Clinical trial NCT02961257: Trial Evaluating the Safety of 2 Schedules of Cabazitaxel in Elderly Men With mCRPC Previously Treated With a Docetaxel
Official title: Randomized Multicenter, Phase III Trial Evaluating the Safety of 2 Schedules of Cabazitaxel (Bi-weekly Versus Tri-weekly) Plus Prednisone in Elderly Men (≥ 65years) With mCRPC Previously Treated With a Docetaxel-containing Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer Metastatic
Lead sponsor: Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Sponsor class: OTHER
First posted: 2016-11-10
Enrollment: 196
Sex: MALE
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the incidence of grade ≥ 3 neutropenia and/or neutropenic complications (febrile neutropenia, neutropenic infection) with two schedules of cabazitaxel (bi-weekly versus tri-weekly) plus prednisone in elderly men (≥ 65 years) with mCRPC previously treated with a docetaxel-containing regimen.

Detailed description: Randomized, open-label, phase 3 trial in mCRPC patients aged ≥ 65 years.

Number of subjects:

Total:170 to 200 (85 to 100 per arm)

Treatment:

* Arm A : cabazitaxel 25 mg/m² on Day 1 of a 3-week cycle plus daily prednisone or
* Arm B: cabazitaxel 16 mg/m² on Day 1 and Day 15 of a 4-week cycle plus daily prednisone.
* Treatment will be continued for a maximum of 10 cycles unless there is documented disease progression or unacceptable toxicity.
* Standard cabazitaxel premedication will be used
* Prophylactic G-CSF (GRANOCYTE) will be injected from Day 3 to Day 7 after every administration cycle of cabazitaxel· All new hormonal treatment, including ODM-201, prior to study entry is allowed.
* Patients who received Radium-223 are eligible for this study
* Treatment with LHRH should not be discontinued.

Exploratory assessments:

CT-Scan (abdominal/pelvic/chest) or whole body MRI and Bone scan: at screening, every 3 months and EOT.

FACT-P questionnaire:at C1D1,each subsequent visit and EOT

Exploratory substudy Blood samples will be collected in France (4 or 6 sites) and the Netherlands (2 sites). Biomarker analysis will be conducted at the Urology and The Tumor Immunology Laboratory at Radboud UMC in NL.

Biomarker schedule Arm A (25mg/m2): Baseline - Week 6 - Week 12 - at progression Arm B (16mg/m2): Baseline - Week 6 - Week 12 - at progression Optional sample points are at C1D8.

Number of subjects: 50

Statistical analysis:

A sample size of 77 to 90 evaluable patients per arm will achieve 80% power to detect a 20% difference in G3 neutropenia incidence between the 2 arms. The incidence in group cabazitaxel 25 mg/m2 q3w is assumed to be 32% and 12% on bi-weekly cabazitaxel arm. The test used is a two-sided Fisher's exact test at 0.05 significance level. Assuming 10% non-evaluable patients, 85 to 100 patients should be included in each arm for a total of 170 to 200.

Patients will be stratified according to G8 score (\< 14 vs. ≥ 14), and age (\< 70 vs. ≥ 70) before randomization.

Exploratory sub-study The trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 nThe trial is powered on a clinical endpoint, namely to detect a 20% difference in G3 neutropenia incidence between arms (32% in arm A vs 12% arm B; power 80% with two-sided alpha of 5%, correcting for 10% non-evaluable patients (=17 patients).

From the 153 to 180 evaluable patients, we have 76 to 90 patients in each arm, of which we expect 40-60 evaluable patients for translational studies (calculations performed on 25 per arm).

In arm A, we expect 8 patients (32% of patients) with G3 neutropenia, and 17 patients that do not. In arm B, we expect 3 patients (12% of patients) with G3 neutropenia, and 22 patients that do not. For the MDSC analyses, we therefore will be comparing 11 patients with G3 neutropenia to 39 patients.

