Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Comparing Sequential Therapy With TPF/Chemoradiation (ST) To Cisplatinum-Based Chemoradiotherapy [PARADIGM TRIAL]
Brief Summary: RATIONALE: Drugs used in chemotherapy, such as docetaxel, cisplatin, fluorouracil, and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. It is not yet known which regimen of chemotherapy and radiation therapy is most effective in treating head and neck cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different regimens of chemotherapy and radiation therapy in treating patients who have stage III or stage IV head and neck cancer.


Options:
A: List of Inclusion Criteria:

* Histologically or cytologically confirmed squamous cell carcinoma of the head and neck

  * Stage III or IV\* disease
  * One of the following primary tumor sites:

    * Oral cavity

      * No mandible invasion
    * Oropharynx
    * Hypopharynx
    * Larynx
  * The following primary tumor sites are excluded:

    * Nasal cavity
    * Paranasal cavity
    * Nasopharynx NOTE: \*No evidence of distant metastases by chest x-ray, abdominal ultrasound, or CT scan (for patients with liver function test abnormalities) or bone scan (for patients with local symptoms)
* At least 1 uni- or bi-dimensionally measurable lesion

PATIENT CHARACTERISTICS:

Age

* Over 18

Performance status

* WHO 0-1

Life expectancy

* Not specified

Hematopoietic

* Neutrophil count \> 1,500/mm\^3
* Platelet count \> 100,000/mm\^3
* Hemoglobin \> 10 g/dL

Hepatic

* Bilirubin normal
* AST or ALT within eligibility range
* Alkaline phosphatase within eligibility range

Renal

* Creatinine clearance \> 60 mL/min

Cardiovascular

* No unstable cardiac disease despite treatment
* No myocardial infarction within the past 6 months

Pulmonary

* No chronic obstructive pulmonary disease, defined as requiring hospitalization for pneumonia or respiratory decompensation within the past year

  * Obstruction caused by the tumor allowed

Neurologic

* No symptomatic peripheral neuropathy \> grade 2
* No symptomatic altered hearing \> grade 2
* No history of significant neurologic or psychiatric disorders, including dementia or seizures

Other

* No active drug addiction, including alcohol, cocaine, or intravenous drugs within the past 6 months
* No other malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or other cancer curatively treated by surgery alone
* No active, clinically significant, uncontrolled infection
* No autoimmune disease requiring therapy
* No unhealed or clinically active peptic ulcer disease
* No hypercalcemia
* No other serious illness or medical condition
* No involuntary weight loss \> 25% of body weight within the past 2 months
* HIV negative
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for at least 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Not specified

Chemotherapy

* No prior chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* No prior radiotherapy

Surgery

* No prior organ transplantation
* No prior surgery for this cancer

  * Biopsy allowed

Other

* More than 30 days since prior participation in another investigational study
* No other concurrent anticancer therapy
B: Inclusion Criteria:

* Treatment naïve stage III (hypopharynx, or nasopharynx primary) or stage IVa/IVb (all sites) histologically proven SCCHN with no definitive evidence of metastatic disease
* Patients with unknown primary site of tumor and histologically proven squamous cell carcinoma of a cervical lymph node felt to arise from a site in the head and neck are eligible
* Patients must have at least one measurable site of disease according to RECIST criteria
* Age ≥ 18 years
* Karnofsky performance status \> 70%
* Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb \>9 g/dL
* Adequate liver function as shown by:
* Serum bilirubin ≤ 1.5 x ULN
* ALT and AST ≤ 2.5x ULN
* INR and PTT ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for \>2 weeks at time of randomization.)
* Adequate renal function: serum creatinine ≤ 1.5 x ULN
* Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x 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.
* Signed informed consent

Exclusion Criteria:

* Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
* Patients, who have had a major surgery \[defined as requiring general anesthesia but not including tonsillectomy, neck dissection, or panendoscopy (triple endoscopy or examination under general anesthesia)\], 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; or patients that may require major surgery during the course of the study
* Prior treatment with any investigational drug within the preceding 4 weeks
* Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
* Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
* Unequivocal demonstration of metastatic disease (i.e. M1 disease).
* Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
* 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 IV
* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 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 DLCO that is 50% of the normal predicted value and/or 02 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
* A known history of HIV seropositivity
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
* Nota bene: subjects that require administration of everolimus through a feeding tube are allowed to participate
* Patients with an active, bleeding diathesis
* Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus)
* Patients who have received prior treatment with an mTOR inhibitor for SCCHN (sirolimus, temsirolimus, everolimus).
* Patients with a known hypersensitivity to everolimus (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
* Patients with a know hypersensitivity to cetuximab, cremaphor, paclitaxel, carboplatin, 5FU, hydroxyurea, or any compounds of similar chemical or biologic composition
* History of noncompliance to medical regimens
* Patients unwilling to or unable to comply with the protocol
* Baseline neurologic deficit (\> grade II neuropathy)
* Prior severe infusion reaction (grade 4) to a monoclonal antibody
C: Inclusion Criteria:

