Clinical trial NCT01718353: Early Switch From First-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the Opposite Sequence, Exploring Molecular Markers in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Official title: Phase II Trial to Evaluate Benefit of Early Switch From First-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the Opposite Sequence, Exploring Molecular Markers and Mechanisms of Taxane Resistance in Men With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Have Not Received Prior Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer Metastatic
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2012-10-31
Enrollment: 63
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Docetaxel and cabazitaxel are cancer chemotherapy agents of the taxane drug class. The purpose of this study is to explore the benefit, for treatment of metastatic castration-resistant prostate cancer (mCRPC), of a regimen in which participants begin treatment with either of these two taxane drugs (docetaxel or cabazitaxel, in combination with prednisone) and are switched to the other taxane drug if prostate-specific antigen (PSA) value does not decrease ≥30% after 4 cycles. As defined in study protocol amendment 3, efficacy results are summarized for all participants combined, irrespective of which agent (docetaxel or cabazitaxel) was administered initially, rather than separately for the two groups based on taxane administered initially. One of the primary outcome measures is percentage of participants with a ≥50% sustained decrease from baseline in PSA at any time during the trial. By providing an opportunity for patients to switch taxane based on early PSA response, there may be a difference in result for this measure versus result in a study where it was not possible to switch. The other primary outcome measures are change from baseline in circulating tumor cells (CTCs) biomarkers percent androgen receptor nuclear localization (%ARNL) and microtubule bundling (MTB).

Detailed description: * Participants were treated until progressive disease, unacceptable toxicity, death, or participant's refusal of further study treatment. All participants were followed until death or the study cut-off date, whichever came first.
* Study cut-off was 1 month after the last participant last treatment.
* Participants alive at the cut-off date were not followed for overall survival.

Eligibility criteria: Inclusion criteria :

* Histologically- or cytologically-confirmed prostate adenocarcinoma with documented distant metastases (M1 disease).
* Progressive disease while receiving hormonal therapy or after surgical castration.
* Effective castration (serum testosterone levels ≤50 ng/dL) by orchiectomy and/or luteinizing hormone releasing hormone agonists or antagonist with or without anti-androgens.

Exclusion criteria:

* Prior chemotherapy for prostate cancer, except estramustine and adjuvant/neoadjuvant treatment completed \>3 years ago. Prior treatment with sipuleucel-T immunotherapy was allowed at the condition participant did not receive prior chemotherapy.
* Less than 28 days elapsed from prior treatment with estramustine, radiotherapy or surgery to the time of random allocation.
* Prior beta isotope therapy, whole pelvic radiotherapy, or radiotherapy to \>30% of bone marrow.
* Adverse events (excluding alopecia and those listed in the specific exclusion criteria) from any prior anticancer therapy of grade \>1(National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v4.03) at the time of random allocation.
* Less than 18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status \>2.
* History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease.
* Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial (pTis, pTa and pT1) bladder cancer were allowed, as well as any other cancer for which chemotherapy had been completed ≥3 years ago and from which the participant had been disease-free for ≥3 years.
* Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to random allocation.
* Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack.
* Any of the following within 3 months prior to random allocation: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event.
* Acquired immunodeficiency syndrome (AIDS)-related illnesses or known HIV disease requiring antiretroviral treatment.
* Any severe acute or chronic medical condition which could impair the ability of the participant to participate in to the study or interfere with interpretation of study results, or participant unable to comply with the study procedures.
* Concomitant treatment with biphosphonates or denosumab except if the dose had been stable for 4 weeks prior to enrollment.
* Absence of signed and dated Institutional Review Board (IRB)-approved participant informed consent prior to enrollment into the study.
* Participants with reproductive potential who did not agree to use an accepted and effective method of contraception during the study treatment period. The definition of "effective method of contraception" was based on the investigator's judgment.
* History of hypersensitivity to docetaxel or polysorbate 80.
* Inadequate organ and bone marrow function.
* Contraindications to the use of corticosteroid treatment.
* Symptomatic peripheral neuropathy grade \>2 (NCI CTCAE v.4.03).
* Treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a two-week wash-out period was necessary for participants who were already on these treatments).

