Weekly Paclitaxel and Cyclophosphamide in Metronomic Administration : Dose Escalation Study of Weekly Paclitaxel

Study Overview
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Brief Summary
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The aim of the study is to determine the MTD of Paclitaxel in association with metronomic Cyclophosphamide.

Detailed Description
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The aim of the study is to determine the MTD of Paclitaxel in association with metronomic Cyclophosphamide for cancer which present no therapeutic solution

Official Title
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Phase I Study : Dose Escalation of Intravenous Weekly Paclitaxel in Association With Metronomic Administration of Cyclophosphamide

Conditions
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Cancer

Intervention / Treatment
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* Drug: Paclitaxel dose escalation
* Drug: Paclitaxel
* Drug: Cyclophosphamide
* Biological: Blood collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with cancer histologically proved No other therapeutic proposal after discussion in multidisciplinary consultation Radiological evidence of the evolving nature of the disease Measurable disease with at least one measurable lesion according to the criteria RECIST 1.1 At least 28 days since prior treatment(systemic treatment or major surgery) Patient who have recovered from any previous toxicity Man or woman de ≥ 18 years and ≤ 65 years Performance Status (ECOG) ≤ 2 within 7 days before inclusion Polynuclear neutrophils ≥ 1500/mm3, platelets ≥ 100 000/mm3, Hemoglobin ≥ 9 g/dl Serum Albumin ≥ 36 g/l and lymphocytes ≥ 700/mm3 Total bilirubin and SGPT/ALT and SGOT/AST ≤ 3 ULN(≤ 5 ULN if liver metastases) Creatinine in normal ranges and Creatinine clairance > 60 ml/min (Cockroft formulae) Central venous access Negative pregnancy test for women who may be pregnant within 7 days before inclusion Effective contraceptive during the treatment period and up to 6 months after the end of treatment (for patients of both sexes during their reproductive and child-bearing age and their partners) Patient covered by government health insurance Informed consent signed by the patient before any specific study procedure Exclusion Criteria: Prior treatment by Paclitaxel Oral treatment impossible Known dysphagia, malabsorption or maldigestion Pre-existing neuropathy clinically symptomatic Known leptomeningeal brain metastases Known allergy to Cremophor, to Paclitaxel or one of its excipients (especially polyoxyethylene castor oil), to Cyclophosphamide or one of its excipients (lactose, sucrose) Active and uncontrolled infection Acute urinary tract infection, pre-existing hemorrhagic cystitis Diabetes insipidus History or progressive psychiatric illness Persons under guardianship or detainees Unable for medical follow-up (geographic, social or mental reasons) Pregnant, or likely to be or breastfeeding women Absence of effective contraception for the duration of treatment and 6 months after completion of therapy (for patients of both sexes in childbearing or reproductive age and their partners)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel Dose escalation<br>A standard dose escalation strategy will be used including 3 to 6 patients at each dose level (Paclitaxel dose escalation + fixed dose of cyclophosphamide) + blood collection | Drug: Paclitaxel dose escalation<br>* Paclitaxel will be administered intravenously over 60 minutes, at D1, D8 and D15, at a given dose. The Paclitaxel dose (mg/infusion) levels are as follows: 40 60 70 75 80 85 90<br>* Other names: Taxol;Drug: Cyclophosphamide<br>* D1 to D28: 50 mg x 2/day/cycle 1 cycle = 28 days<br>* Other names: Endoxan;Biological: Blood collection<br>* At D1, D8, D15 and D21 of cycle 1 and cycle 2:2 blood samples for the correlation between clinical response and biological parameters<br>|
| Experimental: Cohort extension<br>An additional 10 patients will be treated at the recommended dose in order to confirm the recommended paclitaxel dose + blood collection | Drug: Paclitaxel<br>* Patients will be treated at the recommended dose in order to confirm the recommended paclitaxel dose in association with metronomic cyclophosphamide<br>* Other names: Taxol;Drug: Cyclophosphamide<br>* D1 to D28: 50 mg x 2/day/cycle 1 cycle = 28 days<br>* Other names: Endoxan;Biological: Blood collection<br>* At D1, D8, D15 and D21 of cycle 1 and cycle 2:2 blood samples for the correlation between clinical response and biological parameters<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the iv paclitaxel maximum tolerated dose and recommended dose in association with a fixed dose of oral cyclophosphamide | A DLT is defined below: Hematological toxicity: Polunuclear neutrophils < 500/mm3 for more than 7 days Febrile neutropenia (Polunuclear neutrophils < 1 000/mm3 and fever > or = 38.5°C) or documented infection Thrombopenia (Platelets < 25 000/mm3) Impossibility to administer D8 or D15 due to hematological critera Non-hematological toxicity: Any grade 3 or 4 toxicity related to study treatment, with the exception of fatigue and alopecia | 28 days = cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of the nature of adverse events | According to the NCI-CTCAE scale v4.0 | During the study treatment, an expected average of 2 months | 
| Evaluation of objective response after 2 cycles | Objective response (complete response, partial response and stable disease) according to RECIST 1.1 criteria | After 2 cycles = 2 months | 
| Estimation of the free-progression median time | Time between the inclusion and the disease progression (clinical or radiological) | Until disease progression | 
| Calculation of the Growth Modulation Index (GMI) | Time to progression on study treatment and time to progression on prior treatment | Until disease progression | 
| Evaluation of the correlation between clinical response and biological parameters | Biological parameters related to angiogenesis | Day 1, 8, 15, 21 of cycle 1 and cycle 2 | 
| Description of the severity of adverse events | According to the NCI-CTCAE scale v4.0 | During the study treatment, an expected average of 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer