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)

NCT01718353 | Completed Phase 2 Results

• 2 other identifiers: CABAZL06056U1111-1130-9893
• Study Type: interventional
• Target: 63
• Locations: 2 countries
• Sites: 19

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).

Conditions

Prostate Cancer Metastatic

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants With PSA Response

  PSA response was defined as ≥50% decrease in PSA levels in both treatment arms from baseline, during the whole treatment, before treatment switch and after treatment switch. PSA progression was defined as decline of PSA from baseline (an increase of ≥25% \[at least 2ng/ml\] over the nadir value, confirmed by a second PSA value at least 3 weeks apart) and no decline of PSA from baseline (an increase of ≥25% \[at least 2ng/ml\] over the baseline value after 12 weeks of treatment, confirmed by a second PSA value at least 3 weeks apart). Because the purpose of this study is to explore the benefit of a regimen in which participants are switched to a different taxane if PSA does not decrease ≥30% after 4 cycles, irrespective of which agent (docetaxel or cabazitaxel) is administered initially, the data for participants who began treatment with docetaxel and for those who began treatment with cabazitaxel were combined for the efficacy analyses.

  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)

• 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

  Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained androgen receptor (AR) nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced microtubule bundling (MTB). Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. %ARNL was assessed by quantitative analysis of images of CTCs captured by geometrically enhanced differential immunocapture (GEDI). Reduction from baseline in %ARNL (percentage of total cellular AR that is located in the nucleus) may indicate inhibition of AR signaling. Change from baseline in %ARNL at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥50%, Not ≥50%) after Cycle 4.

  Baseline and Cycle 1 Day 8, Cycle 4

• 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

  Analysis of CTCs is a co-primary endpoint. Growth of prostate cancer cells is dependent on sustained AR nuclear signaling. Taxanes (e.g., docetaxel and cabazitaxel) may mediate some of their activity in prostate cancer by impairing AR trafficking along the microtubules from the tumor cell cytoplasm into the nucleus, as a result of taxane-induced MTB. Blood samples were collected at baseline and post-treatment to allow isolation of CTCs, which were evaluated for tumor cell biomarker measures %ARNL and MTB score. MTB in images of CTCs captured by GEDI was qualitatively assessed by three independent operators for increase compared with baseline on a scale of 0 to 3 from no to most MTB increase. Increase from baseline in MTB may indicate inhibition of AR signaling. Change from baseline in MTB at Cycle 1 Day 8 is summarized by categories of participants with PSA decrease from baseline (≥30%, Not ≥30%) after Cycle 4.

  Baseline and Cycle 1 Day 8, Cycle 4

Secondary Outcomes (7)

• Progression Free Survival (PFS)

  From Baseline until DP or death due to any cause or study cut off, whichever was earlier (Maximum duration: 60 weeks)

• PSA Progression Free Survival

  From Baseline until DP or death due to any cause or study cut off date, whichever was earlier (Maximum duration: 60 weeks)

• Percentage of Participants With Objective Response

  From baseline until DP or study cut off, whichever was earlier (Maximum duration: 60 weeks)

• Radiographic Progression-free Survival (rPFS)

  From baseline, every 12 weeks until radiological tumor progression or study cut-off, whichever was earlier (Maximum duration: 60 weeks)

• Clinical Progression-free Survival (cPFS)

  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)

Study Arms (2)

Docetaxel + Prednisone (Treatment A)

EXPERIMENTAL

Docetaxel 75 mg/m\^2 intravenous (IV) infusion on Day 1 of Cycle 1 and every 3 weeks (q3w) thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with \<30% PSA reduction from baseline at the end of Cycle 4 switched to Cabazitaxel 25mg/m\^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until disease progression (DP), death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.

Drug: DOCETAXEL (XRP6976); Drug: Prednisone

Cabazitaxel + Prednisone (Treatment B)

EXPERIMENTAL

Cabazitaxel 25 mg/m\^2 IV infusion on Day 1 of Cycle 1 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily. Participants with \<30% PSA reduction from baseline at the end of Cycle 4 switched to Docetaxel 75mg/m\^2 IV infusion on Day 1 of Cycle 5 and q3w thereafter, in combination with Prednisone (or Prednisolone) 10 mg orally daily until DP, death, unacceptable toxicity or participant's refusal of further study treatment. Participants with ≥30% PSA reduction from baseline at the end of Cycle 4, continued on the same treatment which they received before switching until DP, death, unacceptable toxicity or participant's refusal of further study treatment.

Drug: CABAZITAXEL (XRP6258); Drug: Prednisone

Interventions

DOCETAXEL (XRP6976) DRUG

Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous

Also known as: Taxotere®

Docetaxel + Prednisone (Treatment A)

CABAZITAXEL (XRP6258) DRUG

Pharmaceutical form: Concentrate and solvent for solution for infusion Route of administration: Intravenous

Also known as: Jevtana®

Cabazitaxel + Prednisone (Treatment B)

Prednisone DRUG

Pharmaceutical form: Tablet Route of administration: Oral

Cabazitaxel + Prednisone (Treatment B); Docetaxel + Prednisone (Treatment A)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (19)

Investigational Site Number 840003

Birmingham, Alabama, 35294-3300, United States

Location

Investigational Site Number 840102

Washington D.C., District of Columbia, 20016-2695, United States

Location

Investigational Site Number 840005

Indianapolis, Indiana, 46202, United States

Location

Investigational Site Number 840025

Metairie, Louisiana, 70006, United States

Location

Investigational Site Number 840002

Baltimore, Maryland, 21230, United States

Location

Investigational Site Number 840007

Bethesda, Maryland, 20817, United States

Location

Investigational Site Number 840017

Rockville, Maryland, 20850, United States

Location

Investigational Site Number 840010

Cherry Hill, New Jersey, 08003, United States

Location

Investigational Site Number 840015

East Orange, New Jersey, 07018, United States

Location

Investigational Site Number 840001

New York, New York, 10021, United States

Location

Investigational Site Number 840013

New York, New York, 10029-6574, United States

Location

Investigational Site Number 840009

Charleston, South Carolina, 29414, United States

Location

Investigational Site Number 840012

Seattle, Washington, 98109, United States

Location

Investigational Site Number 840004

Madison, Wisconsin, 53705, United States

Location

Investigational Site Number 124001

Edmonton, Alberta, T6G 1Z2, Canada

Location

Investigational Site Number 124004

Montreal, Quebec, H2L 4M1, Canada

Location

Investigational Site Number 124002

Montreal, Quebec, H2W1S6, Canada

Location

Investigational Site Number 124006

Québec, Quebec, G1R 2J6, Canada

Location

Investigational Site Number 124005

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Related Publications (2)

• 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.

  PMID: 30301829 DERIVED

• 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.

  PMID: 28632486 DERIVED

MeSH Terms

Interventions

Docetaxel; cabazitaxel; XRP6258; Prednisone

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-US@sanofi.com

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2012
• First Posted: October 31, 2012
• Study Start: March 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: November 20, 2017
• Results First Posted: November 20, 2017

Record last verified: 2016-08

Locations

US (14); CA (5)