TALAPRO-2: a placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5598-TPS5598
Author(s):  
Neeraj Agarwal ◽  
Neal D. Shore ◽  
Curtis Dunshee ◽  
Lawrence Ivan Karsh ◽  
Arun Azad ◽  
...  
Keyword(s):  
Performance Status ◽  
Phase Iii ◽  
Asia Pacific ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Dna Breaks ◽  
Double Blind ◽  
Repair Gene ◽  
Patient Reported ◽  
Parp Activity

TPS5598 Background: TALA blocks poly(ADP-ribose) polymerase (PARP) activity and traps PARP on single-strand DNA breaks, preventing DNA damage repair (DDR) and causing death of cells with DDR alterations (eg BRCA1/2).a TALA has been approved in multiple countries as monotherapy for germline BRCA1/2-mutated human epidermal growth factor receptor 2-negative advanced breast cancer. ENZA is an androgen receptor (AR) inhibitor and an established therapy for mCRPC. As PARP activity has been shown to support AR function, inhibition of PARP is expected to reduce AR signaling and increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates homologous recombination repair gene transcription which induces ‘ BRCAness ’. Therefore, combining TALA with ENZA in mCRPC may be efficacious regardless of DDR alterations. TALAPRO-2 (NCT03395197) is a Phase III, 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs) of TALA combined with ENZA. Methods: Enrollment goal is 1037 patients (19 patients, part 1 dose-finding; 1,018 patients, part 2 placebo-controlled). Key eligibility criteria: age ≥18 years; asymptomatic/mildly symptomatic mCRPC; ECOG performance status ≤1; metastatic disease (no brain metastases); and no prior life-prolonging systemic therapy for nonmetastatic CRPC or mCRPC. Prior therapies (excluding novel AR inhibitors) in the castration-sensitive (CSPC) setting are allowed. ADT must continue throughout the study. The randomized double-blind portion (part 2) will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Patients are stratified by prior novel hormonal therapy or docetaxel for CSPC (yes or no) and DDR alteration status (deficient vs nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria by independent review or death. The key secondary endpoint is overall survival. Efficacy will be assessed radiographically every 8 weeks up to Week 25 and every 8–12 weeks thereafter. rPFS will be compared between the two arms by a 1-sided stratified log-rank test. Patient recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia-Pacific region. aDDR alterations are defined as known/likely pathogenic variants or homozygous deletions. Funding: Pfizer Inc. Clinical trial information: NCT03395197 .

TALAPRO-2: A phase 3 randomized study of enzalutamide (ENZA) plus talazoparib (TALA) versus placebo in patients with new metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5089-TPS5089
Author(s):  
Neeraj Agarwal ◽  
Arun Azad ◽  
Neal D. Shore ◽  
Joan Carles ◽  
Andre P. Fay ◽  
...  
Keyword(s):  
Performance Status ◽  
Randomized Study ◽  
Asia Pacific ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Dna Breaks ◽  
Phase 3 ◽  
Double Blind ◽  
Patient Reported ◽  
Parp Activity

TPS5089 Background: TALA blocks poly(ADP-ribose) polymerase (PARP) activity and traps PARP on single-strand DNA breaks, preventing DNA damage repair (DDR) and causing death of cells with DDR alterations (eg, BRCA1/2).a TALA is approved in multiple countries as monotherapy for germline BRCA1/2-mutated human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Olaparib and rucaparib are PARP inhibitors approved for use in mCRPC. ENZA is an androgen receptor (AR) inhibitor and an established therapy for mCRPC. As PARP activity has been shown to support AR function, inhibition of PARP is expected to increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates homologous recombination repair gene transcription, which induces a “ BRCAness” phenotype. A proof-of-concept study combining olaparib and abiraterone (abi) in pts with mCRPC demonstrated improved median radiographic progression-free survival (rPFS) vs placebo plus abi (13.8 vs 8.2 months) and a tolerable safety profile. Therefore, ENZA may be efficacious regardless of DDR alterations. TALAPRO-2 (NCT03395197) is a Phase 3, 2-part study evaluating the efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs) of TALA plus ENZA in pts with mCRPC with or without DDR alterations. Methods: Enrollment goal is 1037 patients (pts; 19 pts, part 1 dose-finding [completed]; 1018 pts, part 2 placebo-controlled [ongoing; accrual completed in unselected cohort]). Key eligibility criteria: age ≥18 years; asymptomatic/mildly symptomatic mCRPC; ECOG performance status ≤1; metastatic disease (no brain metastases); and no prior life-prolonging systemic therapy for nonmetastatic CRPC or mCRPC. Prior therapies (excluding novel AR inhibitors) in the castration-sensitive (CSPC) setting are allowed. ADT must continue throughout the study. The randomized double-blind portion (part 2) will evaluate safety, efficacy, and PROs of TALA (0.5 mg once daily [QD]) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Pts are stratified by prior novel hormonal therapy or docetaxel for CSPC or mCSPC (yes or no) and DDR alteration status (deficient vs nondeficient/unknown). The primary endpoint is rPFS, defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria by independent central review or death. The key secondary endpoint is overall survival. Efficacy is assessed radiographically every 8 weeks up to Week 25 and every 8–12 weeks thereafter. rPFS will be compared between the two arms by a one-sided stratified log-rank test. Pt recruitment is ongoing at 223 sites in 26 countries, including 32 states across the US, and Europe, Israel, South America, South Africa, and Asia-Pacific region. aDDR alterations are defined as known/likely pathogenic variants or homozygous deletions. Clinical trial information: NCT03395197.

TALAPRO-2: A placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS264-TPS264
Author(s):  
Neeraj Agarwal ◽  
Neal D. Shore ◽  
Curtis Dunshee ◽  
Lawrence Ivan Karsh ◽  
Arun Azad ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Performance Status ◽  
Dose Finding ◽  
Phase Iii ◽  
Asia Pacific ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Combination Methods

TPS264 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/2 and traps PARP on DNA, preventing DNA damage repair (DDR) and causing death of cells with DDR mutations (eg BRCA1/2). TALA is approved in multiple countries for germline BRCA1/2-mutated HER2- advanced breast cancer. ENZA is an established therapy for CRPC. PARP1 activity has been shown to support AR function, suggesting that co-blockade of PARP1 may synergize with AR-directed therapy, regardless of DDR deficiency. A combination of TALA with ENZA in mCRPC may improve clinical outcomes in patients with or without DDR-deficient tumors. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient (pt)-reported outcomes (PROs) of the combination. Methods: Enrollment goal is 1037 pts (19 pts, part 1 dose-finding; 1,018 pts, part 2 placebo-controlled). Key eligibility criteria: age ≥18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status ≤1, no brain metastases, and no prior life-prolonging systemic therapy in nonmetastatic CRPC or mCRPC state. Prior docetaxel or novel hormonal therapy (excluding novel AR inhibitors) in castration sensitive (CSPC) setting is allowed. The randomized double-blind portion will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Randomization is stratified by prior NHT or docetaxel for CSPC (yes/no) and DDR mutation status (deficient vs nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8–12 weeks thereafter. rPFS will be compared between two arms by a 1-sided stratified log-rank test. Pt recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia Pacific region. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.

scholarly journals Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer

2016 ◽  
Vol 34 (22) ◽  
pp. 2636-2643 ◽  
Author(s):  
Cora Sternberg ◽  
Andrew Armstrong ◽  
Roberto Pili ◽  
Siobhan Ng ◽  
Robert Huddart ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
End Point ◽  
Castration Resistant ◽  
Phase Iii Study

Purpose Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. Patients and Methods Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. Results In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. Conclusion In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11524-11524
Author(s):  
Yoshitaka Honma ◽  
Yukinori Kurokawa ◽  
Akira Sawaki ◽  
Yoichi Naito ◽  
Shiro Iwagami ◽  
...  
Keyword(s):  
Failure Time ◽  
Performance Status ◽  
Phase Iii ◽  
Rank Test ◽  
Clinical Activity ◽  
Double Blind ◽  
Kit Mutation ◽  
Phase Iii Trial ◽  
To Receive ◽  
Advanced Gist