1. Histologically or cytologically proven squamous cell carcinoma of the head and neck.
2. Primary tumor sites eligible : oral cavity, oropharynx, hypopharynx Although they are admittedly of squamous cell types, the following tumors will be excluded because of them responsiveness to chemotherapy: tumors of the nasal and paranasal cavities and of the nasopharynx.
3. Stage 3 or 4 disease without evidence of distant metastases verified by chest X Ray, abdominal ultrasound, or CT (liver function test abnormalities); bone scan in case of local symptoms.
4. At least one uni or bidimensionally measurable lesion.
5. Tumor considered inoperable after evaluation by a multidisciplinary team (i.e. a surgeon, a medical oncologist and a radiation oncologist). Criteria for inoperability are:

   1. technical unresectability: tumor fixation/invasion to base of the skull or cervical vertebrae, involvement of the nasopharynx, and fixed lymph nodes.
   2. Physician decision based on low surgical curability. This category will include the following:

   i) All T3-4 stages. ii) All N2-3 stages excluding T1 N2. iii) Patients for organ preservation. Reason for inoperability will be recorded in the CRF.
6. No previous chemotherapy or radiotherapy for any reason and no previous surgery for SCCHN (other than biopsy) are allowed at time of study entry.
7. Age \> 18 years.
8. Karnofsky performance status \> 70. (ECOG 0-1) (Appendix II)
9. No active alcohol addiction.
10. Life expectancy \> 6 months.
11. Signed informed consent prior to beginning protocol specific procedures.
12. Adequate bone marrow, hepatic and renal functions as evidenced by the following:

    a) Hematology (Bone marrow): i) Neutrophils \> 2.0 109/L ii) Platelets \> 100 x 109/L iii) Hemoglobin \> 10 g/dL b) Hepatic function i) Total bilirubin \< 1 x UNL ii) ASAT (SGOT) and ALAT (SGPT) \< 2.5 x ULN iii) Alkaline phosphatase \< 5 x ULN Patients with ASAT or ALAT \> 1.5 x ULN associated with alkaline phosphatase \> 2.5 x ULN are not eligible for the study.

    c) Renal function : serum creatinine \< 1 x UNL. In case of borderline value the creatinine clearance \> 60 ml/min (calculated by the Cockcroft-Gault method as follows :
13. Patients must be available for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating center.

    -

Exclusion Criteria:

1. Pregnant or lactating women or women of childbearing potential not using adequate contraception.
2. Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin, or other cancer curatively treated by surgery and with no evidence of disease for at least 5 years. Any prior treatment with radiotherapy or chemotherapy is an exclusion criterion.
3. Symptomatic peripheral neuropathy \> grade 2 by NCIC-CTG criteria
4. Symptomatic altered hearing \> grade 2 by NCIC-CTG criteria.
5. Other serious illnesses or medical conditions including:

   1. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry.
   2. History of significant neurologic or psychiatric disorders including dementia or seizures.
   3. Active uncontrolled infection.
   4. Active peptic ulcer.
   5. Hypercalcemia.
   6. Chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry
6. History of hypersensitivity reaction to polysorbate 80 (Appendix IV)
7. Patients requiring intravenous alimentation.
8. Patients who experienced a weight loss of more than 20% of their body weight in the 3 months preceding study entry.
9. Concomitant treatment with any other anticancer therapy.
10. Participation in a therapeutic clinical trial within 30 days of study entry
D: Inclusion Criteria:

1. Histological proven, resectable squamous epithelial carcinoma of the oropharynx and the cavity of the mouth
2. R0-resection possible
3. All T N2 M0 / all T N3 M0 / if T3 or T4a also N0-1 M0
4. Leucocytes \> 4000/mm³ bzw. neutrophils \> 2000/mm³, thrombocytes \> 100000/mm³
5. adequate kidney function, defined as serum creatinine und urea in normal range, Creatinine clearance \> 60 ml/min
6. adequate liver function with glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT) and bilirubin in normal range
7. electrolytes in normal range
8. risks of anesthesia complications normal or minor increased
9. Eastern Cooperative Oncology Group (ECOG) 0-2 / Karnofsky \>= 60%
10. Age 18 - 80 years
11. signed written informed consent
12. effective contraception for both male and female subjects if the risk of conception exists

    Exclusion Criteria:
13. T1 N0 M0 / T1 N1 M0 / T2 N0 M0 / T2 N1 M0
14. Resection without curative intention: primary tumor is not treatable with resection methods
15. Infiltration of the lower jaw
16. M1 status
17. Tumor not measurable with Innovation Center Computer Assisted Surgery (ICCAS) methods
18. No prior chemotherapy or radiation (a primary surgery is allowed)
19. Metachronous or oder synchronous malignoma (Exception: basal cell carcinoma)
20. Life expectance \< 3 months
21. ECOG \> 2; Karnofsky \< 60%
22. acute infections or fever
23. known HIV-infection or other immune suppression
24. severe cardio pulmonary concomitant diseases
25. chronic disease with continuous therapy (uncontrolled diabetes, rheumatoid arthritis) especially continuous therapy with steroids
26. other concomitant diseases which, in the investigator's opinion, would exclude the patient from the study
27. Contraindications which permit a therapy with Docetaxel, Cisplatin, 5-FU or radiation therapy
28. missing patient's compliance
29. regular Follow-up visits not possible
30. Pregnancy or lactation period
31. legal incapacity or limited legal capacity
32. Participation in another clinical trial or administration of a not approved substance within 30 days before registration

Answer: A