Clinical trial NCT02512458: Study of the Effect of Chemotherapy With Cabazitaxel on Prostate Cancer
Official title: A Study of Cabazitaxel Treatment in Castration Resistant Bone Metastatic Prostate Cancer Patients Evaluating the Tumor Microenvironment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bone Metastatic Prostate Cancer
Lead sponsor: Hellenic Cooperative Oncology Group
Sponsor class: OTHER
Collaborators: name: Sanofi
First posted: 2015-07-31
Enrollment: 60
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a prospective, open-label, single arm translational study of cabazitaxel in bone Castration Resistant metastatic Pancreatic Cancer (mCRPC) patients. Patient will be treated with intravenous (iv) cabazitaxel 25mg/m2 every (q) 21days per standard clinical practice for up to 10 cycles or until disease progression or unacceptable toxicity or physician's decision or patient's consent withdrawal (whichever occurs first).

Detailed description: This is an open-label, interventional study to explore the effect of Cabazitaxel on survival pathways and androgen signaling in the tumor microenvironment (bone marrow) of patients with castration resistant metastatic prostate cancer.

A total of 30 evaluable patients are needed. An estimated 50% chance of failure to harvest evaluable bone marrow biopsy or aspirate is anticipated based on investigators prior experience. Thus a total of 60 patients will be accrued in the study. This will provide the investigators an 80% power to detect an effect size of at least 0.82, using a two-sided paired t-test and at a 0.05 significance level.The changes in androgen signaling (androgen receptor expression and other survival pathway markers, between baseline and 9 weeks will be assessed by paired t-test and Wilcoxon signed-rank test. The association between serum Prostate-Specific Androgen (PSA) and bone marrow androgen signaling level will be evaluated using scatter plot and spearman's correlation coefficient. Similar methods will be used to explore the association between circulating androgens and those in the bone marrow.

Biomarker data will also be summarized and compared between baseline and after treatment using paired t-test or Wilcoxon signed-rank test.

ECOG changes from baseline will be provided for each treatment period. All Adverse Events (AE) will be graded using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) classification, version 4.3.

Summary tables of Adverse Events (AE)s, Treatment Emergent Adverse Event(TEAE), Serious Adverse Events (SAE)s and withdrawals for adverse events will be provided by treatment period. Adverse events will be summarized by worst severity grade AEs.

All registered subjects who take at least 1 dose of agent will be included in the safety analyses. Adverse events will be summarized by worst severity grade. AEs, as well as treatment-emergent AEs, will be summarized by system organ class, and preferred term. Investigational Medicinal Products (IMP) -related adverse events, adverse events leading to death or to discontinuation from treatment, events classified as NCI-CTCAE v4 Grade 3 or Grade 4 (or moderate/severe if other rating scale is used), (IMP)-related events, and serious adverse events will be summarized separately.

Eligibility criteria: Inclusion Criteria:

* Male patients older than 18 years
* Histologically proven adenocarcinoma of the prostate
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Serum testosterone levels \< 50ng/ml (1.7 nmol/L)
* Ongoing gonadal androgen deprivation therapy with Luteinizing Hormone-Releasing Hormone (LHRH) analogues or orchiectomy. Patients, who have not had an orchiectomy, must be maintained on effective LHRH analogue therapy for the duration of the trial
* Progression of disease despite androgen ablation - Either documented osseous or soft tissue metastatic disease progression or by PSA criteria progression
* Presence of bone metastases
* Off diethylstilbestrol (DES) or steroids treatment for ≥ 4 weeks and for antiandrogens \> 4 weeks.
* No prior treatment with cabazitaxel
* Able to comply with study requirements
* Written information delivered to the patient. Patient must be willing and able to comply with protocol requirements. All patients must sign an informed consent indicating that they are aware of the investigational nature of this study. Patients must also have signed an authorization for the release of their protected health information.

