Study in Locally Advanced Squamous Cell Carcinoma of Head and Neck
Condition: Head and Neck Cancer
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
Intervention: Everolimus; Placebo
Intervention description: Phase II Portion (2 21-day cycles of induction therapy) Cisplatin (75 mg/m2 day 1) Paclitaxel (175 mg/m2, day 1) Cetuximab(400 mg/m2 loading dose day 1 then 250mg/m2 weekly ) Everolimus 5 mg PO daily. Following induction patients received [paclitaxel (100 mg/m2 IV weekly), 5-FU (600 mg/m2 IV day 1-5), hydroxyurea 500 mg BID PO (day 1-5), and hyperfractionated twice daily radiotherapy (150 cGy per fraction) day 1-5 of a 14 day cycle which is repeated to deliver the prescribed radiotherapy dose.; Phase II Portion (2 21-day cycles of induction therapy) Cisplatin (75 mg/m2 day 1) Paclitaxel(175 mg/m2, day 1) Cetuximab(400 mg/m2 loading dose day 1 then 250mg/m2 weekly ) Placebo PO daily. Following induction patients received [paclitaxel (100 mg/m2 IV weekly), 5-FU (600 mg/m2 IV day 1-5), hydroxyurea 500 mg BID PO (day 1-5), and hyperfractionated twice daily radiotherapy (150 cGy per fraction) day 1-5 of a 14 day cycle which is repeated to deliver the prescribed radiotherapy dose.
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Cisplatin; Cetuximab; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Maximum age: 89 Years
Healthy volunteers: No
Keywords: Squamous Cell Carcinoma

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)
    

Eligibility criteria:

        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