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Percentage of Participants With PSA Response
timeFrame: Baseline, Pre-dose every 3 weeks, 30 days after last treatment administration (End of treatment [EOT]), every 3 months (for 1 year) then every 6 months until PSA progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
measure: Drug-target Engagement in Circulating Tumor Cells (CTCs): Change From Baseline at Cycle 1 Day 8 in Percent Androgen Receptor Nuclear Localization (%ARNL) by Categories of PSA Decrease From Baseline (≥50%, Not ≥50%) After Cycle 4
timeFrame: Baseline and Cycle 1 Day 8, Cycle 4
measure: Drug-target Engagement in CTCs: Change From Baseline at Cycle 1 Day 8 in MTB by Categories of PSA Decrease From Baseline (≥30%, Not ≥30%) After Cycle 4
timeFrame: Baseline and Cycle 1 Day 8, Cycle 4
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From Baseline until DP or death due to any cause or study cut off, whichever was earlier (Maximum duration: 60 weeks)
measure: PSA Progression Free Survival
timeFrame: From Baseline until DP or death due to any cause or study cut off date, whichever was earlier (Maximum duration: 60 weeks)
measure: Percentage of Participants With Objective Response
timeFrame: From baseline until DP or study cut off, whichever was earlier (Maximum duration: 60 weeks)
measure: Radiographic Progression-free Survival (rPFS)
timeFrame: From baseline, every 12 weeks until radiological tumor progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
measure: Clinical Progression-free Survival (cPFS)
timeFrame: Baseline, Pre-dose every 3 weeks, EOT, every 3 months (for 1 year) until first SRE occurrence or death or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
measure: Overall Survival
timeFrame: From baseline until death due to any cause or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
measure: Percentage of Participants With ≥30% and ≥50% Reduction in PSA Response
timeFrame: From baseline until DP or study cut-off, whichever was earlier (Maximum duration: 60 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number 840003
state: Alabama
city: Washington, D.C.
country: United States
facility: Investigational Site Number 840102
state: District of Columbia
city: Indianapolis
country: United States
facility: Investigational Site Number 840005
state: Indiana
city: Metairie
country: United States
facility: Investigational Site Number 840025
state: Louisiana
city: Baltimore
country: United States
facility: Investigational Site Number 840002
state: Maryland
city: Bethesda
country: United States
facility: Investigational Site Number 840007
state: Maryland
city: Rockville
country: United States
facility: Investigational Site Number 840017
state: Maryland
city: Cherry Hill
country: United States
facility: Investigational Site Number 840010
state: New Jersey
city: East Orange
country: United States
facility: Investigational Site Number 840015
state: New Jersey
city: New York
country: United States
facility: Investigational Site Number 840001
state: New York
city: New York
country: United States
facility: Investigational Site Number 840013
state: New York
city: Charleston
country: United States
facility: Investigational Site Number 840009
state: South Carolina
city: Seattle
country: United States
facility: Investigational Site Number 840012
state: Washington
city: Madison
country: United States
facility: Investigational Site Number 840004
state: Wisconsin
city: Edmonton
country: Canada
facility: Investigational Site Number 124001
state: Alberta
city: Montreal
country: Canada
facility: Investigational Site Number 124004
state: Quebec
city: Montreal
country: Canada
facility: Investigational Site Number 124002
state: Quebec
city: Québec
country: Canada
facility: Investigational Site Number 124006
state: Quebec
city: Sherbrooke
country: Canada
facility: Investigational Site Number 124005
state: Quebec
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Tagawa ST, Antonarakis ES, Gjyrezi A, Galletti G, Kim S, Worroll D, Stewart J, Zaher A, Szatrowski TP, Ballman KV, Kita K, Tasaki S, Bai Y, Portella L, Kirby BJ, Saad F, Eisenberger MA, Nanus DM, Giannakakou P. Expression of AR-V7 and ARv567es in Circulating Tumor Cells Correlates with Outcomes to Taxane Therapy in Men with Metastatic Prostate Cancer Treated in TAXYNERGY. Clin Cancer Res. 2019 Mar 15;25(6):1880-1888. doi: 10.1158/1078-0432.CCR-18-0320. Epub 2018 Oct 9.
citation: Antonarakis ES, Tagawa ST, Galletti G, Worroll D, Ballman K, Vanhuyse M, Sonpavde G, North S, Albany C, Tsao CK, Stewart J, Zaher A, Szatrowski T, Zhou W, Gjyrezi A, Tasaki S, Portella L, Bai Y, Lannin TB, Suri S, Gruber CN, Pratt ED, Kirby BJ, Eisenberger MA, Nanus DM, Saad F, Giannakakou P; TAXYNERGY Investigators. Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naive, Metastatic, Castration-Resistant Prostate Cancer. J Clin Oncol. 2017 Oct 1;35(28):3181-3188. doi: 10.1200/JCO.2017.72.4138. Epub 2017 Jun 20.