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Title A Phase II, Randomized, Double Blind, Placebo-Controlled study of Lapatinib (TYKERB) for Non-HPV Locally Advanced Head and Neck Cancer wtih Concurrent ChemoRadiation

IRB RTOG3501

CC 121202C

Hospital Main Campus

Phase Phase 2

Disease Head and Neck

Drug Lapatinib

Description

1. To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient population sufficiently improves progression-free survival (PFS) to warrant a Phase III trial

1. To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient population improves overall survival (OS);
2. To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient population improves control of distant metastasis;
3. To evaluate toxicity and tolerability between treatment arms;
4. To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient population improves local regional control;
5. To investigate quality of life and patient-reported outcomes between treatment arms;
6. To explore HER2 expression, amplification and heterodimerization, EGFR ligand expression, EGFR polymorphisms, hypoxia, and EMT characteristics as biomarkers of lapatinib response, sensitivity, and resistance, PFS, and metastasis.

Inclusion Criteria

1. Pathologically (histologically or cytologically) proven diagnosis (from primary lesion and/or lymph nodes) diagnosis of squamous cell carcinoma of the oropharynx, hypopharynx, or larynx;
2. For patients with an oropharynx primary, the tumor must be negative for p16 by immunohistochemistry;
3. Selected stage III or IV disease (T2 N2-3 M0 or T3-4 any N M0, T1 N2b, N2c, or N3 p16 negative oropharynx cancer, or T1-2 any N hypopharynx cancer), including no distant metastases, based upon the following minimum diagnostic workup:
   • History/physical examination within 28 calendar days prior to registration, including an examination by a Medical Oncologist and Radiation Oncologist and documentation of the patient's weight;
   • Examination by an ENT or Head & Neck Surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 42 days prior to registration;
   • Chest CT scan, or PET/CT scan within 42 calendar days prior to registration to rule out metastatic disease;
   • Contrast enhanced CT scan or MRI, or PET/CT scan of the tumor site and neck nodes within 42 calendar days prior to registration;
   • EKG and ECHO or MUGA scan within 84 calendar days prior to registration;
4. Zubrod Performance Status 0-1 within 14 calendar days prior to registration;
5. Age ≥ 18
6. CBC/differential obtained within 14 calendar days prior to registration, with adequate bone marrow function defined as follows:
   • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm³;
   • Platelets ≥ 100,000 cells/mm³;
   • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.);
7. Adequate renal and hepatic function within 14 calendar days prior to registration, defined as follows:
   • Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min within 14 calendar days prior to registration, determined by 24-hour collection or estimated by Cockcroft-Gault formula
   • CCr male = [(140 - age) x (wt in kg)][(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)
   • Total bilirubin < 2 x the institutional ULN;
   • AST or ALT ≤ 3 x the institutional ULN;
8. Magnesium, calcium, glucose, potassium, and sodium within 14 calendar days prior to registration, with the following required parameters:
   • Magnesium: > 0.9 mg/dl or < 3 mg/dl;
   • Calcium: > 7 mg/dl or < 12.5 mg/dl;
   • Glucose: > 40 mg/dl or < 250 mg/dl;
   • Potassium: > 3 mmol/L or lt; 6 mmol/L;
   • Sodium: > 130 mmol/L or < 155 mmol/L.
9. Negative serum pregnancy test within 14 calendar days prior to registration for women of childbearing potential;
10. Women of childbearing potential and men who are sexually active must practice adequate contraception during treatment and for at least 60 calendar days following treatment.
11. Patients must be deemed able to comply with the treatment plan and follow-up schedule.
12. Patients must provide study specific informed consent prior to study entry, including, for oropharyngeal cancer patients, consent for mandatory submission of tissue for required, central p16 review.

Exclusion Criteria

1. Patients with T1N1 or T1N2a oropharynx cancer or T1N1, T1N2a or T2 N1 non-hypopharynx tumors;
2. Patients with simultaneous primaries or bilateral tumors;
3. Gross total excision (e.g., by tonsillectomy) of the primary tumor; however, partial removal of the tumor to alleviate an impending airway obstruction does not make the patient ineligible.
4. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; noninvasive cancers (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) are permitted even if diagnosed and treated < 3 years ago;
5. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable;
6. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
7. Primary site of tumor of oral cavity, nasopharynx, sinuses, or salivary glands;
8. Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal sampling of neck disease; radical or modified neck dissection is not permitted.
9. Prior allergic reaction to the study drugs;
10. Prior therapy that specifically and directly targets the EGFR/HER2 pathway;
11. Patients who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment);
12. Pregnant women or women of childbearing potential and men who are sexually active and not willing or able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
13. Severe, active co-morbidity, defined as follows:
    1. Uncontrolled cardiac disease, such as uncontrolled hypertension or unstable angina;
    2. Transmural myocardial infarction within the last 6 months;
    3. History of congestive heart failure and/or history of left ventricular ejection fraction < 50%;
    4. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
    5. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 calendar days prior to registration;
    6. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
    7. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.