Clinical trial NCT00573989: Intensity-Modulated Radiation Therapy, Pemetrexed, and Erlotinib in Treating Patients With Recurrent or Second Primary Head and Neck Cancer
Official title: Phase I/II Clinical Trial of Combined Pre-Irradiation With Pemetrexed and Erlotinib Followed by Maintenance Erlotinib for Recurrent and Second Primary Squamous Cell Carcinoma of the Head and Neck
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Head and Neck Cancer
Keywords: recurrent squamous cell carcinoma of the hypopharynx
recurrent squamous cell carcinoma of the larynx
recurrent verrucous carcinoma of the larynx
recurrent squamous cell carcinoma of the lip and oral cavity
recurrent verrucous carcinoma of the oral cavity
metastatic squamous neck cancer with occult primary squamous cell carcinoma
recurrent metastatic squamous neck cancer with occult primary
recurrent squamous cell carcinoma of the oropharynx
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-12-14
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as pemetrexed and erlotinib, may make tumor cells more sensitive to radiation therapy. Erlotinib and pemetrexed may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving intensity-modulated radiation therapy together with pemetrexed and erlotinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with intensity-modulated radiation therapy and pemetrexed and to see how well they work in treating patients with recurrent or second primary head and neck cancer.

Detailed description: OBJECTIVES:

Primary

* Evaluate the acute toxicity and feasibility of intensity modulated radiotherapy (IMRT) in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in patients with recurrent or second primary squamous cell carcinoma of the head and neck. (Phase I)
* Determine the maximum tolerated dose and recommended phase II dose of erlotinib hydrochloride in these patients. (Phase I)
* Determine progression-free survival (PFS) at 1 year in these patients. (Phase II)

Secondary

* Determine median PFS, median overall survival (OS), and OS at 1 and 2 years in these patients.
* Determine objective tumor response as measured by CT scan or MRI in these patients.
* Evaluate the acute and chronic toxicity of IMRT in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in these patients.
* Evaluate the impact of treatment on quality of life as measured by FACT-H\&N, PSS-HN, MD Anderson Dysphagia Inventory (MDADI), and swallowing by direct functional measurements at different time points.
* Evaluate the level of phosphorylation of different tyrosine residues within the cytoplasmic domain of EGFR, bound adaptors, as well as markers of downstream pathways activation by nano LC-MS/MS in tumor tissue and correlate with levels of P-AKT and P-ERK by immunohistochemistry and with response to treatment.
* Measure the levels of TS and p53 and correlate with treatment response.

OUTLINE: This is a phase I, dose-escalation study of erlotinib hydrochloride followed by a phase II study.

* Phase I: Patients undergo intensity modulated radiotherapy (IMRT) once daily, 5 days a week, for 6 weeks. Patients receive pemetrexed disodium IV over 10 minutes on day 1 of radiotherapy. Treatment with pemetrexed disodium repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral erlotinib hydrochloride once daily beginning on day 1 of radiotherapy and continuing for up to 2 years in the absence of disease progression or unacceptable toxicity.
* Phase II: Patients undergo IMRT and receive pemetrexed sodium as in phase I. Patients also receive erlotinib hydrochloride at the maximum tolerated dose determined in phase I.

Quality of life is assessed at baseline, weekly during treatment, at 1, 6, and 12 months, and then annually thereafter.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Eligibility criteria: Inclusion:

\* Histologically or cytologically confirmed diagnosis of recurrent or second primary squamous cell carcinoma (SCC) of the head and neck, including any of the following:

* Oral cavity
* Oropharynx
* Hypopharynx
* Larynx
* Recurrent neck metastases with unknown primary

Exception from pathology confirmation of tumor recurrence is accepted for patients who originally had pathologically confirmed SCC of the Head and Neck, the new tumor is located in the head and neck area and it is clinically considered as a recurrence of the original tumor, and a tumor biopsy is technically difficult and would expose the patient to unjustified risk. The treating physicians should agree and document the clinical definition of tumor recurrence and should document the increased risk for biopsy.

* Measurable disease by CT scan or MRI OR evaluable disease
* No definitive evidence of distant metastasis
* Unresectable disease by a preliminary ENT evaluation OR refused surgery
* Patients may have received chemotherapy as a component of their primary tumor treatment but not for recurrent or metastatic disease. No prior treatment with systemic anti-EGFR inhibitors or Pemetrexed is permitted
* Has undergone prior head and neck radiotherapy (for SCC of the head and neck) to a dose of ≤ 72 Gy that involved most of the recurrent tumor (\> 75%) OR has a second primary tumor volume in areas previously irradiated to \> 45 Gy
* The entire tumor volume must be included in a treatment field that limits the total spinal cord dose to 54 Gy (prior plus planned dose)
* Must have disease recurrence or persistence for ≥ 6 months after completion of prior radiotherapy
* ECOG performance status 0-1
* Age ≥ 18 years
* ANC \> 1,500/µL
* Platelet count \> 100,000/µL
* Total bilirubin \< 1.5 times upper limit of normal (ULN)
* AST/ALT \< 2 times ULN
* Creatinine \< 1.5 times ULN
* Willing and able to take folic acid and vitamin B12 supplementation
* Recovered from prior surgery, chemotherapy, or radiotherapy
* At least 6 months since prior radiotherapy
* At least 5 days since prior aspirin or other non-steroidal anti-inflammatory agents (8 days for long acting agents \[e.g., piroxicam\])
* Fertile patients must use effective contraception

Exclusion:

* Nasopharyngeal carcinoma
* Concurrent uncontrolled illness, including, but not limited to, any of the following:

  * Ongoing or active infection
  * Psychiatric illness or social situation that would limit compliance with study requirements
  * Significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension; unstable angina; recent myocardial infarction \[within the past 3 months\]; uncontrolled congestive heart failure; or cardiomyopathy with decreased ejection fraction)
* Active interstitial lung disease
* Presence of third space fluid that cannot be controlled by drainage
* Other concurrent investigational agents
* Pregnant or nursing
* HIV positive

Primary outcomes:
measure: Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I)
timeFrame: 56 Days
measure: Progression-free Survival (PFS) at 1 Year (Phase II)
timeFrame: 1 year
Secondary outcomes:
measure: Median Progression Free Survival
timeFrame: 2 years
measure: Median Overall Survival
timeFrame: up to 5 years
measure: Overall Survival
timeFrame: 1 and 2 years
measure: Evaluation of Acute and Chronic Toxicity
timeFrame: 1 year
measure: Change in Quality of Life- FACT H&N
timeFrame: baseline and 12 months
measure: Change in Quality of Life: PSS-HN
timeFrame: baseline and 6 months
measure: Change in Quality of Life: MDADI
timeFrame: baseline and 12 months
measure: Evaluation of Biomarkers
timeFrame: throughout study completion, up to 2 years
measure: Objective Tumor Response
timeFrame: 1 year
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: UNC Linberger Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Mercedes Porosnicu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Health Sciences
name: Kathryn M. Greven, MD
role: PRINCIPAL_INVESTIGATOR
References: