Please select the eligibility criteria that correspond to the clinical trial below.
Title: Selection of Chemoradiotherapy Based on Response to Induction Chemotherapy - a Phase II Study in Locally Advanced Squamous Cell Carcinoma of Head and Neck
Brief Summary: Primary

Compare response rates (relative change in tumor size) to induction chemotherapy consisting of cisplatin/paclitaxel/cetuximab +/- everolimus.

Secondary:

Determine the maximum administered dose (MAD), maximum tolerated dose (MTD), dose limiting toxicity (DLT), and safety of everolimus with cisplatin/paclitaxel/cetuximab induction chemotherapy (phase I portion)


Options:
A: DISEASE CHARACTERISTICS: Histologically or cytologically proven locally advanced squamous cell carcinoma of the head and neck Stage III or IV without distant metastases Unresectable Primary tumor sites: Oral cavity Oropharynx Hypopharynx Larynx Must have at least one measurable lesion

PATIENT CHARACTERISTICS: Age: 18 to 70 Performance status: WHO 0-1 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 2,000/mm3 Platelet count at least 100,000/mm3 Hemoglobin at least 10 g/dL Hepatic: Bilirubin no greater than upper limit of normal (ULN) SGOT and SGPT no greater than 2.5 times ULN Alkaline phosphatase no greater than 5 times ULN No SGOT and SGPT greater than 1.5 times ULN AND alkaline phosphatase greater than 2.5 times ULN Renal: Creatinine no greater than 1.4 mg/dL OR Creatinine clearance at least 60 mL/min Cardiovascular: At least 6 months since prior myocardial infarction No unstable, treated cardiac disease Pulmonary: At least one year since prior hospitalization for chronic obstructive pulmonary disease Neurologic: No neurologic or psychiatric disorders (e.g., dementia or seizures) No concurrent peripheral neuropathy greater than grade 1 Other: No active uncontrolled infection No active peptic ulcer No alteration in hearing At least 5 years since any other neoplastic disease except curatively treated basal or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer curatively treated by surgery Not pregnant or nursing Fertile patients must use effective contraception No other psychological, familial, sociological, or geographical condition that would prevent compliance

PRIOR CONCURRENT THERAPY: Biologic therapy: No primary prophylactic colony stimulating factors during the first course of therapy Chemotherapy: No prior or concurrent chemotherapy Endocrine therapy: At least 3 weeks since prior corticosteroid No chronic corticosteroid therapy (greater than 3 months) Radiotherapy: No prior radiotherapy Surgery: No prior surgery for this cancer Other: At least 30 days since prior treatment in a clinical trial No concurrent use of drugs that interact with fluorouracil (e.g., cimetidine, allopurinol, folic acid or leucovorin calcium) No other concurrent investigational drugs or anticancer treatment
B: Inclusion criteria:

* Tumor type: Histologically or cytologically proven squamous cell carcinoma of the head and neck (SCCHN) presenting with locally advanced disease at diagnosis. Primary tumor sites eligible are: oral cavity, oropharynx, hypopharynx and larynx.
* Extent of the disease:

  * Patients are required to have at least one measurable lesion.
  * Stage III or IV without evidence of distant metastases, according to the TNM staging system. Absence of metastases must be checked by chest X-ray (with or without Computed tomography (CT) ), abdominal ultrasound or CT in case of liver function test abnormalities, and bone scan in case of local symptoms.
  * Tumor considered as inoperable after evaluation by a multidisciplinary team. Reason for inoperability will be reported in the CRF
* World Health Organization (WHO) performance status 0 or 1
* Laboratory data:

  * Haematology:
* Neutrophil count \> or = 2.0\*10\^9/L
* Platelet count \> or = 100\*10\^9/L
* Hemoglobin \> or = 10 g/dl (6.2 mmol/L)

  * Hepatic function:
* Total serum bilirubin \< or = 1 time the upper normal limit (UNL) of the participating center
* Aspartate transaminase (ASAT/SGOT) and Alanine transaminase (ALAT/SGPT) \< or = 2.5UNL
* Alkaline phosphatase \< or = 5 UNL
* Patients with ASAT or ALAT \> 1.5UNL associated with alkaline phosphatase \>2.5UNL are not eligible for the study

  * Renal function:
* serum creatinine \< or = 120µmol/L (1.4 mg/dl) if values are \>120µmol/L, creatinine clearance should be \> or = 60 ml/min
* Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, those conditions should be discussed with the patient before registration in the trial
* Patients informed consent form obtained

Exclusion criteria:

* Tumors of the nasopharynx, the nasal and paranasal cavities.
* Previous chemotherapy or radiotherapy for any reason and previous surgery for SCCHN at time of study entry.
* Prior treatment within a therapeutic clinical tria within 30 days prior to study entry
* Concurrent treatment with any other anticancer therapy
* Chronic treatment (\> or = 3 months) with corticosteroids at a daily dose \> or = 20mg methylprednisolone or equivalent.
* Concomitant use of drugs which could interact with 5-fluorouracil (e.g. cimetidine, allopurinol, folic or folinic acid, methotrexate and metronidazole)
* 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
* Symptomatic peripheral neuropathy \> or = grade 2 by NCIC-CTG criteria
* Clinical altered hearing
* Pregnant, lactating women or of childbearing potential unless adequate
* with other serious illness or medical condition including but not limited to:

  * unstable cardiac disease despite treatment
  * myocardial infarction within 6 months prior to study entry
  * history of significant neurologic or psychiatric disorders including dementia or seizures
  * active uncontrolled infection
  * active peptic ulcer
  * chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
C: Inclusion Criteria:

1. Recurrent and/or metastatic head and neck squamous cell carcinoma not amenable to curative treatment with surgery and/or chemotherapy and/or radiation.
2. At least one measurable lesion by MRI or CT-scan according to RECIST 1.1.
3. Progressive disease within 1 year after first line platinum-based chemotherapy given either as a part of the multimodal curative treatment or in the palliative setting.
4. ECOG performance status 0 -2, in stable medical condition
5. Patients must have an expected survival of at least 3 months
6. Paraffin-embedded tumor tissue available for immunohistochemistry but not mandatory
7. Patients must be over 18 years old and must be able to give written informed consent.
8. Women of child-bearing age or sexually active female patients with reproductive potential must have a negative pregnancy test (serum or urine within the 7 days prior to enrollment).
9. Patients must have adequate organ function (Hemoglobin ≥ 9 g/100 ml, Neutrophils ≥ 1,500/mm3, Platelets ≥ 100,000/mm3, total bilirubin \<1 time the upper limit of normal (ULN) for age, serum alanine aminotransferase (ALT) \< 1.5 1.5 x ULN for age, aspartate aminotransferase (AST) \< 1.5 ´ ULN for age , serum creatinine \<1.5 x ULN for age.
10. Signed informed consent prior to beginning protocol specific procedure.
11. Sexually active patients must use effective contraception during the period of therapy and up to 150 days after the last treatment dose. Acceptable contraception includes, but is not limited to: oral hormone therapy, partner vasectomy, or double barrier contraception (which is defined as a male condom plus spermicide in combination with either a female condom, or diaphragm, or cervical cap or intrauterine device)

Exclusion Criteria:

1. Non-squamous head and neck cancer
2. Nasopharynx cancer
3. More than two lines of chemotherapy for palliative treatment
4. Surgery or investigational drugs or chemotherapy within 4 weeks before study inclusion. Curative radiation therapy (60-70 Gy) within 8 weeks. For palliative radiation therapy (i.e 8 Gy on a painful lesion) no delay is needed.
5. Previous treatment with cabazitaxel
6. Significant active cardiac disease including: uncontrolled high blood pressure according to the CTCAE 4 grading, unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, or serious cardiac arrhythmias
7. Other uncontrolled illnesses (active infections requiring antibiotics, bleeding disorders, uncontrolled diabetes ...)
8. Previous malignancy from which the patient has been disease-free for \< 5years, as other than SCCHN.
9. Previous treatments with taxanes and/or anti-EGFR therapy are not an exclusion criteria.
10. Active grade \> 2 peripheral neuropathy
11. Active grade \> 2 stomatitis
12. Known brain or leptomeningeal involvement
13. History of severe hypersensitivity reaction (\> grade 3) to polysorbate 80 containing drugs
14. Concurrent or planned treatment with strong inhibitors of cytochrome P450 3A/5. A one-week washout period is necessary for patients who are already on these treatments.
15. Organic brain syndrome or significant psychiatric abnormality that would preclude participation in the full protocol and follow up.
D: 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

Answer: D