Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15120-e15120
Author(s):  
Leonard G. Gomella ◽  
Chadi Nabhan ◽  
Todd DeVries ◽  
James Boyd Whitmore ◽  
Mark Walter Frohlich ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Salvage Therapy ◽  
Failure Time ◽  
Phase Iii ◽  
Comparable Efficacy ◽  
Cellular Immunotherapy ◽  
Three Phase ◽  
Castrate Resistant ◽  
The Impact ◽  
Phase Iii Studies

e15120 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Three phase III sipuleucel-T trials (D9901, D9902A and D9902B [IMPACT]) allowed control patients (pts) to receive salvage treatment with an autologous product derived from previously frozen cells (APC8015F). We previously reported that salvage therapy with APC8015F demonstrated no deleterious effect and may have improved outcomes in control pts, potentially reducing the observed survival benefit seen with sipuleucel-T. Thus, we performed an exploratory analysis of pooled data from phase III studies to estimate the impact of APC8015F treatment on the OS benefit conferred by sipuleucel-T. Methods: We analyzed the effect of salvage APC8015F therapy on OS, and used a rank-preserving structural failure time (RPSFT) model to estimate control arm OS if treatment with APC8015F had not occurred. This allows estimation of the effect of sipuleucel-T treatment on OS, adjusting for salvage effect. Results: Median OS from randomization in the three pooled trials was 25.4 months with sipuleucel-T (n=488) and 21.5 months with control (n=249). Of the control arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from randomization in the control population was 23.6 months for pts receiving APC8015F and 12.7 months for those who did not. Using the RPSFT model, and assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for control pts was 17.3 months, representing an 8.1 month median increase in OS with sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: These analyses estimated a median OS benefit for sipuleucel-T between 3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable efficacy to sipuleucel-T, respectively. The results suggest a possible greater treatment effect of sipuleucel-T than was reported in the three phase III studies. Future studies should account for potential crossover treatment bias as this may diminish estimates of OS benefit.

An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 144-144
Author(s):  
Chadi Nabhan ◽  
Leonard G. Gomella ◽  
Todd DeVries ◽  
James Boyd Whitmore ◽  
Mark Walter Frohlich ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Failure Time ◽  
Cellular Immunotherapy ◽  
Impact Study ◽  
Treatment Benefit ◽  
Positive Treatment Effect ◽  
Positive Treatment ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Impact

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.

Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4650-4650 ◽  
Author(s):  
Douglas G. McNeel ◽  
Daniel W. Lin ◽  
Thomas Gardner ◽  
Nadeem A. Sheikh ◽  
James Boyd Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hypereosinophilic Syndrome ◽  
Phase Iii ◽  
Cellular Immunotherapy ◽  
Cancer Specific Survival ◽  
Phase Iii Trials ◽  
Castrate Resistant ◽  
Humoral Responses ◽  
The Impact ◽  
Eosinophil Counts

4650 Background: Sipuleucel-T is the first autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. In the IMPACT trial, pts treated with sipuleucel-T had transient increases in eosinophil counts compared with control. In this retrospective analysis, we assess potential correlations between eosinophilia, overall survival (OS), prostate cancer-specific survival (PCSS) and immune response following sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, and IMPACT) were pooled. The analysis included CBCs performed at baseline and wks 2–34. Eosinophilia was defined as either >ULN (with normal baseline), or a max change from baseline within the top quartile, at any time between wks 2–16. Results: Increased eosinophil counts were seen in sipuleucel-T pts by wk 6, decreasing to near baseline by wk 14; eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts eligible for analysis, 105 (27.9%) had eosinophilia. Baseline disease characteristics associated with eosinophilia were indicative of better prognosis (i.e., longer Halabi predicted survival [p=0.007], lower PSA [P=0.033], higher Hgb [p<0.001], and no prior docetaxel [p=0.012]). In univariate analyses, eosinophilia correlated with improved OS (HR=0.75; 95%CI: 0.56–1.01; p=0.057) and PCSS (HR=0.71; 95%CI: 0.53–0.97; p=0.031); trends persisted after adjusting for Halabi. The magnitude of eosinophilia positively correlated with antigen-specific humoral responses (p ≤0.039 for wks 6, 14 and 26) and elevations in the cytokines at wk 6 (IL2 [p=0.011], IL5 [p=0.038] and TARC [p=0.001]). AEs occurring more frequently (p<0.05) in pts with eosinophilia were infusion-related: pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of hypereosinophilic syndrome were reported. Conclusions: Increases in eosinophils after sipuleucel-T correlated with improved OS and PCSS. Large increases in eosinophil counts were associated with humoral responses and Th2-type cytokine production. Further studies of eosinophilia as a biomarker for sipuleucel-T response, particularly in earlier disease settings, are of interest.

Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 240-240
Author(s):  
Neal D. Shore ◽  
Karim Fizazi ◽  
Teuvo Tammela ◽  
Murilo Luz ◽  
Manuel Philco Salas ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Safety Profile ◽  
Final Analysis ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Open Label ◽  
Double Blind ◽  
Secondary Endpoints ◽  
The Impact

240 Background: DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) based on significantly prolonged metastasis-free survival compared with PBO (median 40.4 vs 18.4 months; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.0001) and a favorable safety profile in the phase III ARAMIS trial. Following unblinding at the primary analysis, crossover from PBO to DARO was permitted for the subsequent open-label treatment phase. Sensitivity analyses were performed to assess the effect of PBO–DARO crossover on OS benefit. Methods: Patients (pts) with nmCRPC receiving androgen deprivation therapy were randomized 2:1 to DARO (n = 955) or PBO (n = 554). In addition to OS, secondary endpoints included times to pain progression, first cytotoxic chemotherapy, first symptomatic skeletal event, and safety. The OS analysis was planned to occur after approximately 240 deaths, and secondary endpoints were evaluated in a hierarchical order. Iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses to adjust for the treatment effect of PBO–DARO crossover. The IPE method used a parametric model for the survival times and iteratively determined the model parameter describing the magnitude of the treatment effect, whereas a grid search and non-parametric log-rank test were used for the RPSFT analysis. The IPE and RPSFT analyses both generated a Kaplan–Meier curve for the PBO arm that predicts what would have been observed in the absence of PBO–DARO crossover. Results: After unblinding, 170 pts (30.7% of those randomized to PBO) crossed over from PBO to DARO; median treatment duration from unblinding to the final data cut-off was 11 months. Final analysis of the combined double-blind and open label periods was conducted after 254 deaths (15.5% of DARO and 19.1% of PBO pts) and showed a statistically significant OS benefit for DARO vs PBO (HR 0.69; 95% CI 0.53–0.88; P = 0.003). Results from the IPE (HR 0.66; 95% CI 0.51–0.84; P < 0.001) and RPSFT (HR 0.68; 95% CI 0.51–0.90; P = 0.007) analyses were similar to those from the intention-to-treat population, showing that the impact of PBO–DARO crossover was small. Additional analyses accounting for the effect of PBO–DARO crossover will be presented. The safety profile of DARO continued to be favorable at the final analysis, and discontinuation rates at the end of the double-blind period remained unchanged from the primary analysis (8.9% with DARO and 8.7% with PBO). Conclusions: Early treatment with DARO in men with nmCRPC is associated with significant improvement in OS regardless of pts crossing over from PBO to DARO. The safety profile of DARO remained favorable at the final analysis. Clinical trial information: NCT02200614.

Use of placebo in cancer medicine: The experience of a National Clinical Trials organization

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6104-6104
Author(s):  
J. L. Pater ◽  
W. Parulekar
Keyword(s):  
Clinical Trials ◽  
Supportive Care ◽  
Study Design ◽  
Standard Of Care ◽  
Phase Iii ◽  
Design Data ◽  
Standard Of Care Treatment ◽  
Prevention Trials ◽  
The Impact ◽  
Phase Iii Studies

