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A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy.

ABSTRACT: Background:This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy. Patients and methods:Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0?mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded. Results:A total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7?weeks (range 0.6-102.7?weeks) for the tasquinimod arm and 19.2?weeks (range 0.4-80.0?weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9)?weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P?=?0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). Conclusions:Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%. ClinicalTrials:gov identifier NCT01732549.

SUBMITTER: Fizazi K

PROVIDER: S-EPMC6246397 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy.

Fizazi K K Ulys A A Sengeløv L L Moe M M Ladoire S S Thiery-Vuillemin A A Flechon A A Guida A A Bellmunt J J Climent M A MA Chowdhury S S Dumez H H Matouskova M M Penel N N Liutkauskiene S S Stachurski L L Sternberg C N CN Baton F F Germann N N Daugaard G G

Annals of oncology : official journal of the European Society for Medical Oncology 20171101 11

<h4>Background</h4>This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy.<h4>Patients and methods</h4>Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); ...[more]

PMID: 29059273

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Project description:Temsirolimus maintenance therapy after docetaxel induction chemotherapyis safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;does not diminish quality of life; anddelays radiological and/or symptomatic progression by approximately 6 months.No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life.After successful docetaxel induction (75 mg/m(2) every 3 weeks; 6-10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs).Patients received a median of 7 cycles of temsirolimus (range, 1-28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1-33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8-23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable.Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.

Project description:Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.Bristol-Myers Squibb.

Project description:Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 ?mol/mol creatinine vs ?60 ?mol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497.Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]).The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients.Bristol-Myers Squibb.

Project description:UnlabelledWhat's known on the subject? and What does the study add? Previous studies have reported better outcomes in cancer patients that enrolled in clinical trials, suggesting that trial participation in itself might be beneficial. We investigated the potential positive effect of clinical trial participation on survival outcomes of patients with metastatic castration-resistant prostate cancer who were treated with first-line docetaxel-containing chemotherapy. After accounting for potential baseline inequalities, participation in a clinical trial itself was associated with significantly longer overall survival in these patients.Objective• To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants).Patients and methods• Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed. • All patients received docetaxel either as clinical trial participants (n= 142; 11 separate studies) or as non-participants (n= 105). • Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation.Results• There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage. • Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P= 0.027) among trial participants vs non-participants.Conclusions• Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial. • Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers' attitudes because of greater contact with medical services. • With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.

Dataset Information

A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy.

Publications

A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy.

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