Reducing Dexamethasone Around Docetaxel Infusion

Study Overview
=================
Brief Summary
-----------------
The manufacturer recommends two different regimens of prophylactic dexamethasone to prevent hypersensitivity and fluid retention reactions caused by docetaxel: a 3-day regime of dexamethasone 8mg twice a day starting the day before chemotherapy for breast cancer and for prostate cancer 3 times 8mg dexamethasone on the day of docetaxel infusion, given the concurrent use of prednisone 2dd5mg. There is little evidence that supports this high dose regimen used nowadays. There is need to re-evaluate this high dosage of dexamethasone for three main reasons. First, dexamethasone can give side effects such as manifestation of latent diabetes mellitus, immunosuppression, personality changes, irritability, euphoria, or mania and mood swings. Second, dexamethasone is an immune suppressor, which might inhibit chemotherapy-induced apoptosis and compromise the efficacy of chemotherapeutic agents. Third, dexamethasone is a CYP3A4 inducer, which might increase docetaxel clearance. This study aims to evaluate the feasibility of reducing prophylactic of dexamethasone around docetaxel infusion.

Official Title
-----------------
Phase 1 Study to Evaluate the Safety of REducing the Prophylactic Dose of DEXamethasone Around Docetaxel Infusion in Patients With Early or Advanced Breast Cancer and Prostate Cancer

Conditions
-----------------
Breast Cancer, Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Dexamethasone
* Drug: Prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with early breast cancer, or advanced breast cancer or prostate cancer patients receiving docetaxel (minimal 3 cycles monotherapy or in the regimen 4xAC > 4xdocetaxel or 3xFEC>3xdocetaxel or 6xTAC) Age ≥18 years WHO performance status 0-2 Adequate bone marrow function: white blood cells (WBCs) ≥3.0 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l Adequate liver function: bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL (<5 x UNL in case of liver metastases), Alkaline Phosphatase ≤5 x UNL Adequate renal function: the calculated creatinine clearance should be ≥50 mL/min Survival expectation must be > 3 months Written informed consent according to the local Ethics Committee requirements Exclusion Criteria: Known hypersensitivity for docetaxel, paclitaxel or other chemotherapeutic agent or products containing polysorbate 80 or an earlier experience of anaphylaxis for food, insect bites, medication or another foreign substance. Existence of edema of the limbs or trunk or elsewhere localized. Active second malignancy Diabetes Mellitus Serious other diseases such as recent myocardial infarction (last 6 months), clinical signs of cardiac failure or clinically significant arrhythmias Female patients who are pregnant or breast-feeding Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Breast cancer<br>Dose of prophylactic dexamethasone will be reduced as follows: STEP 1: 12 mg dexamethasone per day (8-4mg/day) for 3 days starting 1 day before administration. (n=6) STEP 2: 8mg dexamethasone per day (8mg once a day) for 3 days starting 1 day before administration. (n=6) STEP 3: day -1: 4 mg, day 0: 8 mg, day 1: 4 mg. (n=6) STEP 4: day -1: 0 mg, day 0: 8 mg, day 1: 4 mg. (n=6) STEP 5: day -1: 0 mg, day 0: 8 mg, day 1: 0 mg. (n=6) STEP 6: day -1: 0 mg, day 0: 4 mg, day 1: 0 mg. (n=6) | Drug: Dexamethasone<br>* Dose of prophylactic dexamethasone will be reduced for all patients<br>* Other names: dexa;|
| Experimental: Prostate cancer<br>Dose of prophylactic dexamethasone will be reduced as follows: STEP 1: 2dd 8 mg at 12 and 1 hr before treatment (besides standard prednisone 5mg bid) (n=6) STEP 2: 8mg dexamethasone 1 hour before treatment (and standard prednisone 5mg bid). (n=6) STEP 3: 4mg dexamethasone 1 hour before treatment (and standard prednisone 5mg bid). (n=6) STEP 4: 0mg dexamethasone (only standard prednisone 5mg bid). (n=6) | Drug: Dexamethasone<br>* Dose of prophylactic dexamethasone will be reduced for all patients<br>* Other names: dexa;Drug: Prednisone<br>* standard prednisone 5 mg bid for patients with prostate cancer<br>* Other names: prednison;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal dose/recommended dose (RD) of pre-medication dexamethasone around docetaxel infusion, dependent of occurrence of grade III/IV fluid retention and HSR according to the NCI CTCAE v4.03. | If one grade III/IV HSR or fluid retention reaction occurs in one of the six patients within one cohort, then three additional patients will be treated at that dose level. If there are no additional grade III/IV HSR or fluid retention in that additional 3 patients accrual to the next lower dose level will be started. If a grade III/IV HSR or fluid retention occurs in at least 2/6 or 2/9 patients, that dose will not be tolerated as safe and the last previous dose level of dexamethasone will be the RD. | up to 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose (mmol/L) response due to prophylactic dexamethasone on day 0 before chemotherapy. |  | up to 30 weeks | 
| Insulin(mU/L), response due to prophylactic dexamethasone on day 0 before chemotherapy. |  | up to 30 weeks | 
| IGF-1(nmol/L) response due to prophylactic dexamethasone on day 0 before chemotherapy. |  | up to 30 weeks | 
| Number of participants with toxicity of chemotherapy according to NCI CTCAE v4.03 compared in each dose level of dexamethasone. |  | up to 30 weeks | 
| Patient's quality of life (descriptive). |  | up to 30 weeks | 
| Number of patients with single nucleotide polymorphisms in the glucocorticoid receptor. |  | one week |