Exclusion Criteria:

* Histologic variants in the primary tumor (histologic variants other than adenocarcinoma)
* Concurrent therapy with other therapeutic or hormonal agent, including androgen receptor antagonists (bicalutamide, flutamide, nilutamide, enzalutamide), any dose of megestrol acetate (Megace), ketoconazole, abiraterone acetate, finasteride (Proscar), dutasteride (Avodart) any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES),
* Active infection or intercurrent illnesses that are not controlled
* Prior radiation therapy completed \< 4 weeks prior to enrolment
* Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
* Structurally unstable bone lesions suggesting impending fracture
* Any "currently active" second malignancy, other than non-melanoma skin cancer. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next 3 months
* Active psychiatric illnesses/social situations that would limit compliance with protocol requirements.
* Active or uncontrolled autoimmune disease that may require corticosteroid therapy during study.
* Severely compromised immunological state, including being positive for the human immunodeficiency virus (HIV)
* Known acute or chronic hepatitis B or C
* Other investigational therapies (targeted or vaccine) will require a 4 week washout period before treatment initiation
* Ιnitiation of bisphosphonate or denosumab therapy within 4 weeks prior to first dose of study drug. Patients on stable doses of bisphosphonates or denosumab that show subsequent tumor progression may continue on this medication; however, patients are discouraged to initiate bisphosphonate therapy during the study.
* Patients receiving an investigational drug within 4 weeks prior to enrolment
* History of severe hypersensitivity reaction (grade ≥3) to polysorbate 80 containing drugs
* Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)
* 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)
* Inadequate organ or bone marrow function

Primary outcomes:
measure: Molecular effects of treatment with Cabazitaxel on the tumor microenvironment
timeFrame: On week 9 and on week 36
Secondary outcomes:
measure: Eastern Cooperative Oncology Group (ECOG) performance status
timeFrame: Up to 30 weeks
measure: PSA response
timeFrame: Up to 30 weeks
measure: Radiological progression-free survival according to Prostate Cancer Working Group 2 (PCWG2)
timeFrame: Up to 30 weeks or until Disease Progression
measure: Pain status using a numerical rating scale from 0 to 10.
timeFrame: Up to 30 weeks
measure: Time to best clinical benefit (based on pain, analgesic consumption, and performance status)
timeFrame: Up to 30 weeks
measure: Overall survival
timeFrame: Up to 40 months
measure: Explore the potential association between serum PSA with bone marrow (BM) androgen (testosterone, dehydrotestosterone, androstenedione, cortisol, pregnenolone and progesterone) levels and androgen receptor expression while on Cabazitaxel
timeFrame: Up to 30 weeks
measure: Prospective collection of BM biopsies and aspirates to measure the effect of Cabazitaxel on markers of bone metabolism(N-terminal Androgen Receptor(AR),C-terminal AR,splice variant presence,NKX3.1,AR coactivator expression,CYP17,p53,Aurora kinase,UBE2C)
timeFrame: Up to 30 weeks
measure: Correlation between levels of circulating androgens(testosterone, dehydrotestosterone,androstenedione,cortisol,pregnenolone and progesterone)and those in the bone marrow before and during treatment with Cabazitaxel with measures of efficacy
timeFrame: Up to 30 weeks
measure: Number of participants with Serious and Non-Serious Adverse Events graded according to National Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
timeFrame: Up to 30 weeks
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Athens Medical Center, Dept of Medical Oncology
state: Maroussi
city: Thessaloníki
country: Greece
facility: EUROMEDICA General Clinic of Thessaloniki
state: Thessaloniki
city: Athens
country: Greece
facility: General Hospital of Athens "Alexandra", Unit of Medical Oncology, Dept of Clinical Therapeutics
city: Athens
country: Greece
facility: Agii Anargiri Cancer Hospital, 3rd Dept of Medical Oncology
city: Ioannina
country: Greece
facility: Ioannina University Hospital, Dept of Medical Oncology
city: Thessaloniki
country: Greece
facility: Papageorgiou General Hospital, Dept of Medical Oncology
Study officials:
affiliation: Unit of Medical Oncology,Department of Clinical Theraputics,General Hospital of Athens "Alexandra"
name: Eleni Efstathiou, MD,Ass. Prof
role: STUDY_CHAIR
References: