Head and Neck Cancer, Squamous Cell Cancer
Conditions
Keywords
Paclitaxel, Carboplatin, Temsirolimus, Head and Neck, recurrent and/or metastatic, 09-131
Brief summary
The purpose of this study is to find out the good and bad effects that occur when temsirolimus is added to standard chemotherapy with carboplatin and paclitaxel.
Interventions
DRUGTemsirolimus + Weekly Paclitaxel + Carboplatin
Temsirolimus Per dose escalation scheme Level 1 (15 mg) 2 (20 mg) Level 3 (25 mg) IVPB 30 minutes weekly (3 weeks on, 1 week off) days 1 and 8. Paclitaxel 80 mg/m2 IVPB 1 hour weekly (2 weeks on, 1 week off) days 1 and 8. Carboplatin AUC 1.5 IVPB 30 minutes days 1 and 8. On Day 15 of each cycle, patients begin the rest week.
Sponsors
NATL COMP CA NETWORK
Pfizer
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have microscopically confirmed head and neck squamous cell carcinoma (HNSCC), recurrent and/or metastatic. * Confirmation of HNSCC may be obtained from the primary site or metastatic disease. * Patients must be at least 18 years of age. * Karnofsky Performance status must be ≥ 70%. * Disease must be measurable by RECIST criteria. * At least 6 weeks must have elapsed from previous radiation therapy. Patient must have recovered from the acute toxic effects of treatment prior to study enrollment. * Adequate organ function, as follows: * Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 X 109/L, platelets ≥ 100 X 109/L, and hemoglobin ≥ 9 g/dL. * Hepatic: total bilirubin within normal limits (≤ 1.0 mg/dL); alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 X ULN (upper limit of normal) * Renal: Serum creatinine ≤ 1.3 mg/dL. Patients with serum creatinine \> 1.3 mg/dL may be eligible if creatinine clearance (CrCl) ≥ 45 mL/min based on the standard Cockroft and Gault formula. * Patients of childbearing potential must have a negative serum pregnancy test within 14 days of treatment. Patients must agree to use a reliable method of birth control during and for 3 months following the last dose of study drug. * Patients must sign an informed consent document.
Exclusion criteria
* Previous exposure to temsirolimus or other mTOR inhibitors * More than 2 prior cytotoxic regimens in the recurrent/metastatic disease setting * History of any brain metastases * Patients who require concomitant medications that are metabolized by hepatic CYP3A4, due to potential drug-drug interaction with temsirolimus * Patients with known active interstitial pneumonitis * Active infection or serious underlying medical condition that would impair the patient's ability to receive protocol treatment. * Women who are pregnant or lactating * Other active malignancy, other than indolent malignancies which the investigator determines are unlikely to interfere with treatment and safety analysis * Diagnosis of Nasopharyngeal cancer is excluded. * Patients with multifocal peripheral sensory alterations or paresthesias (including tingling) interfering with function, per patient report (example: activities of daily living) * Therapeutic anticoagulation with Coumadin (warfarin) * Hypertriglyceridemia ≥ grade 2 (CTCAE version 3.0). * Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry. If O2 saturation is ≤ 88% at rest, further pulmonary function tests (PFTs) should be ordered to confirm normal pulmonary function and eligibility.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II Recommended Dose for the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin. | 2 years | — |
| To Determine the Objective Response Rate (CR or PR) After Two Cycles of Treatment With the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin as Palliative Therapy for Recurrent or Metastatic HNSCC | 6 weeks | Evaluation of target lesions: Complete Response - disappearance of all target lesions Partial Response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter Progressive Disease - at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one of more new lesions Stable Disease - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Adverse Events | 2 years | Safety will be assessed in terms of AEs according to CTCAE version 3.0 |
| Median Overall Survival | 2 years | — |
| Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | 2 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1, Dose Level 1 Temsirolimus 15mg, Paclitaxel 80mg/m2, Carboplatin AUC 5 | 4 |
| Phase 1, Dose Level 2 Temsirolimus 20mg, Paclitaxel 80mg/m2, Carboplatin AUC | 7 |
| Phase 1, Dose Level 3 Temsirolimus 25mg, Paclitaxel 80mg/m2, Carboplatin AUC 1.5 | 7 |
| Phase 2, Dose Level 3 Temsirolimus 25mg, Paclitaxel 80mg/m2, Carboplatin AUC 1.5 | 30 |
| Total | 48 |
Baseline characteristics
| Characteristic | Phase 1, Dose Level 1 | Phase 1, Dose Level 2 | Phase 1, Dose Level 3 | Phase 2, Dose Level 3 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants | 10 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 6 Participants | 20 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 6 Participants | 26 Participants | 41 Participants |
| Region of Enrollment United States | 4 Participants | 7 Participants | 7 Participants | 30 Participants | 48 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 6 Participants | 22 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 6 / 7 | 7 / 7 | 28 / 30 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 7 / 7 | 30 / 30 |
| serious Total, serious adverse events | 2 / 4 | 4 / 7 | 5 / 7 | 21 / 30 |
Outcome results
Primary
Phase II Recommended Dose for the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin.
Time frame: 2 years
Population: The phase II recommended dose of Temsirolimus was established at dose level three (Carboplatin AUC 1.5, Taxol 80 mg/m2, Temsirolimus 25 mg). 6 participants treated on Phase I, dose level 3 and 30 participants treated on the Phase II portion were combined for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Phase II Recommended Dose for the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin. | 25 mg |
Primary
To Determine the Objective Response Rate (CR or PR) After Two Cycles of Treatment With the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin as Palliative Therapy for Recurrent or Metastatic HNSCC
Evaluation of target lesions: Complete Response - disappearance of all target lesions Partial Response - at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter Progressive Disease - at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one of more new lesions Stable Disease - neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started
Time frame: 6 weeks
Population: The phase II recommended dose of Temsirolimus was established at dose level three (Carboplatin AUC 1.5, Taxol 80 mg/m2, Temsirolimus 25 mg). 6 participants treated on Phase I, dose level 3 and 30 participants treated on the Phase II portion were combined for analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Temsirolimus + Weekly Paclitaxel + Carboplatin | To Determine the Objective Response Rate (CR or PR) After Two Cycles of Treatment With the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin as Palliative Therapy for Recurrent or Metastatic HNSCC | Partial Response | 15 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | To Determine the Objective Response Rate (CR or PR) After Two Cycles of Treatment With the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin as Palliative Therapy for Recurrent or Metastatic HNSCC | Stable Disease | 19 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | To Determine the Objective Response Rate (CR or PR) After Two Cycles of Treatment With the Combination of Temsirolimus + Weekly Paclitaxel + Carboplatin as Palliative Therapy for Recurrent or Metastatic HNSCC | Not Evaluable | 2 Participants |
Secondary
Median Overall Survival
Time frame: 2 years
Population: The phase II recommended dose of Temsirolimus was established at dose level three (Carboplatin AUC 1.5, Taxol 80 mg/m2, Temsirolimus 25 mg). 7 participants treated on Phase I, dose level 3 and 30 participants treated on the Phase II portion were combined for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Median Overall Survival | 5.9 months |
Secondary
Number of Participants Who Experienced Adverse Events
Safety will be assessed in terms of AEs according to CTCAE version 3.0
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants Who Experienced Adverse Events | 48 Participants |
Secondary
Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | PIK3CA Mutation | 4 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | AKT3 S472F Mutation | 1 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | PTEN R130Q Mutation | 1 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | TSC2 Mutation | 2 Participants |
| Temsirolimus + Weekly Paclitaxel + Carboplatin | Number of Participants With Potential Molecular Markers of Resistance to mTOR Inhibition | TSC1 Mutation | 2 Participants |