For all continuous variables, including all immune subpopulations present in blood, mean (sd) will be presented if the distribution seems to be symmetric and in case of a skewed distribution the median and IQR. For categorical data, number and percentage will be presented. For comparison of continuous data linear regression analyses or correlation (Spearman or Pearson) will used. For comparison of continuous data with categorical data logistic regression analysis will be used. For comparison of two sets of categorical data the chi-square test of Fisher's exact test will be utilized. For the radiological PFS analyses the estimates of the hazard ratio and corresponding 95% confidence interval will be tested using a Cox Proportional hazard model. For the overall survival, a stratified log-rank test will be used to compare between groups.

Eligibility criteria: Inclusion Criteria:

1. Patient aged ≥ 65 years with mCRPC previously treated with docetaxel
2. Medical or surgical castration with castrate level of testosterone (\< 50 ng/dl) based on the EAU definition of castrate level of testosterone
3. Progressive disease according to PCWG2
4. Histologically proven prostate carcinoma
5. Health status allowing use of chemotherapy: G8 \> 14; or G8 score ≤ 14 with geriatric assessment concluding to reversible impairment allowing use of chemotherapy
6. ECOG-PS 0, 1 or 2(ECOG-PS 2 should be related to prostate cancer)
7. Adequate hematologic, liver and renal functions:

   1. Neutrophil count ≥1.5 109/L
   2. Haemoglobin ≥10 g/ dL
   3. Platelet count ≥100.109/L
   4. Total bilirubin ≤ 1 the upper limit of normal (ULN)
   5. Transaminases ≤ 1.5 ULN
   6. Serum creatinine ≤ 2.0 ULN
8. Ongoing LHRH therapy at study entry
9. Signed informed consent

Exclusion Criteria:

1. History of severe hypersensitivity reaction (≥grade 3) to docetaxel
2. History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs
3. Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)
4. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Appendix E)
5. PS \>2 not related to prostate cancer disease
6. G8 ≤ 14 with geriatric assessment contra-indicating standard cabazitaxel regimen
7. Concomitant vaccination with yellow fever vaccine
8. Patient who cannot be regularly followed or cannot answer to quality of life questionnaires because of psychological, social, familial or geographic reasons
9. Participation in another clinical trial with any investigational drug within 30 days prior to study enrolment.

