Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4692-TPS4692 ◽  
Author(s):  
Mario A. Eisenberger ◽  
Anne-Claire Hardy-Bessard ◽  
Loic Mourey ◽  
Paul N. Mainwaring ◽  
Daniel Ford ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps

TPS4692^ Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M, more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m2 (61%) vs ≥ 25 mg/m2 (74%), it is of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label, multinational, phase III study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response in pts with measurable disease and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended continuing the study without change.

PROSELICA study update: Comparison of two doses of cabazitaxel (Cbz) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS5099-TPS5099 ◽  
Author(s):  
Mario A. Eisenberger ◽  
Anne-Claire Hardy-Bessard ◽  
Daniel Ford ◽  
Loic Mourey ◽  
Phillip Parente ◽  
...  
Keyword(s):  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Therapeutic Index ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Lower Grade ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Previously Treated ◽  
Ecog Ps

TPS5099 Background: Cbz 25 mg/m2 IV Q3W + P 10 mg PO QD has an established safety profile and significantly improves overall survival (OS) vs mitoxantrone + P in pts with mCRPC previously treated with a D-containing regimen (phase III TROPIC study; NCT00417079; median OS: 15.1 vs 12.7 mos; HR: 0.70; P < 0.0001). Pooled data on file suggest that lower Grade 3–4 neutropenia rates are observed with Cbz < 25 vs ≥ 25 mg/m2 (61% vs 74%). In an attempt to further improve the therapeutic index of Cbz in the second-line treatment of mCRPC, PROSELICA (NCT01308580) was designed to assess whether Cbz 20 mg/m2 is associated with lower hematologic toxicity and has non-inferior efficacy compared with the standard 25 mg/m2dose. Methods: PROSELICA is a randomized, open-label, multinational, phase III study comparing the efficacy and tolerability of IV Cbz 20 with 25 mg/m2, Q3W. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, confirmed mCRPC and prior therapy with a D-containing regimen are eligible. Pts are randomized 1:1 to Cbz dosing arms; all pts receive P 10 mg PO QD and are treated until disease progression, unacceptable toxicity or consent withdrawal (max. 10 cycles). Pts are stratified by ECOG PS, measurable disease and region of the world. The primary endpoint is OS (non-inferiority). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in subgroups. Planned enrollment is 1200 pts. The study started in May 2011; by 31 Dec 2012, 851 pts had been enrolled. 158 sites are enrolling pts. Based on a review of safety and efficacy endpoints, the last Data Monitoring Committee meeting (Dec 2012) recommended continuing the study without change. Clinical trial information: NCT01308580. [Table: see text]

First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4696-TPS4696
Author(s):  
Stephane Oudard ◽  
Lisa Sengelov ◽  
Paul N. Mainwaring ◽  
Antoine Thiery- Vuillemin ◽  
Christine Theodore ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Current Standard ◽  
Open Label ◽  
Measurable Disease ◽  
Ecog Ps

TPS4696^ Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients (pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models. Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts, designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first DMC meeting recommended continuing the study without change.

Phase II study of first-line sagopilone combined with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
T. M. Beer ◽  
D. C. Smith ◽  
A. Hussain ◽  
M. Alonso ◽  
J. Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Significant Activity ◽  
Castration Resistant Prostate Cancer ◽  
Current Standard ◽  
Efficacy Evaluation ◽  
Eligibility Criteria ◽  
Measurable Disease ◽  
Grade 3

5059 Background: Epothilones comprise a new class of microtubule stabilizing agents, and sagopilone is a novel, fully synthetic epothilone that has shown significant activity against a broad range of tumor models. Methods: Chemotherapy-naïve metastatic CRPC patients received sagopilone 16 mg/m2 IV over 3 hours every 21 days and prednisone 5 mg PO BID. The primary efficacy evaluation was based on PSA decline (≥50% PSA reduction confirmed at least 28 days apart). The Simon 2-Stage design required 3 responders among the first 13 evaluable patients and 13 responders among the first 46 evaluable patients to declare the agent of interest for further investigation. Results: Between August 2006 and May 2008, 53 patients were enrolled and treated. Sites of metastases were: bones, lymph nodes, and viscera in 72%, 68%, and 25% patients, respectively. Median PSA was 107.5 (6.2–1727) ng/ml. A median of 5 (2–12) cycles were delivered. The median dose delivered per cycle was 13.3 mg/m2. Two patients did not meet all eligibility criteria and were excluded from efficacy analyses; 3 additional patients were excluded from PSA decline and progression-free survival analyses due to missing baseline PSA assessment. Twenty of 48 patients (42%; 80% CI: 32%-52%) had a confirmed PSA decline in excess of 50% and 30 (63%; 95% CI: 47%-76%) had a 30% reduction in PSA within 3 months of enrollment. Of 39 patients with measurable disease by RECIST, 1 had a complete, 9 had a partial confirmed response (26%; 95% CI: 13%-42%). The median PFS was 6.4 months (95% CI: 4.7 to 10.2). All 53 patients are evaluable for safety. Toxicities occurring in ≥ 20% patients included peripheral neuropathy 74% (19% grade 3), fatigue 40% (6% grade 3, 2% grade 4), extremity pain 36% (6% grade 3), arthralgia 23% (no grade 3, 4), and constipation 21% (no grade 3, 4). Conclusions: Sagopilone is active in metastatic chemotherapy-naïve CRPC patients, with probability of PSA decline, measurable disease responses, and PFS approximating the current standard of docetaxel + prednisone. Neuropathy and fatigue are the most common toxicities, while hematologic toxicity is rare. Further evaluation of this agent in prostate cancer is warranted. [Table: see text]

Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
Andrew J. Armstrong ◽  
Russell Zelig Szmulewitz ◽  
Daniel Peter Petrylak ◽  
Arnauld Villers ◽  
Arun Azad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
High Volume ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]

A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3519-3519 ◽  
Author(s):  
Daisuke Takahari ◽  
Yasuhide Yamada ◽  
Hiroshi Matsumoto ◽  
Hideo Baba ◽  
Kazuhiro Yoshida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Open Label ◽  
Phase Iii Trial ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

3519 Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.

Regorafenib for previously treated metastatic colorectal cancer (mCRC): A subgroup analysis of 364 patients in the USA treated in the international, open-label phase IIIb CONSIGN study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 735-735 ◽  
Author(s):  
Udit Verma ◽  
Yull Edwin Arriaga ◽  
Heinz-Josef Lenz ◽  
Charles A. Henderson ◽  
Jyotsna Fuloria ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Safety Profile ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Duration Of Treatment ◽  
Open Label ◽  
Phase Iiib ◽  
The Usa ◽  
Grade 3 ◽  
Ecog Ps

735 Background: In the phase III CORRECT study, regorafenib significantly improved overall survival and progression-free survival (PFS) vs placebo in patients with treatment-refractory mCRC. CONSIGN (NCT01538680) was a large phase IIIb study that included 2872 patients from 25 countries; it was designed to provide continued access to regorafenib for patients with mCRC who failed standard therapy and to further characterize the safety of regorafenib. In CONSIGN, adverse events (AEs) and PFS were consistent with those reported in phase III studies. We present a retrospective subgroup analysis of patients enrolled in CONSIGN in the USA. Methods: Patients with mCRC who progressed on standard therapies and had an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety. PFS (per investigator) was the only efficacy variable assessed. Results: A total of 364 patients in the USA were assigned to treatment (all evaluable for safety). The median age was 60 years; 38% and 62% had ECOG PS 0 and 1, respectively. KRAS mutation was present in 59%, KRAS wt in 38%; 74% had ≥ 3 prior regimens for metastatic disease. Median duration of treatment was 2.3 months (range: 0–30). Median PFS (95% CI) was 2.3 (2.0–2.6) months (2.1 months KRAS wt; 2.3 months KRAS mutant). NCI-CTCAE v4.0 grade ≥ 3 AEs occurred in 81% of patients and were considered drug-related in 53% (Table). Grade ≥ 3 hepatobiliary disorders occurred in 2%. Grade ≥ 3 treatment-emergent laboratory toxicities included bilirubin (9%), AST (6%), and ALT (3%). Conclusions: In patients from the USA enrolled in CONSIGN, the safety profile of regorafenib was consistent with that of the overall population and the known safety profile of regorafenib in mCRC. Median PFS was in the range of that reported in phase III trials. Clinical trial information: NCT01538680. [Table: see text]

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

2017 ◽  
Vol 35 (1) ◽  
pp. 40-47 ◽  
Author(s):  
Tomasz M. Beer ◽  
Eugene D. Kwon ◽  
Charles G. Drake ◽  
Karim Fizazi ◽  
Christopher Logothetis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Castration Resistant ◽  
Grade 3

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

A QTc study of cabazitaxel in patients with advanced solid tumors.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 257-257
Author(s):  
James Lloyd Wade ◽  
Shaker R. Dakhil ◽  
Ari David Baron ◽  
Sylvie Rottey ◽  
Frederick E. Millard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Solid Tumors ◽  
Prostate Cancer Screening ◽  
Study Drug ◽  
Qtc Interval ◽  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Grade 3 ◽  
Ecog Ps

257 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; P < 0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. Methods: This prospective, multinational, open-label study ( NCT01087021 ) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula QTcF). Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n = 65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n = 63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1–7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n = 94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n = 91) and AUC (n = 92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common Grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No Grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. Conclusions: Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.

Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4088-4088 ◽  
Author(s):  
Ghassan K. Abou-Alfa ◽  
Tim Meyer ◽  
Ann-Lii Cheng ◽  
Irfan Cicin ◽  
Luigi Bolondi ◽  
...  
Keyword(s):  
Liver Function ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Previously Treated ◽  
Baseline Characteristics ◽  
Grade 3 ◽  
Ecog Ps ◽  
Tumor Types

4088 Background: Class-specific AEs occurring with tyrosine kinase inhibitors have been associated with improved efficacy outcomes in several tumor types including aHCC. In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of VEGFR, MET, and AXL, improved overall survival (OS) and progression-free survival (PFS) vs placebo (P) in pts with previously treated aHCC. Here, we retrospectively evaluate the association of palmar-plantar erythrodysaesthesia (PPE) and hypertension (HTN) with OS and PFS for C in the CELESTIAL trial. Methods: 707 pts with aHCC were randomized 2:1 to receive 60 mg C or P once daily. Eligible pts had Child-Pugh score A, ECOG PS ≤1, must have received prior sorafenib, and could have received up to two prior regimens of systemic therapy for HCC. OS and PFS with C were evaluated for pts with any grade PPE or grade ≥3 HTN within the first 8 weeks of study treatment. Results: Overall, 374 (80%) pts in the C arm and 179 (76%) pts in the P arm completed ≥8 weeks of treatment. In the first 8 weeks, 188 (40%) of C-treated pts developed any grade PPE vs 11 (5%) of P-treated pts, and 61 (13%) of C-treated pts developed grade ≥3 HTN vs 3 (1%) of P-treated pts. Median OS with C was 14.4 mo for pts with any grade PPE vs 8.4 mo for pts without PPE (HR 0.59, 95% CI 0.47-0.74), and median PFS with C was 6.5 mo vs 3.7 mo, respectively (HR 0.63, 95% CI 0.51-0.78). Median OS with C was 16.1 mo for pts with grade ≥3 HTN vs 9.5 mo for pts without grade ≥3 HTN (HR 0.56, 95% CI 0.39-0.80), and median PFS with C was 7.4 mo vs 4.4 mo, respectively (HR 0.59, 95% CI 0.43-0.82). Some imbalances in baseline characteristics were present. Pts with PPE had better ECOG PS (60% vs 47% ECOG 0), better liver function (48% vs 34% ALBI grade 1), and less macrovascular invasion (24% vs 30%) than those without. Likewise, pts with grade ≥3 HTN had better ECOG PS (61% vs 51% ECOG 0), better liver function (56% vs 37% ALBI grade 1), and less macrovascular invasion (20% vs 29%) than those without. Conclusions: The development of PPE or grade ≥3 HTN with C was associated with prolonged OS and PFS in pts with previously treated aHCC although some imbalances in baseline characteristics between comparator groups were present. Clinical trial information: NCT01908426.

A phase II study of patupilone in patients (pts) with metastatic castration- resistant prostate cancer (CRPC) who have progressed after docetaxel

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5139-5139 ◽  
Author(s):  
E. K. Beardsley ◽  
F. Saad ◽  
B. Eigl ◽  
P. Venner ◽  
S. Hotte ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Disease Response ◽  
Measurable Disease ◽  
Psa Response ◽  
Grade 3 ◽  
Ecog Ps

5139 Background: Chemotherapy for pts with CRPC who have progressed after docetaxel remains to be defined. Patupilone is an epothilone with broad spectrum pre-clinical activity including in taxane resistant models. Methods: Multicenter, 2-stage design. Pts with metastatic CRPC with progressive disease during or within 6 months of receiving docetaxel were eligible. Patupilone was initially given 10mg/m 2 IV every 3 weeks. PSA response rate (≥50% decline) was the primary endpoint (H0 = 15%, H1 = 25%, α = 0.1, β = 0.2). Secondary endpoints were measurable disease response, serial pain and analgesics scores, progression free survival (PFS) and overall survival (OS). Results: 83 pts were enrolled from March 2007-June 2008. 401 cycles administered (median 5, range 1–15). Baseline characteristics (range): median age 67 (47–85), PSA 212 (2.6–11520), hemoglobin 118 (89–160), median time to progression after docetaxel 1.0 months (0.0–6.0), number of prior chemotherapy regimens 1:2:3+ in 45:28:10 pts, ECOG PS 0–1:2 in 73:10 pts, disease in bone/lymph nodes/viscera in 76/47/14 pts respectively. In the first 6 pts, gastrointestinal serious adverse events (AE) occurred in 4 pts (diarrhea and vomiting) which lead to a dose reduction of patupilone to 8 mg/m2 for subsequent patients. Grade 3/4 related adverse events at this dose included fatigue (16%), diarrhea (13%) and anorexia (5%). There were no grade 3/4 hematologic AEs. In 78 pts evaluable for PSA response, PSA declines of ≥30% and ≥50% have occurred in 44/78 (56%) and 35/78 (45%) with a confirmed PSA response in 25 pts (32%). Partial response occurred in 5% and stable disease in 64% of 44 evaluable pts. Pain response (2 point decline on 6 point scale) occurred in 36 (51%) of 71 pts eligible for analysis. Median PFS for PSA and non-PSA outcomes (measurable disease/symptomatic progression or death) was 7.6 months (3.7–11.5) and 5.6 months (3.9–7.3) respectively. Follow up for OS is continuing. Conclusions: Patupilone 8 mg/m2 every 3 weeks was well tolerated and associated with encouraging PFS, PSA and pain responses in pts with docetaxel resistant/refractory disease. Further investigation of patupilone in this population is warranted. [Table: see text]

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