6104 Background: The use of placebos in cancer clinical trials requires careful evaluation. Factors that must be considered include the impact of placebo on endpoint measurement, the efficacy of placebo relative to standard of care treatment, patient altruism/acceptance of a non-active intervention and the resulting increase in complexity of study conduct with respect to randomization, drug supply, data management, analysis and the unblinding process. Methods: We reviewed the experience of the National Cancer Institute of Canada Clinical Trials Group with the use of placebo in the randomized phase III setting from 1982–2005. Results: Since 1982, 34 studies were identified that utilized a placebo as part of study design. Data is presented below according to the type of study and date of study activation. The numbers in brackets represent those studies in which placebo was used alone in the control arm. Supportive care studies were the most common type of study employing a placebo as part of study design and constituted almost 50% of our Group’s experience. Therapeutic studies involving placebo were conducted in multiple sites including breast (4), lung (6), myeloma (1), melanoma (1), ovary (1) and pancreas (1). Conclusion: Phase III studies involving a placebo constitute an important part of our clinical trial activity and cross the spectrum of supportive care, therapeutic and prevention trials. The use of placebo in cancer studies may increase due to the relative ease of blinding in studies that evaluate targeted, oral therapies with minimal toxicities as well as the need for unbiased assessment of increasingly used endpoints such as time to progression. [Table: see text] No significant financial relationships to disclose.

An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 110-110 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Failure Time ◽  
Cox Model ◽  
Controlled Trial ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Primary Analysis ◽  
Significant Difference ◽  
The Impact

110 Background: The GRID study showed that regorafenib improves progression-free survival compared with placebo in patients with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p<0.0001; Demetri 2013). At the time of the primary analysis, no significant difference in the secondary endpoint of overall survival (OS) was observed (HR 0.77; p=0.199), but this result may have been confounded by the high rate of crossover to regorafenib (85%) of placebo patients at progression. We conducted exploratory analyses of updated OS data to assess the effect of correcting for this protocol-planned crossover. Methods: The data cut-off for this updated OS analysis was 31 January 2014 (2 years after the primary analysis). OS was corrected using two randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE); both methods are considered as best choice among all correction analytics. Hazard ratios and 95% CI were derived using the Cox model. Results: A total of 139 deaths had occurred at the time of data cut-off: 91 events (68.4% of patients) in the regorafenib group and 48 (72.7%) in the placebo group. A total of 22 patients remained on regorafenib treatment (median duration 2.1 years, range 0.9–2.4). The updated hazard ratio for OS favored regorafenib (0.85, 95% CI: 0.60 - 1.21; p=0.18). Median OS was estimated as 17.4 months in both groups, with crossover from placebo. The corrected HRs for OS are less than the uncorrected HR (Table). Conclusions: The updated analysis of OS in the GRID trial is consistent with the primary analysis. An exploratory analysis correcting for the impact of cross-over on OS suggests a survival benefit for regorafenib in GIST. Clinical trial information: NCT01271712. [Table: see text]

Impact of gender on the safety profile of chemotherapy plus bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3534-3534
Author(s):  
Gemma Zucchelli ◽  
Roberto Moretto ◽  
Marta Schirripa ◽  
Rossana Intini ◽  
Daniele Rossini ◽  
...  
Keyword(s):  
Safety Profile ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Logistic Regression Models ◽  
Antiemetic Prophylaxis ◽  
Safety Population ◽  
High Incidence ◽  
Males And Females ◽  
The Impact ◽  
Phase Iii Studies

3534 Background: Based on retrospective experiences, gender seems to affect the safety profile of chemotherapy (CT), with a higher incidence of CT-related adverse events (AEs) among females than males. Here we focus on the impact of gender on the toxicity of FOLFOXIRI/bevacizumab (bev) as compared with doublets (FOLFOX or FOLFIRI)/bev in two randomized phase III studies by GONO: TRIBE and TRIBE2. Methods: The risk of experiencing CT-related AEs in males and females was estimated in univariable analysis in the overall safety population and according to treatment arms (doublets/bev and FOLFOXIRI/bev). In order to assess the independent weight of gender on the risk of developing AEs, multivariable logistic regression models were built. Results: Among 1187 patients enrolled in TRIBE and TRIBE2 studies, 1176 (684 males, 58%, and 492 females, 42%) were included in the safety population. Overall, women had a significantly higher risk of CT-related AEs, in particular gastrointestinal and hematologic AEs, asthenia and alopecia, independently of the treatment arm. The risk of CT-related AEs was increased with FOLFOXIRI/bev vs doublets/bev independently of gender (p for interaction: 0.329). Notably, among women treated with FOLFOXIRI/bev 50% and 68% experienced any grade of vomiting and nausea, respectively. Conclusions: Female mCRC patients have a higher risk to develop CT-related AEs. In women treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis. [Table: see text]

Effect of dosing cycles on safety of denileukin diftitox (Dd) in cutaneous T-cell lymphoma (CTCL) patients: Integrated analysis of three phase III studies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19557-e19557
Author(s):  
Y. Kim ◽  
J. Beynon
Keyword(s):  
Treatment Cycle ◽  
Cell Lymphoma ◽  
Safety Data ◽  
Subsequent Treatment ◽  
Phase Iii ◽  
Integrated Analysis ◽  
Cutaneous T Cell Lymphoma ◽  
Three Phase ◽  
Large Phase ◽  
Phase Iii Studies

e19557 Background: Dd is a novel IL-2 receptor-targeted recombinant fusion protein that is approved for treatment of persistent/recurrent CTCL expressing CD25. To date, Dd is the most extensively studied agent in CTCL. The safety of Dd was assessed with respect to dosing cycle in CTCL subjects in 3 large phase III studies: 93–04–10 (study 10), L4389–11 (study 11) and L4389–14 (study 14). Methods: Subjects received Dd doses of 9 or 18 mcg/kg IV daily for 5 days, repeating every 21 days for up to 8 cycles; study 11 also included a placebo arm. Subjects in studies 10 and 11 were CD25(+); study 14 also included CD25(-) subjects. Safety data from these studies were integrated and are presented by dosing cycle. Results: Table 1 shows a summary of all reported adverse events (AEs) by cycle for the 3 studies. For subjects completing at least 4 cycles of Dd treatment the incidence of any AEs was lower in the 3rd and 4th cycles as compared to the 1st and 2nd cycles and the incidence of AEs continued to decrease after cycle 4. Conclusions: In the studies analyzed, the incidence of AEs decreased with each subsequent treatment cycle for subjects receiving Dd. [Table: see text] [Table: see text]

Abstract WP9: Impact of Sex Differences on the Treatment Effect of Mechanical Thrombectomy: A Subgroup Analysis of the RESILIENT Trial

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Octavio M Pontes-Neto ◽  
Daniel G Abud ◽  
Luis Castro-Afonso ◽  
Rui Kleber Martins-Filho ◽  
Guilherme Nakiri ◽  
...  
Keyword(s):  
Sex Differences ◽  
Treatment Effect ◽  
Mechanical Thrombectomy ◽  
Phase Iii ◽  
Public Healthcare ◽  
Anterior Circulation ◽  
Vessel Occlusion ◽  
Study Population ◽  
Baseline Characteristics ◽  
The Impact

Background: Despite evidence supporting the overall efficacy of mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) of the anterior circulation, it is unclear whether the treatment effect of MT differs by sex in different populations. We assessed the impact of sex differences in the treatment effect of MT in the RESILIENT trial. Methods: RESILIENT was a prospective, multicenter, randomized phase III trial that was designed to assess the safety, efficacy, and cost-effectiveness of mechanical thrombectomy as compared to medical treatment alone in patients treated under the less than ideal conditions typically found in the public healthcare system of a developing country. Results: Among 221 patients enrolled in the trial, 104 (47,1%) were female. Baseline characteristics were well balanced between sexes, except for a higher prevalence of hypertension (76% vs. 57.4%; p=0.004) and diabetes (34.3% vs. 21.7%; p=0.039) and a lower frequency of alcohol abuse (4% vs. 28.9%; p=0.001) in females. After adjustment for baseline characteristics, we found a significant interaction (p=0.026) between sex and the effect of MT with a lower efficacy of MT for functional independency at 90 days among women (aOR=1.13;95%CI:0.42-3.02) compared to men (aOR=4.78; 95%CI:1.88-12.15). Conclusions: In our study population of patients with AIS caused by LVO of the anterior circulation, women were less likely to benefit from MT than men. Further studies are necessary to investigate these findings.

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