17 81%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	14 66.7%
Unknown or Not Reported	7 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 71.4%
More than one race	0 0%
Unknown or Not Reported	6 28.6%
Smoking Status (Count of Participants)
Yes, current	7 33.3%
Yes, past	13 61.9%
No	1 4.8%
Cancer Location (Count of Participants)
Oropharynx	16 76.2%
Oral Cavity	2 9.5%
Auditory Canal	1 4.8%
Hypopharynx	1 4.8%
Unknown primary	1 4.8%
HPV Status (Count of Participants)
Positive	10 47.6%
Negative	6 28.6%
Unknown	5 23.8%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)
Description	The ratio (fold change) of tumor EGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
Time Frame	At baseline (pre-loading dose) and day 7 post-loading dose

Outcome Measure Data

Analysis Population Description

15 participants had a sample size sufficient for EGFR analysis.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	15
Mean (Full Range) [fold change]	0.56

2. Primary Outcome

Title	Mean Change in Tumor Phosphorylated EGFR (pEGFR)
Description	The ratio (fold change) of tumor pEGFR post-loading dose/pre-loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
Time Frame	At baseline (pre-loading dose) and day 7 post-loading dose

Outcome Measure Data

Analysis Population Description

10 participants had a sample size sufficient for pEGFR analysis.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	10
Mean (Full Range) [fold change]	0.81

3. Primary Outcome

Title	Progression Free Survival Rate
Description	Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years.
Time Frame	At 1 and 2 years

Outcome Measure Data

Analysis Population Description

Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	21
1 year	47.8 227.6%
2 year	37.2 177.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment: Cetuximab + RT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Estimates of proportion event-free at 1 and 2 years calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals were calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.

4. Primary Outcome

Title	Overall Survival Rate
Description	Percentage of participants alive at 1 and 2 years after enrollment.
Time Frame	At 1 and 2 Years

Outcome Measure Data

Analysis Population Description

Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	21
1 year	68.8 327.6%
2 years	47.6 226.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment: Cetuximab + RT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Survival proportion estimates at 1 and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.

5. Primary Outcome

Title	Number of Participants With Treatment Related Toxicities
Description	Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the total number of incidents outnumbers the number of participants. Toxicities are graded according to the CTCAE v4.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	21
All Grades: Cutaneous Toxicity	16 76.2%
All Grades: Mucositis	19 90.5%
All grades: Dysphagia	14 66.7%
All grades: Hematologic Toxicity	3 14.3%
Grades 3-4: Cutaneous Toxicity	4 19%
Grades 3-4: Mucositis	8 38.1%
Grades 3-4: Dysphagia	5 23.8%
Grades 3-4: Hematologic Toxicity	0 0%

6. Secondary Outcome

Title	Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa
Description	Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level at post-loading dose/pre-loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.
Time Frame	At baseline (pre-loading dose) and day 7 post-loading dose

Outcome Measure Data

Analysis Population Description

6 participants had a sample size sufficient for EGFR analysis.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	6
Mean (Full Range) [ratio]	0.84

7. Secondary Outcome

Title	Change in Tumor pEGFR Level Relative to pEGFR in Normal Mucosa
Description	Normal mucosa pEGFR was assessed for comparison with pEGFR in tumor sample. The fold change in tumor pEGFR level post-loading dose/pre loading dose of cetuximab, relative to fold change in normal mucosa pEGFR level post-loading dose/pre-loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal pEGFR.
Time Frame	At baseline (pre-loading dose) and day 7 post-loading dose

Outcome Measure Data

Analysis Population Description

7 participants had a sample size sufficient for pEGFR analysis.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	7
Mean (Full Range) [ratio]	4.69

8. Post-Hoc Outcome

Title	Freedom From Local Regional Progression (FFLRP)
Description	Percentage of participants without local or regional failure from the time of enrollment to 1 and 2 years.
Time Frame	At 1 and 2 years

Outcome Measure Data

Analysis Population Description

Patients who completed the full course of cetuximab+RT or had cetuximab+RT stopped for toxicity.

Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
Measure Participants	21
1 year	63.9 304.3%
2 years	51.2 243.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment: Cetuximab + RT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Estimates of proportion LRP event-free at 1 and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.

