Cabazitaxel - PF Induction Chemotherapy

Study Overview
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Brief Summary
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The primary objective of this study is to determine the first-cycle maximum tolerated dose (MTD) and recommended Phase II (RP2D) dose of Cabazitaxel when combined with Cisplatin and Follow-Up induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck for three cycles.

Detailed Description
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The primary study objectives are the following: To assess the safety, the maximum tolerated dose (MTD) and the dose limiting toxicity of cabazitaxel when combined with cisplatin and Follow-Up (FU) induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). To establish the phase II recommended dose of cabazitaxel when combined with cisplatin and Follow-Up induction in patients with locally advanced squamous cell carcinoma of the head and neck. The secondary study objectives, in regards to the combined Cabazitaxel-Platinum Fluorouracil regimen in patients with newly diagnosed squamous cell carcinoma of the head and neck, are the following: To assess the toxicity profile To assess best Overall Response Rate (complete and partial responses) after completion of 3 cycles of treatment To assess Progression Free Survival (PFS) and Overall Survival (OS) after 3 years Analysis of the secondary variables will be primarily descriptive in nature due to the small sample size. All results will be considered hypothesis generating to be confirmed in a future study. Patient, for whom an informed consent has been obtained and who have met the inclusion/exclusion criteria after having the screening evaluation performed within a one-week window, will be assigned to a dose level according to the dose escalation rule described in the protocol. Treatment consists of an Induction chemotherapy period, which is the period when the patient will undergo 3 cycles of Cabazitaxel-Platinum Fluorouracil (PF). The Induction chemotherapy will be followed by Consolidation Therapy, which is 6-7 weeks of Chemoradiation treatment or Surgery + Recovery time, depending on their primary site and overall medical condition. Both treatment periods will consist of approximately 16 weeks (9 weeks of Induction and 7 weeks of Consolidation, if Chemoradiation Radiation Therapy (CRT)), or shorter than 16 weeks, if surgery. After three cycles, the patients will be assessed for clinical, radiographic, and pathologic response to Cabazitaxel-Platinum Fluorouracil before beginning Chemoradiation Radiation Therapy or surgery. Patients, who do not complete three cycles of Cabazitaxel-Platinum Fluorouracil for reasons of toxicity, progressive disease, choice, or other medical necessity, will be treated with standard Chemoradiation Radiation Therapy or surgery depending on their primary site and overall medical condition. Once the Consolidation treatment is completed, the follow-up of patients will be for 3 years.