11524 Background: Pimitespib (PIM) is a novel class of orally active selective HSP90 inhibitors. KIT and PDGFRA are clients of HSP90 for their functional stability; therefore, HSP90 is a rational therapeutic target on GIST in pts with acquired resistance, such as secondary mutation in KIT, to approved tyrosine kinase inhibitors. A phase II trial showed clinical activity of PIM in pts with advanced GIST refractory to standard treatments whose medical need remains unmet. This phase III trial evaluated the efficacy and safety of PIM for this unmet clinical need. Methods: Eligible pts had histologically confirmed advanced GIST refractory to IM, SU, and REG, ≥1 measurable lesion, and ECOG performance status 0 or 1. Pts were randomized 2:1 to receive either PIM 160 mg once daily on a 5-days-on/ 2-days-off schedule or PL. Pts eligible for unblinding at the time of progressive disease were allowed to crossover to open-label PIM. The primary endpoint was progression-free survival (PFS) by blinded central radiological review based on modified RECIST 1.1. Secondary endpoints included overall survival (OS), PFS in the pts crossed over to PIM (secondary PFS), and safety. Crossover-adjusted OS was derived using the rank preserving structural failure time (RPSFT) model. Exploratory endpoints included pharmacogenomics (PGx). Results: From Oct 2018 to Apr 2020, 86 pts were randomized to receive either PIM (n = 58) or PL (n = 28). Baseline characteristics were well balanced between the two arms. Median PFS was 2.8 months (mo) (95% CI: 1.6–2.9) for PIM vs. 1.4 mo (95% CI: 0.9–1.8) for PL. The hazard ratio (HR) for PFS was 0.51 (95% CI: 0.30–0.87) ( p = 0.006, stratified log-rank test). Median OS was 13.8 mo (95% CI: 9.2–not reached) for PIM vs. 9.6 mo (95% CI: 5.5–not reached) for PL (HR for OS 0.63; p = 0.081), with 60.7 % of PL pts crossed over to PIM; secondary PFS was 2.7 mo (95% CI: 0.7–4.1). The RPSFT-adjusted median OS of PL was 7.6 mo (adjusted HR for OS 0.42; p = 0.007). Furthermore, the results of PGx analysis suggested that PIM was also effective in pts with secondary KIT mutation detected from blood samples. The most common ( > 5%) grade 3 or higher adverse events (AEs) in PIM/PL were diarrhea (13.8%/0%), anemia (6.9%/10.7%), decreased appetite (6.9%/0%), and tumor hemorrhage (5.2%/0%). AEs leading to PIM/PL study discontinuation were observed in 4/2 pts (6.9%/7.1%), respectively. Conclusions: This randomized trial demonstrated that PIM significantly improved PFS with OS prolongation in pts with advanced GIST refractory to IM, SU, and REG, as a HSP90 inhibitor for the first time. PIM was tolerated and AEs were manageable. With a mechanism of action different from that of standard therapies, PIM has the potential to be a new standard treatment in GIST. Clinical trial information: JapicCTI-184094.

Health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in combination with abiraterone.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 234-234 ◽  
Author(s):  
Noel W. Clarke ◽  
Antoine Thiery-Vuillemin ◽  
Pawel J. Wiechno ◽  
Boris Alekseev ◽  
Nuria Sala ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Short Form ◽  
Progression Free Survival ◽  
Brief Pain Inventory ◽  
Phase Iii ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
The Impact

234 Background: A Phase II trial showed that addition of olaparib (O) to abiraterone (A) led to significant radiographic progression-free survival benefit for patients (pts) with mCRPC vs placebo (P) + A (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.44–0.97). We report predefined exploratory HRQoL analyses. Methods: This randomized, double-blind trial enrolled pts with mCRPC, post-docetaxel. Pts were randomized (71 per arm) to receive either O (300 mg bd, tablets) + A (1000 mg od) or P + A; all received prednisone (5 mg bd). Pts completed Functional Assessment of Cancer Therapy-Prostate (FACT-P total score [TS]; range 0–156, higher score = better HRQoL), Brief Pain Inventory–Short Form (BPI-SF) and worst bone pain (wbp) questionnaires (both range 0–10, higher score = more severe pain). Adjusted mean change from baseline was analysed using a mixed model for repeated measures, improvement by logistic regression and deterioration by log-rank test. Results: Overall compliance rates (O + A vs P + A) were 97% vs 96%, 92% vs 85%, and 96% vs 92% for FACT-P, BPI-SF and wbp, respectively. Best FACT-P TS response of ‘improved’ (increase ≥6 points from baseline at two consecutive visits) was reported by 22/67 (33%) evaluable pts in the O + A vs 18/64 (28%) pts in the P + A arm; the odds ratio (1.32; 95% CI 0.64–2.78) favored the O + A arm. Best FACT-P TS response of ‘worsened’ (decrease ≥6 points from baseline) was reported by 15 (22%) vs 22 (34%) pts. Adjusted mean change from baseline in FACT-P TS across all visits was -0.60 vs -2.09 in the O + A and P + A arms, respectively (difference 1.48; 95% CI -3.96–6.92). Time to deterioration (TTD) results are shown in the table. Clinical trial information: NCT01972217. Conclusions: Whilst not statistically significant, in this study a higher percentage of pts treated with O + A vs P + A had improved HRQoL, with fewer pts negatively affected. Ongoing phase III studies will help elucidate the impact of O on HRQoL in pts with mCRPC. (NCT01972217)[Table: see text]

PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA7507-LBA7507 ◽  
Author(s):  
Luis Paz-Ares ◽  
Filippo De Marinis ◽  
Mircea Dediu ◽  
Michael Thomas ◽  
Jean-Louis Pujol ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Performance Status ◽  
Phase Iii ◽  
Controlled Study ◽  
Rank Test ◽  
Induction Treatment ◽  
Double Blind ◽  
Risk Of Death ◽  
Continuation Maintenance

LBA7507 Background: The PARAMOUNT trial showed that pem continuation maintenance therapy significantly reduced the risk of disease progression over plb (HR=0.62; 95% CI: 0.49-0.79; p <0.0001) in patients (pts) with advanced NS NSCLC who had not progressed during pem-cis induction. Here we present the final OS data. Methods: In a double-blind, plb-controlled study, alpha-controlled for OS, 939 pts received induction (4 cycles of pem 500 mg/m2 and cis 75 mg/m2 on d1 of 21d cycles), and 539 pts who had not progressed and had an ECOG performance status (PS) of 0/1 were randomized (2:1) to maintenance pem (500 mg/m2, on day 1 of 21-day cycles) plus BSC or plb plus BSC until disease progression. All received B12, folic acid, and dexamethasone. After 397 deaths, a log-rank test compared OS between arms using anominal α level of 0.0498. Results: Pt characteristics were balanced between arms: median age 61 years; 58% men; 32% PS 0; 95% Caucasian; 86% adenocarcinoma; 45% complete/partial response (CR/PR) to induction. Pem resulted in a statistically significant 22% reduction in risk of death (HR=0.78). The HR was the same when measured from the beginning of induction. Survival improvement was similar for pts with an induction outcome of CR/PR versus stable disease. Conclusions: Pem continuation maintenance therapy offers superior OS compared with plb. These final results confirm that pem-cis induction followed by continuation pem further benefits pts compared with induction therapy alone, offering a change in the treatment paradigm for advanced NS NSCLC. [Table: see text]

A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA4511-LBA4511 ◽  
Author(s):  
W. K. Kelly ◽  
S. Halabi ◽  
M. A. Carducci ◽  
D. J. George ◽  
J. F. Mahoney ◽  
...  
Keyword(s):  
Performance Status ◽  
Thrombotic Event ◽  
Phase Iii ◽  
Rank Statistic ◽  
Castration Resistant Prostate Cancer ◽  
Primary Analysis ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Significance Level ◽  
Disease Response

LBA4511 Background: The preclinical activity of vascular endothelial growth factor (VEGF) blockade, the inverse relationship of plasma and urine VEGF levels and survival in mCRPC patients (pts), and encouraging phase II data testing estramustine and docetaxel with bevacizumab suggested that VEGF blockade was an appropriate potential strategy in mCRPC. A phase III study testing the effect of adding bevacizumab to standard docetaxel and prednisone therapy administered every 3 weeks in pts with mCRPC was conducted. Methods: 1050 pts with chemotherapy naïve, mCRPC with evidence of progressive disease despite castrate testosterone levels and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function were eligible. Pts were prospectively randomized with equal probability to receive docetaxel (D:75 mg/m2 IV over 1 hour q 21 days), plus prednisone (P) 5 mg po BID with either bevacizumab (B:15 mg/kg given intravenously q 3 weeks following D) or placebo. All patients received dexamethasone 8 mg PO 12, 3 and 1 hour prior to D. Randomization was stratified by predicted 24 mo survival probability, age and history of prior arterial thrombotic event. The primary endpoint was overall survival (OS). The trial was designed with 86% power to detect a 21% decrease in the hazard rate of death (equivalent to an increase in median OS from 19 months to 24 months) assuming a two-sided significance level of 0.05. The primary analysis was based on the stratified log-rank statistic adjusted for the stratification factors following observation of 748 deaths. Results: See Table . Conclusions: Despite an improvement in PFS, measurable disease response and post-therapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC, and was associated with greater morbidity and mortality. The median OS of pts treated with standard DP (21.5 m) was longer than previously reported (19 m). [Table: see text] [Table: see text]