Adverse Events

Time Frame	3 years
Arm/Group Title	Treatment: Cetuximab + RT
Arm/Group Description	Patients received a single loading dose of cetuximab and a cetuximab infusion delivered once a week during radiotherapy.
All Cause Mortality
	Treatment: Cetuximab + RT
	Affected / at Risk (%)	# Events
Total	12/21 (57.1%)
Serious Adverse Events
	Treatment: Cetuximab + RT
	Affected / at Risk (%)	# Events
Total	12/21 (57.1%)
Cardiac disorders
Sinus tachycardia	1/21 (4.8%)	1
Ventricular fibrillation	1/21 (4.8%)	1
Gastrointestinal disorders
Dry mouth	2/21 (9.5%)	3
Dysphagia	3/21 (14.3%)	4
Esophagitis	1/21 (4.8%)	2
Gastrointestinal disorders - Unspecified	1/21 (4.8%)	1
Mucositis oral	3/21 (14.3%)	4
Pancreatitis	1/21 (4.8%)	1
General disorders
Chills	1/21 (4.8%)	1
Fatigue	1/21 (4.8%)	1
Fever	1/21 (4.8%)	1
Multi-organ failure	2/21 (9.5%)	2
Infections and infestations
Skin infection	1/21 (4.8%)	1
Tracheitis	1/21 (4.8%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	1/21 (4.8%)	1
Metabolism and nutrition disorders
Dehydration	1/21 (4.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	3/21 (14.3%)	3
Psychiatric disorders
Delirium	1/21 (4.8%)	1
Psychiatric disorders - Unspecified	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/21 (4.8%)	1
Epistaxis	1/21 (4.8%)	1
Pneumonitis	1/21 (4.8%)	1
Stridor	1/21 (4.8%)	1
Vascular disorders
Hypertension	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment: Cetuximab + RT
	Affected / at Risk (%)	# Events
Total	20/21 (95.2%)
Blood and lymphatic system disorders
Anemia	3/21 (14.3%)	6
Blood and lymphatic system disorders - Unspecified	2/21 (9.5%)	5
Gastrointestinal disorders
Abdominal pain	1/21 (4.8%)	1
Constipation	4/21 (19%)	4
Diarrhea	2/21 (9.5%)	3
Dry mouth	19/21 (90.5%)	50
Dysphagia	16/21 (76.2%)	49
Esophagitis	16/21 (76.2%)	24
Gastrointestinal disorders - Unspecified	3/21 (14.3%)	6
Mucositis oral	20/21 (95.2%)	52
Nausea	7/21 (33.3%)	9
Oral pain	4/21 (19%)	5
Salivary duct inflammation	9/21 (42.9%)	33
Stomach pain	1/21 (4.8%)	1
Vomiting	2/21 (9.5%)	3
General disorders
Chills	2/21 (9.5%)	2
Fatigue	7/21 (33.3%)	7
Fever	2/21 (9.5%)	2
Pain	2/21 (9.5%)	3
Infections and infestations
Papulopustular rash	1/21 (4.8%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	17/21 (81%)	35
Investigations
Aspartate aminotransferase increased	1/21 (4.8%)	1
Blood bilirubin increased	1/21 (4.8%)	4
Creatinine increased	1/21 (4.8%)	2
Lymphocyte count decreased	3/21 (14.3%)	6
Platelet count decreased	1/21 (4.8%)	4
Weight loss	1/21 (4.8%)	1
White blood cell decreased	1/21 (4.8%)	1
Metabolism and nutrition disorders
Anorexia	1/21 (4.8%)	1
Dehydration	10/21 (47.6%)	17
Hyperglycemia	2/21 (9.5%)	5
Hyperkalemia	1/21 (4.8%)	1
Hypernatremia	1/21 (4.8%)	1
Hypoalbuminemia	1/21 (4.8%)	1
Hypoglycemia	2/21 (9.5%)	2
Hypomagnesemia	1/21 (4.8%)	2
Hyponatremia	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/21 (4.8%)	1
Trismus	6/21 (28.6%)	11
Nervous system disorders
Dysgeusia	19/21 (90.5%)	48
Facial muscle weakness	1/21 (4.8%)	1
Headache	2/21 (9.5%)	2
Myelitis	1/21 (4.8%)	1
Paresthesia	1/21 (4.8%)	1
Psychiatric disorders
Anxiety	2/21 (9.5%)	2
Insomnia	1/21 (4.8%)	1
Psychiatric disorders - Unspecified	1/21 (4.8%)	1
Renal and urinary disorders
Urinary frequency	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/21 (9.5%)	2
Productive cough	1/21 (4.8%)	1
Sore throat	3/21 (14.3%)	3
Skin and subcutaneous tissue disorders
Dry skin	8/21 (38.1%)	15
Nail loss	1/21 (4.8%)	1
Pruritus	1/21 (4.8%)	1
Rash acneiform	10/21 (47.6%)	16
Rash maculo-papular	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders - Unspecified	1/21 (4.8%)	1
Skin ulceration	1/21 (4.8%)	1
Vascular disorders
Hot flashes	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.