Erlotinib, Celecoxib and Reirradiation for Recurrent Head and Neck Cancer
Study Details
Study Description
Brief Summary
There is no optimal treatment for patients with recurrent head and neck cancer after previous radiation. Chemotherapy alone is not curative and patients survive an average of only 6 to 10 months. Surgery is not always possible and often cannot remove every cancerous cell. On the other hand, reirradiation with chemotherapy cures approximately 25 to 30% of patients but has significant toxicity with as many as 15 to 20% suffering from life-threatening or fatal complications. Therefore, less toxic and more effective reirradiation regimens are urgently needed. There are extensive data from animal studies and preliminary human studies showing that blocking epidermal growth factor receptor (EGFR) and COX-2 enhances radiation effect and is more effective than either treatment alone. Erlotinib is a FDA approved oral inhibitor of EGFR and celecoxib is a FDA approved COX-2 inhibitor. Both have been well studied in humans and appear to have less severe toxicity than conventional chemotherapeutic agents.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Despite advances in the treatment of head and neck cancer, locoregional recurrences are the predominant site of treatment failure and are frequently the cause of death. Second primary tumors in the head and neck occur in up to 30% of patients at 10 years of follow-up after eradication of the original tumor due to field cancerization. The standard approach to patients with recurrent but non-metastatic disease has been surgical salvage alone. Unfortunately, this strategy is feasible in only a select group of patients and 5 year survival rates have ranged from 15-40%.
Most patients with previously irradiated unresectable recurrent or metastatic head and neck cancer are treated with chemotherapy alone. This approach has offered limited palliation with response rates of 10-40%, median survival of 5 to 10 months. While this may be an acceptable option for patients with clearly incurable widespread metastatic disease, it may not be the best approach for those patients with potentially curable locoregional disease.
While geographic misses and second primary tumors occur, the majority of patients have radioresistant tumors. Therefore, reirradiation alone is unlikely to be effective. High dose reirradiation with concomitant chemotherapy represents a more aggressive approach resulted in encouraging 3-year survival rates of 15 to 35%. This approach represents a potentially curative option for patients with unresectable or partially resected disease arising in a previously irradiated volume. However, the high rates of acute and late toxicity with this approach have limited widespread application of this approach.
Extensive preclinical and clinical data suggest that both epidermal growth factor receptor (EGFR) antagonists and cyclooxygenase-2 (COX-2) inhibitors enhance the effectiveness of ionizing radiation. In locally advanced head and neck cancer, a recent phase III trial concurrent anti-EGFR monoclonal antibody and radiation demonstrated improved local control, disease free survival and overall survival compared to radiation alone without the increased mucosal toxicity associated with concurrent chemotherapy. COX-2 inhibition and anti-EGFR therapy demonstrates activity against recurrent/metastatic head and neck cancer in a recent phase I study. Head and neck cancer represents an ideal site to study biologic markers of tumor response because of the accessibility of tumors for biopsy. Therefore, we propose the combination of Erlotinib and Celecoxib with radiation in a cohort of previously irradiation patients with head and neck cancer.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: erlotinib + celecoxib
|
Drug: erlotinib + celecoxib
In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Toxicity [30 DAYS]
Number of participants with acute and late toxicity
Secondary Outcome Measures
- Clinical Response [20 months]
Response to Concurrent Erlotinib, Celecoxib, and Reirradiation according to Response Evaluation Criteria in Solid Tumors - Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
- Locoregional Progression [20 months]
Patients with locoregional and/or distant progression
- Locoregional Control, Progression-free Survival, Overall Survival and Late Toxicity [1 year]
At a median follow-up of 11 months, the 1 year locoregional control, progression-free survival, and overall survival rates.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 18 years or older
-
Histologically or cytologically confirmed diagnosis of squamous cell or poorly differentiated carcinomas of the head and neck or lymphoepithelioma
-
Prior radiation to the head and neck, surgery or chemotherapy is allowed
-
Karnofsky performance status of >= 70%
-
Intact organ and bone marrow function
-
Obtained informed consent
Exclusion Criteria:
-
Demonstration of metastatic disease (i.e. M1 disease).
-
Incomplete healing from previous surgery
-
Pregnancy or breast feeding (men and women of child-bearing potential are eligible but must consent to using effective contraception during therapy and for at least 3 months after completing therapy)
-
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
-
Patients with clinically significant pulmonary dysfunction, cardiomyopathy, or any history of clinically significant CHF are excluded. The exclusion of patients with active coronary artery disease will be at the discretion of the attending physician.
-
Uncontrolled active infection unless curable with treatment of their cancer.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mount Sinai School of Medicine | New York | New York | United States | 10029 |
Sponsors and Collaborators
- Johnny Kao
Investigators
- Principal Investigator: Johnny Kao, M.D., Icahn School of Medicine at Mount Sinai
Study Documents (Full-Text)
None provided.More Information
Publications
- J. Kao, S. H. Packer, M. Teng, V. Gupta, K. Misiukiewicz, E. M. Genden; Mount Sinai School of Medicine, New York, NY, J Clin Oncol 28:15s, 2010 (suppl; abstr 5561).
- Kao J, Garofalo MC, Milano MT, Chmura SJ, Citron JR, Haraf DJ. Reirradiation of recurrent and second primary head and neck malignancies: a comprehensive review. Cancer Treat Rev. 2003 Feb;29(1):21-30. Review.
- Salama JK, Vokes EE, Chmura SJ, Milano MT, Kao J, Stenson KM, Witt ME, Haraf DJ. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):382-91. Epub 2005 Oct 5.
- GCO 06-0509
Study Results
Participant Flow
| Recruitment Details | All patients were evaluated by head and neck surgery, medical oncology, and radiation oncology before trial entry. Patients were enrolled at least 6 months after they had completed prior radiation. Patients were enrolled between March 2007 and December 2009. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Erlotinib + Celecoxib |
|---|---|
| Arm/Group Description | erlotinib + celecoxib: In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression |
| Period Title: Overall Study | |
| STARTED | 15 |
| COMPLETED | 14 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | Erlotinib + Celecoxib |
|---|---|
| Arm/Group Description | erlotinib + celecoxib: In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression |
| Overall Participants | 14 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
64
|
| Sex: Female, Male (Count of Participants) | |
| Female |
3
21.4%
|
| Male |
11
78.6%
|
| 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 |
2
14.3%
|
| White |
10
71.4%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
2
14.3%
|
| ECOG Performance Status (participants) [Number] | |
| 0 |
0
0%
|
| 1 |
5
35.7%
|
| 2 |
9
64.3%
|
| Tobacco use, pack-years (participants) [Number] | |
| None to minimal |
2
14.3%
|
| <20 |
6
42.9%
|
| 20-40 |
3
21.4%
|
| >40 |
2
14.3%
|
| Unknown |
1
7.1%
|
| Recurrent vs secondary primary (participants) [Number] | |
| Primary recurrence |
7
50%
|
| Second or later recurrence |
4
28.6%
|
| Second primary cancer |
3
21.4%
|
| Histology (participants) [Number] | |
| Squamous cell carcinoma |
13
92.9%
|
| Adenoid cystic |
1
7.1%
|
| Primary Site (participants) [Number] | |
| Sinonasal |
3
21.4%
|
| Ear/facial skin |
2
14.3%
|
| Oropharynx |
3
21.4%
|
| Oral cavity |
1
7.1%
|
| Hypopharynx |
4
28.6%
|
| Larynx |
1
7.1%
|
| Primary tumor classification (participants) [Number] | |
| Tx-T3 |
4
28.6%
|
| T4 |
10
71.4%
|
| Lymph node status (participants) [Number] | |
| N0 |
3
21.4%
|
| N1 |
11
78.6%
|
Outcome Measures
| Title | Toxicity |
|---|---|
| Description | Number of participants with acute and late toxicity |
| Time Frame | 30 DAYS |
Outcome Measure Data
| Analysis Population Description |
|---|
| Erlotinib and celecoxib were administered orally |
| Arm/Group Title | Celecoxib 200mg | Celecoxib 400mg | Celecoxib 600mg |
|---|---|---|---|
| Arm/Group Description | Dose Level 1: Patients administered 150mg Erlotinib daily and 200mg Celecoxib twice daily | Dose Level 2: Patients administered 150mg Erlotinib daily and 400mg Celecoxib twice daily | Dose Level 3: Patients administered 150mg Erlotinib daily and 600mg Celecoxib twice daily |
| Measure Participants | 3 | 8 | 3 |
| Number [participants] |
0
0%
|
1
NaN
|
2
NaN
|
| Title | Clinical Response |
|---|---|
| Description | Response to Concurrent Erlotinib, Celecoxib, and Reirradiation according to Response Evaluation Criteria in Solid Tumors - Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions |
| Time Frame | 20 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib + Celecoxib |
|---|---|
| Arm/Group Description | erlotinib + celecoxib: In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression |
| Measure Participants | 14 |
| Complete Response(CR) |
6
42.9%
|
| Pathologic partial response (pPR) |
1
7.1%
|
| Progressive disease (PD) |
5
35.7%
|
| No evidence of disease (NED) |
2
14.3%
|
| Title | Locoregional Progression |
|---|---|
| Description | Patients with locoregional and/or distant progression |
| Time Frame | 20 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib + Celecoxib |
|---|---|
| Arm/Group Description | erlotinib + celecoxib: In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression |
| Measure Participants | 14 |
| free of disease |
4
28.6%
|
| isolated locoregional progression |
4
28.6%
|
| isolated distant progression |
2
14.3%
|
| both locoregional and distant progression |
1
7.1%
|
| no evidence of disease, died of comorbid illness |
3
21.4%
|
| Title | Locoregional Control, Progression-free Survival, Overall Survival and Late Toxicity |
|---|---|
| Description | At a median follow-up of 11 months, the 1 year locoregional control, progression-free survival, and overall survival rates. |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib + Celecoxib |
|---|---|
| Arm/Group Description | Recommended dose of celecoxib was 400mg |
| Measure Participants | 15 |
| locoregional control |
60
428.6%
|
| progress-free survival |
37
264.3%
|
| overall survival rates |
55
392.9%
|
| long term toxicity |
0
0%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Erlotinib + Celecoxib | |
| Arm/Group Description | erlotinib + celecoxib: In this phase I/II study, patients will be treated with daily erlotinib 150 mg and twice-daily celecoxib 200 to 600 mg for 14 days. Re-irradiation with IMRT will start on day 15 and will continue for 5.5 to 6.5 weeks along with erlotinib and celecoxib. After completion of radiation, patients will be given the option of continuing on erlotinib for 2 years or until unacceptable toxicity or disease progression | |
All Cause Mortality |
||
| Erlotinib + Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Erlotinib + Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/14 (100%) | |
| Gastrointestinal disorders | ||
| pharyngocutaneous fistula | 1/14 (7.1%) | 1 |
| rectal bleeding | 1/14 (7.1%) | 1 |
| mucositis | 3/14 (21.4%) | |
| General disorders | ||
| nausea | 1/14 (7.1%) | 1 |
| Pain | 3/14 (21.4%) | |
| Fatigue | 2/14 (14.3%) | |
| Metabolism and nutrition disorders | ||
| Metabolic (Na, K, Ca) | 1/14 (7.1%) | |
| Musculoskeletal and connective tissue disorders | ||
| bone necrosis | 1/14 (7.1%) | 1 |
| trismus | 1/14 (7.1%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| folliculitis | 1/14 (7.1%) | 1 |
| Dermatitis | 1/14 (7.1%) | |
| Acneiform Rash | 1/14 (7.1%) | |
Other (Not Including Serious) Adverse Events |
||
| Erlotinib + Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/14 (100%) | |
| Blood and lymphatic system disorders | ||
| abnormal white blood cell count | 5/14 (35.7%) | |
| abnormal hemoglobin count | 12/14 (85.7%) | |
| Eye disorders | ||
| Dry eye | 1/14 (7.1%) | |
| Conjuncitivitis | 1/14 (7.1%) | |
| Gastrointestinal disorders | ||
| Mucositis | 10/14 (71.4%) | |
| Diarrhea | 1/14 (7.1%) | |
| Rectal bleeding | 1/14 (7.1%) | |
| General disorders | ||
| Pain | 11/14 (78.6%) | |
| Xerostomia | 5/14 (35.7%) | |
| Fatigue | 3/14 (21.4%) | |
| Nausea | 1/14 (7.1%) | |
| Hepatobiliary disorders | ||
| Elevated Liver Function Tests | 3/14 (21.4%) | |
| Metabolism and nutrition disorders | ||
| Metabolic (Na, K, Ca) | 4/14 (28.6%) | |
| Skin and subcutaneous tissue disorders | ||
| Dermatitis | 12/14 (85.7%) | |
| Acneiform rash | 12/14 (85.7%) | |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Dr. Johnny Kao |
|---|---|
| Organization | Florida Radiation Oncology Group |
| Phone | 813-661-6442 |
| johnnykaomd@gmail.com |
- GCO 06-0509