PALETTE: Final overall survival (OS) data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10009-10009 ◽  
Author(s):  
Winette T.A. Van Der Graaf ◽  
Jean-Yves Blay ◽  
Sant P. Chawla ◽  
Dong-Wan Kim ◽  
Binh Bui Nguyen ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Advanced Disease ◽  
Cox Model ◽  
Statistical Significance ◽  
Performance Status ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Interaction Factor

10009 Background: At ASCO 2011 we presented an increase in median progression-free survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR 0.31) in a randomized double-blind, placebo-controlled phase III trial in advanced non-adipocytic STS patients pretreated with chemotherapy. Now we present final OS data and predictive factors for OS, such as ethnicity, ancestry and well-known prognostic and predictive factors in STS patients treated with chemotherapy. Methods: At clinical cut-off median follow-up was 25 months. Comparison of both treatments for OS was performed using a two-sided log rank test stratified for number of prior lines of systemic therapy for advanced disease and WHO performance status (PS). HR was calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline characteristics as potential predictive factors for OS were: PS (0 vs 1), number of lines of prior therapy for advanced disease (0-1 vs 2+), age (≤55 yrs vs > 55 yrs), gender, ethnicity (Hispano or Latino vs other), geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs 3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model was fitted with the investigated factor, treatment arm and associated interaction factor. Data of all 369 randomized patients (123 placebo, 246 pazopanib) were used for the analyses. Results: Median OS (95% CI) was 10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic treatment was administered in 63% of placebo, and in 49% of pazopanib treated patients. None of the investigated factors showed any statistical significant predictive value for OS. Conclusions: Although pazopanib demonstrated a statically significant increase in PFS compared to placebo, final OS analysis, which showed a trend in favor of pazopanib in patients with metastatic non-adipocytic STS, did not reach statistical significance. The factors studied were not predictive for OS.

Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4551-4551 ◽  
Author(s):  
A. Oliver Sartor ◽  
Daniel Heinrich ◽  
Joe M. O'Sullivan ◽  
Sophie D. Fossa ◽  
Ales Chodacki ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Performance Status ◽  
Standard Of Care ◽  
High Energy ◽  
Alpha Particles ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Radium 223 ◽  
Ecog Ps

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; two-sided P = .00185; HR = .695; 95% CI, .552-.875).SREs were lower in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo v 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration (≥ 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time to ECOG PS deterioration (≥ 2 points) was significantly delayed by Ra-223 v pbo (P = .003; HR = .62; 95% CI, .46-.85). Conclusions: Ra-233 significantly delayed time to 1st SRE and SRE components, notably SCC. Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 improves OS with excellent safety and may provide a new standard of care for CRPC pts with bone mets. [Table: see text]

A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4135-TPS4135 ◽  
Author(s):  
Charles S. Fuchs ◽  
Sergio Jobim Azevedo ◽  
Alfredo Carrato ◽  
Vincent Haddad ◽  
Lara Rachel Lipton ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Rank Test ◽  
Metastatic Adenocarcinoma ◽  
Double Blind ◽  
Patient Reported ◽  
Adenocarcinoma Of The Pancreas

TPS4135 Background: Ganitumab (AMG 479) is an investigational, fully human, monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study in patients with metastatic pancreatic cancer, addition of ganitumab 12 mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS) and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposure-efficacy analysis showed that patients with higher ganitumab exposure levels (AUCss at or above median) had longer PFS and OS (Lu. JCO. 2011;29:4049). Methods: In this phase III study, patients are randomized 2:2:1 to placebo + G, ganitumab 12 mg/kg + G, or ganitumab 20 mg/kg + G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas; ECOG score 0 or 1; ≥ 18 years old; adequate organ function; and fasting (or non-fasting) glucose ≤ 160 mg/dL. The primary endpoint is OS. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab + G vs placebo + G. Key secondary endpoints include PFS, objective response, safety, and patient-reported outcomes. An additional objective is to define a subpopulation with improved OS based upon baseline levels of circulating biomarkers. Enrollment began in April 2011. As of January 23, 2012, 463 of 825 patients have been enrolled. The study is overseen by an independent data monitoring committee. Status: open. Supported by Amgen Inc. in collaboration with Takeda Global Research & Development Center, Inc.; ClinicalTrials.gov: NCT01231347.

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