Primary outcomes:
measure: Number of grade ≥ 3 neutropenia and/or neutropenic complications
timeFrame: Up to 11 months
Secondary outcomes:
measure: Dose reductions
timeFrame: through study completion, an average of 40 weeks
measure: Radiological progression-free survival (rPFS)
timeFrame: Up to 11 months
measure: Time to PSA progression
timeFrame: Up to 11 months
measure: Time to first symptomatic Skeletal-Related Event (SRE) and incidence of SREs
timeFrame: Up to 11 months
measure: Time to opioid treatment (if relevant)
timeFrame: Up to 11 months
measure: Prostate-specific antigen (PSA) response rate
timeFrame: Up to 11 months
measure: Quality of Life (FACT-P)
timeFrame: Up to 11 months
measure: Objective response rate (ORR) in measurable lesions (RECIST criteria 1.1 - only on metastasis
timeFrame: Up to 11 months
measure: Overall Survival (OS)
timeFrame: up to 11 months
measure: Factors influencing survival
timeFrame: Up to 11 months
measure: Time to onset of grade ≥3 neutropenia
timeFrame: Up to 11 months
measure: Grade ≥3 neutropenia duration ( from date of onset of grade ≥ 3 until grade ≤ 2)
timeFrame: Up to 11 months
measure: Time to onset of grade ≥3 neutropenia by cycle
timeFrame: Up to 11 months
measure: Adverse events
timeFrame: Up to 11 months
measure: Dose delay
timeFrame: Up to 11 months
Other outcomes:
measure: Proportion of patients achieving a best objective response of SD, PR or CR according to RECIST 1.1 specifically comparing those achieving >30% and >50% decrease in MDSC post-induction compared to those who did not achieve this reduction.
timeFrame: Up to 6 months
measure: Proportion of patients achieving a >50% PSA response at 12 weeks and at any time specifically comparing those achieving >30% and >50% decrease in MDSC post-induction compared to those who did not achieve this reduction.
timeFrame: Up to 6 months
measure: Radiological progression-free survival (rPFS) according to PCWG2 criteria for all patients, in relation to percentage MDSC change (% maximum change and those achieving >30% and >50% decrease)
timeFrame: Up to 6 months
measure: Correlations between extent of MDSC (continuous) and NLR decline (continuous)
timeFrame: Up to 6 months
measure: Differences in peripheral blood immune populations (MDSCs, regulatory T-cells, T-effector and natural killer [NK] cells) with cabazitaxel responsiveness for Q2W and Q3W dosing schedule at week 6 and week 12
timeFrame: Up to 6 months
measure: correlation between MDSC decline (>30% or >50%) with neutropenia (presence or absence)
timeFrame: Up to 6 months
measure: Associations between cabazitaxel dose, presence of neutropenia (C1D8), NLR conversion (wk6 and wk12) and MDSC decline (wk6 and wk12)
timeFrame: Up to 6 months
measure: To evaluate changes in peripheral blood immune populations at failure on cabazitaxel, with particular focus on CD38-positive MDSC subsets
timeFrame: Up to 6 months
measure: Associations between baseline MDSC and molecular underpinning (from cfDNA, specifically studying MYCN amplification and PTEN / TP53 aberration)
timeFrame: Up to 6 months
Locations:
city: Besançon
country: France
facility: Hôpital Jean Minjoz
city: Bordeaux
country: France
facility: Hôpital Saint André, CHU de Bordeaux
city: Brest
country: France
facility: Clinique Pasteur-CFRO
city: Caen
country: France
facility: Centre Maurice Tubiana
city: Compiègne
country: France
facility: Polyclinique Saint-Côme
city: Créteil
country: France
facility: CHU Henri-Mondor
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lille
country: France
facility: Centre Oscar Lambret Lille
city: Metz
country: France
facility: Hôpital Belle-Isle
city: Montfermeil
country: France
facility: GHIRM
city: Nîmes
country: France
facility: Institut de Cancérologie du Gard - CHU
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Universitaire Tenon
city: Paris
country: France
facility: Hôpital Cochin
city: Poitiers
country: France
facility: CHU de Poitiers
city: Rouen
country: France
facility: CHU de Rouen
city: Saint-brieuc
country: France
facility: Clinique Armoricaine de Radiologie
city: Saint-Mandé
country: France
facility: HIA Bégin 69 avenue de Paris
city: Sens
country: France
facility: Centre Hospitalier de Sens
city: Strasbourg
country: France
facility: Hôpitaux universitaires de Strasbourg
city: Suresnes
country: France
facility: Hôpital FOCH
city: Valenciennes
country: France
facility: Centre de cancérologie Les Dentellières
city: Bernburg
country: Germany
facility: Urologisch-onkologische Schwerpunktpraxis
city: Gladbach
country: Germany
facility: Urologie und Kinderurologie Marienkrankenhaus Bergisch
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Köln
country: Germany
facility: Uniklinik Köln, Urologie, Uro-Onkologie, spezielle urologische und Roboter-assistierte Chirurgie
city: Magdeburg
country: Germany
facility: Universitäts-klinik für Urologie und Kinderurologie
city: Magdeburg
country: Germany
facility: Urologische Praxis am Hasselbachplatz
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik für Urologie und Kinderurologie,
city: Nürtingen
country: Germany
facility: Studienpraxis Urologie
Study officials:
affiliation: Hôpital Européen Georges Pompidou, Oncology Department
name: Stephane OUDARD, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pobel C, Auclin E, Procureur A, Clement-Zhao A, Simonaggio A, Delanoy N, Vano YA, Thibault C, Oudard S. Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review. Future Oncol. 2021 Jan;17(1):91-102. doi: 10.2217/fon-2020-0672. Epub 2020 Dec 2.