Official Title
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Phase I Study of Cabazitaxel - Platinum Fluorouracil Induction Chemotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Cabazitaxel 10mg/m2
* Drug: Cabazitaxel 12.5mg/m2
* Drug: Cabazitaxel 15mg/m2
* Drug: Cabazitaxel 17.5mg/m2
* Drug: Cabazitaxel 20mg/m2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with stage IV only, previously untreated, locally advanced SCCHN (patients may have had previous surgery, but not chemotherapy or radiotherapy). During the dose escalation phase before the MTD and DLT are established for cabazitaxel combined with cisplatin and FU induction chemotherapy primary sites allowed include the oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, and unknown primary regardless of Human Papilloma Virus (HPV) status. Metastatic SCCHN will be allowed in escalation phase. Once MTD and DLT for cabazitaxel combined with cisplatin and FU induction chemotherapy are established (expansion cohort) primary sites allowed include the oral cavity, oropharynx (HPV negative only), larynx, hypopharynx, nasopharynx, and unknown primary (HPV negative only). No patients with metastases will be allowed in this phase (expansion cohort). Age >/= 18 years Eastern Cooperative Oncology Group PS 0-1 Predicted life expectancy >/= 12 weeks Absolute Neutrophilic Count (ANC) >/= 1.5 x 10^9/L, Platelets >/= 100 x 10^9/L; bilirubin </= 1.5 x Upper Limit of Normal (ULN), Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) </= 2.5 x ULN or </= 5 x ULN if patient has documented liver metastases; serum creatinine </= 1.5 x ULN Patients in the expansion cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors(RECIST) Patients must be accessible for repeat dosing and follow-up Patients - both males and females - with reproductive potential must agree to practice effective contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test at baseline and on Day 1 Patients must provide verbal and written informed consent to participate in the study Exclusion Criteria: Locally advanced HPV positive oropharyngeal or unknown primary SCCHN for the expansion cohort only (Once MTD and DLT for cabazitaxel combined with cisplatin and FU induction chemotherapy established). History of significant cardiac disease unless the disease is well-controlled Grade 2 peripheral neuropathy No excessive alcohol consumption will be allowed Serious comorbid illness, and involuntary weight loss of more than 20% of body weight in the 3 months preceding study entry History of cerebrovascular accident (CVA) within 12 months prior to registration or that is not stable History of any psychiatric condition that might impair the patient's ability to understand or to comply with the requirements of the study or to provide informed consent Pregnant or breast-feeding females Gastrointestinal (GI) abnormalities including inability to take oral medication, requirement for IV alimentation, active peptic ulcer, or prior surgical procedures affecting absorption History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drug Any type of active seizure disorder Use of drugs that have a risk of causing QT interval prolongation within 14 days prior to Day 1 dosing Use of strong or moderate CYP3A4 or CYP1A2 inhibitors/inducers, with the exception of low-dose steroids, within 14 days prior to Day 1 dosing Symptomatic brain metastases that are not stable, require steroids, or that have required radiation within the last 28 days Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's ongoing participation in the study History of Hepatitis C or Human Immunodeficiency Virus (HIV) infection, autoimmune disease, or major organ transplant. Surgery, irradiation or chemotherapy within the previous 4 weeks Any other concomitant anticancer therapies Patients will be excluded if they received any prior chemotherapy, radiotherapy, or treatment with biologic response modifiers (except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) History of colitis or chronic diarrheal illness History of, or active, co-morbid medical condition, which in the opinion of the investigator, would raise significant risk to the patient.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabazitaxel 10mg/m2<br>Cabazitaxel on D1 Dose: 10mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days) | Drug: Cabazitaxel 10mg/m2<br>* Cabazitaxel on D1 Dose: 10mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days)<br>* Other names: Cabazitaxel-PF Induction Chemotherapy;|
| Experimental: Cabazitaxel 12.5mg/m2<br>Cabazitaxel on D1 Dose: 12.5mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days) | Drug: Cabazitaxel 12.5mg/m2<br>* Cabazitaxel on D1 Dose: 12.5mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days)<br>* Other names: Cabazitaxel-PF Induction Chemotherapy;|
| Experimental: Cabazitaxel 15mg/m2<br>Cabazitaxel on D1 Dose: 15mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days) | Drug: Cabazitaxel 15mg/m2<br>* Cabazitaxel on D1 Dose: 15mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days)<br>* Other names: Cabazitaxel-PF Induction Chemotherapy;|
| Experimental: Cabazitaxel 17.5mg/m2<br>Cabazitaxel on D1 Dose: 17.5mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days) | Drug: Cabazitaxel 17.5mg/m2<br>* Cabazitaxel on D1 Dose: 17.5mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days)<br>* Other names: Cabazitaxel-PF Induction Chemotherapy;|
| Experimental: Cabazitaxel 20mg/m2<br>Cabazitaxel on D1 Dose: 20mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days) | Drug: Cabazitaxel 20mg/m2<br>* Cabazitaxel on D1 Dose: 20mg/m2 IV x 1 Route: Intravenous infusion over 60 minutes, mixed as described in protocol over 1 hour Schedule: Day 1, every 21 days (+ 2 days) Cisplatin on D1 Dose: 100 mg/m2 Route: Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline Schedule: Day 1, every 21 days (+ 2 days) 5 Fluorouracil on D1-D4 Dose: 800 mg/m2/day Route: 24-hour continuous infusion over 4 days Schedule: Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days) + 2 days)<br>* Other names: Cabazitaxel-PF Induction Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | MTD is defined as the dose level immediately below the DLT. The study will be conducted until MTD and recommended Phase II dose are established. | at 1 week | 
| Maximum Tolerated Dose (MTD) | MTD is defined as the dose level immediately below the DLT. The study will be conducted until MTD and recommended Phase II dose are established. | at 4 weeks | 
| Maximum Tolerated Dose (MTD) | MTD is defined as the dose level immediately below the DLT. The study will be conducted until MTD and recommended Phase II dose are established. | at 7 weeks | 
| Maximum Tolerated Dose (MTD) | MTD is defined as the dose level immediately below the DLT. The study will be conducted until MTD and recommended Phase II dose are established. | at 9 weeks | 
| Dose-limiting toxicity (DLT) | DLT is defined as a grade3 toxicity lasting more than 7 days or grade 4 or 5 toxicity, with the exception of febrile neutropenia which will be considered as ½ DLT per full dose per episode. The DLT will be the basis for determining the MTD. Treatment cohorts will be dosed in escalating order only after the safety of the previous dose level is established, or until an MTD has been determined. | at 1 week | 
| Dose-limiting toxicity (DLT) | DLT is defined as a grade3 toxicity lasting more than 7 days or grade 4 or 5 toxicity, with the exception of febrile neutropenia which will be considered as ½ DLT per full dose per episode. The DLT will be the basis for determining the MTD. Treatment cohorts will be dosed in escalating order only after the safety of the previous dose level is established, or until an MTD has been determined. | at 4 weeks | 
| Dose-limiting toxicity (DLT) | DLT is defined as a grade3 toxicity lasting more than 7 days or grade 4 or 5 toxicity, with the exception of febrile neutropenia which will be considered as ½ DLT per full dose per episode. The DLT will be the basis for determining the MTD. Treatment cohorts will be dosed in escalating order only after the safety of the previous dose level is established, or until an MTD has been determined. | at 7 weeks | 
| Dose-limiting toxicity (DLT) | DLT is defined as a grade3 toxicity lasting more than 7 days or grade 4 or 5 toxicity, with the exception of febrile neutropenia which will be considered as ½ DLT per full dose per episode. The DLT will be the basis for determining the MTD. Treatment cohorts will be dosed in escalating order only after the safety of the previous dose level is established, or until an MTD has been determined. | at 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Profile | The toxicity profile of cabazitaxel when combined with cisplatin and FU induction chemotherapy will be assessed | at 9 weeks | 
| Overall Response Rate | The Best Overall Response Rate (complete and partial responses) will be assessed after completion of 3 cycles of treatment. | at 9 weeks | 
| Progression Free Survival/Overall Survival | The Progression Free Survival and Overall Survival will be assessed during the 3-year follow-up period. The follow-up period is every 3 months for the first 2 years post consolidation (week 16) thereafter every 6 months for the 3rd year post consolidation (week 16). | for 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, PF Induction Chemotherapy, Squamous Cell Carcinoma, Head and Neck, Sanofi-Aventis Oncology, Locally Advanced, Cabazitaxel, Cabazitaxel and Cisplatin