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A Phase I Dose Escalation Study of the mTOR Inhibitor Everolimus (RAD001) and Erlotinib Concurrently With Radiation Therapy in the Re-Irradiation Setting for Head and Neck Cancer

Phase 1
18 Years
Not Enrolling
Recurrent Metastatic Squamous Neck Cancer With Occult Primary, Recurrent Salivary Gland Cancer, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Larynx, Recurrent Verrucous Carcinoma of the Oral Cavity, Salivary Gland Squamous Cell Carcinoma, Tongue Cancer

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Trial Information

A Phase I Dose Escalation Study of the mTOR Inhibitor Everolimus (RAD001) and Erlotinib Concurrently With Radiation Therapy in the Re-Irradiation Setting for Head and Neck Cancer


I. To establish the maximum tolerated dose (MTD) and safety of RAD001 given concurrently
with external beam radiation therapy (EBRT) in the re-irradiation setting for head and neck


I. Obtain preliminary data on response rate. II. Determine progression-free survival at 6
and 12 months and overall survival.

III. Perform correlative studies to evaluate and characterize biological features of
recurrent or second primary tumors, as well as to follow surrogates of mammalian target of
rapamycin (mTOR), epidermal growth factor receptor (EGFR) and hypoxia-inducible factor
1-alpha (HIF-1α) inhibition.

OUTLINE: This is a dose-escalation study of everolimus and erlotinib hydrochloride.

Patients receive RAD001 orally (PO) and erlotinib hydrochloride PO once daily (QD).
Treatment continues for up to 2 years in the absence of disease progression or unacceptable
toxicity. Patients also undergo EBRT twice daily (BID) 5 days a week for 5 weeks.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- Recurrent aerodigestive cancers of squamous cell histology of the head and neck, or
those who have a second head and neck primary cancer, who have received prior
radiation therapy for a head and neck malignancy with curative intent

- Patients must locally advanced disease, without distant metastases; measurable
disease as per Response Evaluation Criteria In Solid Tumors (RECIST) is not required

- Patients who had surgery for recurrent disease or a second primary in a previously
radiated field are eligible if their surgical pathology specimen from the resection
exhibits high risk features such as positive margins or extracapsular extension

- Patient may have more than one recurrence as long as the current recurrence occurs at
least >= 6 months after the end of prior radiation therapy

- Only one prior course of radiotherapy to the head and neck region is allowed; prior
chemotherapy is allowed

- Based on prior radiation treatment records, most (> 50%) of the tumor volume must
have been in areas previously irradiated to >= 45 Gy without exceeding spinal cord
tolerance (combining previous and future radiation dose to the spinal cord of =< 50

- The previous total radiation dose must not have exceeded a maximum dose of 75 Gy

- Karnofsky Performance Status > 70 or Eastern Cooperative Oncology Group (ECOG)
Performance Status 0-1

- Patients must sign study-specific informed consent and Health Insurance Portability
and Accountability Act (HIPAA) forms

- Patient must be willing to have percutaneous endoscopic gastrostomy (PEG) placement
if necessary

- Patients must be able to swallow oral medications

- Patients and/or their partners of childbearing potential are required to use adequate
birth control during and for 6 months after completion of study therapy

- Leukocytes >= 3,000/ul

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x
institutional upper institutional limits

- OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels
above institutional normal

- Hemoglobin >= 9 g/dL

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L; AND fasting triglycerides
=< 2.5 x upper limit of normal (ULN); NOTE: In case one or both of these thresholds
are exceeded, the patient can only be included after initiation of appropriate lipid
lowering medication at any point prior to the initiation of therapy

- International normalized ratio (INR) =< 1.5; (anticoagulation is allowed if target
INR =< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight
[LMW] heparin for > 2 weeks at time of randomization)

Exclusion Criteria:

- Patient has history of using erlotinib or any other EGFR inhibitors (prior
C225/Cetuximab treatment is allowed if given with radiation therapy, but treatment
must have been completed at least 6 months prior to study entry)

