Head and Neck Cancer
Conditions
Keywords
Squamous Cell Carcinoma
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)
Detailed description
Results reported here are for the randomized, phase II portion of the trial.
Interventions
DRUGEverolimus
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.
DRUGPlacebo
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.
Sponsors
Novartis Pharmaceuticals
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Responses | Baseline and 2 months | Change in tumor size (sum of longest diameters of target lesions) after two cycles of induction therapy, expressed as log of ratio of post-treatment to baseline measure. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Everolimus 5 mg PO Daily for 2 21-day cycles
Everolimus: 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. | 25 |
| Placebo Placebo 5 mg PO Daily for 2 21-day cycles
Placebo: 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. | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
Baseline characteristics
| Characteristic | Everolimus | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 58.1 years | 57.2 years | 56.2 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 46 Participants | 23 Participants |
| Region of Enrollment United States | 25 participants | 50 participants | 25 participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 7 Participants |
| Sex: Female, Male Male | 21 Participants | 39 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 1 / 25 |
| other Total, other adverse events | 22 / 25 | 21 / 25 |
| serious Total, serious adverse events | 9 / 25 | 11 / 25 |
Outcome results
Primary
Tumor Responses
Change in tumor size (sum of longest diameters of target lesions) after two cycles of induction therapy, expressed as log of ratio of post-treatment to baseline measure.
Time frame: Baseline and 2 months
Population: One patient from each arm died prior to cycle 2 and is excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Tumor Responses | -0.609 dimensionless (log ratio) | Standard Error 0.086 |
| Placebo | Tumor Responses | -0.796 dimensionless (log ratio) | Standard Error 0.112 |
p-value: 0.19t-test, 2 sided