- Patient has history of receiving RAD001 or any other mTOR inhibitors

- Patient is known to be allergic to any type of EGFR tyrosine kinase inhibitors or
mTOR inhibitors

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent; topical or inhaled corticosteroids are allowed

- As judged by the investigator, any evidence of severe or uncontrolled psychiatric or
systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or
renal disease); history of noncompliance to medical regimens

- Pregnant or breast-feeding women or adults of reproductive potential who are not
using effective birth control methods; adequate contraception must be used throughout
the trial and for 8 weeks after the last dose of study drug, by both sexes; (women of
childbearing potential must have a negative urine or serum pregnancy test within 7
days prior to administration of RAD001)

- Concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John's
Wort; these medications can be discontinued one week prior to enrollment if medically

- Treatment on any other clinical protocols or with a non-approved or investigational
drug within 4 weeks before Day 1 of study treatment

- Any evidence of clinically active interstitial lung disease (patients with chronic
stable radiographic changes who are asymptomatic need not be excluded)

- Known active connective tissue disorders, such as lupus or scleroderma which, in the
opinion of the treating physician, may put the patient at high risk for radiation

- Patients with known human immunodeficiency virus (HIV) infection and/or acquired
immune deficiency (AIDS)

- Patients with known multiple sclerosis

- Patients with nasopharyngeal carcinoma are excluded; other malignancies within the
past 3 years which actively require ongoing treatment except for treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period; close contact with those who have
received attenuated live vaccines should be avoided during treatment with RAD001;
examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction =< 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function as defined as spirometry and diffusion capacity
of carbon monoxide (DLCO) that is 50% of the normal predicted value and/or
oxygen (O2) saturation that is 88% or less at rest on room air

- Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis; Note: A detailed assessment of hepatitis B/C medical history and risk
factors must be done at screening for all patients; hepatitis B virus (HBV)
deoxyribonucleic acid (DNA) and hepatitis C virus (HCV) ribonucleic acid (RNA)
polymerase chain reaction (PCR) testing are required at screening for all
patients with a positive medical history based on risk factors and/or
confirmation of prior HBV/HCV infection

- Steroid or supplemental oxygen required for exacerbations of chronic obstructive
lung disease

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

- Current active smokers are excluded; these patients may be enrolled if they report
that they have refrained from smoking for a minimum of 7 days

- Patients with an active, bleeding diathesis

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of RAD001, erlotinib and radiotherapy in the re-irradiation setting

Outcome Description:

Establish the safety profile of this regimen and establish the MTD of RAD001 with/without erlotinib in conjunction with RT.

Outcome Time Frame:

During the period of radiation treatment or within the first 2 weeks after the completion of radiotherapy

Safety Issue:



United States: Institutional Review Board

Study ID:




Start Date:

April 2011

Completion Date:

May 2011

Related Keywords:

  • Recurrent Metastatic Squamous Neck Cancer With Occult Primary
  • Recurrent Salivary Gland Cancer
  • Recurrent Squamous Cell Carcinoma of the Hypopharynx
  • Recurrent Squamous Cell Carcinoma of the Larynx
  • Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Recurrent Squamous Cell Carcinoma of the Oropharynx
  • Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Verrucous Carcinoma of the Larynx
  • Recurrent Verrucous Carcinoma of the Oral Cavity
  • Salivary Gland Squamous Cell Carcinoma
  • Tongue Cancer
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms
  • Laryngeal Diseases
  • Tongue Neoplasms
  • Carcinoma, Verrucous
  • Neoplasms, Unknown Primary
  • Salivary Gland Neoplasms
  • Hypopharyngeal Neoplasms
  • Laryngeal Neoplasms
  • Paranasal Sinus Neoplasms
  • Oropharyngeal Neoplasms



Fox Chase Cancer Center Philadelphia, Pennsylvania  19111