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.

Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5514-5514 ◽  
Author(s):  
Karim Fizazi ◽  
Neal D. Shore ◽  
Teuvo Tammela ◽  
Albertas Ulys ◽  
Egils Vjaters ◽  
...  
Keyword(s):  
Safety Profile ◽  
Final Analysis ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Primary Analysis ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Secondary Endpoints ◽  
Favorable Safety

5514 Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P<0.0001). We report final analyses of OS and prospectively collected, patient-relevant secondary endpoints, and updated safety results. Methods: 1509 patients (pts) with nmCRPC were randomized 2:1 to DARO 600 mg twice daily (n=955) or PBO (n=554) while continuing ADT. Secondary endpoints included OS, and times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. The OS analysis was planned to occur after approximately 240 deaths. Secondary endpoints were evaluated in a hierarchical order. Results: Final analysis was conducted after 254 deaths were observed (15.5% of DARO and 19.1% of PBO patients). After unblinding at the primary analysis, 170 pts crossed over from PBO to DARO. DARO showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death compared with placebo. All other secondary endpoints were significantly prolonged by DARO (Table), regardless of the effect of crossover and subsequent therapies on survival benefit. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency were generally comparable between DARO and PBO, similar to the safety profile observed at the primary analysis. Incidences of AEs of interest (including falls, CNS effects, and hypertension) were not increased with DARO compared with PBO when adjusted for treatment exposure. AEs in the crossover group were consistent with those for the DARO treatment arm. Conclusions: DARO showed a statistically significant OS benefit for men with nmCRPC. In addition, DARO delayed onset of cancer-related symptoms and subsequent chemotherapy, compared with PBO. With extended follow-up, safety and tolerability were favorable and consistent with the primary ARAMIS analysis (Fizazi et al, N Engl J Med 2019;380:1235-46). Clinical trial information: NCT02200614 .[Table: see text]

Symptomatic Treatment With Lanreotide Microparticles in Inoperable Bowel Obstruction Resulting From Peritoneal Carcinomatosis: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

2012 ◽  
Vol 30 (35) ◽  
pp. 4337-4343 ◽  
Author(s):  
Pascale Mariani ◽  
Joëlle Blumberg ◽  
Alain Landau ◽  
Daniela Lebrun-Jezekova ◽  
Estelle Botton ◽  
...  
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Bowel Obstruction ◽  
Well Being ◽  
Symptomatic Treatment ◽  
Phase Iii ◽  
Primary Analysis ◽  
Open Label ◽  
Double Blind ◽  
Parallel Group ◽  
Intent To Treat

Purpose To investigate the somatostatin analog lanreotide as symptomatic treatment for inoperable bowel obstruction due to peritoneal carcinomatosis. Patients and Methods In all, 80 patients with peritoneal carcinomatosis, inoperable malignant digestive obstruction, and two or more vomiting episodes per day or nasogastric tube (NGT) who were previously treated with intravenous corticosteroids and proton pump inhibitors were randomly assigned to one 30-mg injection of lanreotide microparticles (n = 43) or placebo (n = 37) in a 10-day, double-blind, parallel-group phase. The primary end point was the proportion of patients responding on day 7 (one or fewer episodes of vomiting per day or no vomiting recurrence after NGT removal [for ≥ 3 consecutive days in both cases]). Vomiting frequency/NGT secretion volumes, nausea, abdominal pain, well-being, and safety were also assessed. Patients could then enter an open-label lanreotide-only phase. The study was conducted at 22 European hospitals. Results More patients receiving lanreotide than placebo were responders; this difference was not statistically significant for the intent-to-treat (ITT) population on the basis of diary cards (primary analysis; 41.9% [18 of 43] v 29.7% [11 of 37], respectively; odds ratio, 1.75; 95% CI, 0.68 to 4.49; P = .24) but was statistically significant for the corresponding supportive per protocol analysis (57.7% [15 of 26] v 30.4% [seven of 23]; P < .05) and ITT analysis, on the basis of investigators' assessments (50.0% [19 of 38] v 28.6% [10 of 35]; P < .05). Improvements in well-being were significantly greater with lanreotide on days 3, 6, and 7. No significant differences were observed for other secondary end points. Only two (mild/moderate) treatment-emergent adverse events were considered related to lanreotide. Conclusion These results show that lanreotide has some efficacy and is safe in the symptomatic treatment of patients with inoperable bowel obstruction due to peritoneal carcinomatosis.

START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7500-7500 ◽  
Author(s):  
Charles Andrew Butts ◽  
Mark A. Socinski ◽  
Paul Mitchell ◽  
Nick Thatcher ◽  
Libor Havel ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Phase Iii ◽  
Stage Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Double Blind ◽  
Unresectable Stage ◽  
Clinical Hold ◽  
Stage Iii Nsclc ◽  
Symptom Progression

7500 Background: L-BLP25 is a MUC1 antigen specific cancer immunotherapy. We report results from the phase III START study of L-BLP25 in patients (pts) not progressing after primary chemoradiotherapy (CRT) for stage III NSCLC. Methods: From Jan 2007 to Nov 2011, 1513 pts with unresectable stage III NSCLC that did not progress after CRT (platinum based chemo and ≥50 Gy) were randomized (2:1; double-blind) to L-BLP25 (806 µg lipopeptide) or placebo (PBO) SC weekly x 8 then Q6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 x 1 or saline was given 3 days prior to first L-BLP25/PBO dose. Primary endpoint was overall survival (OS). Results: The primary analysis population (n=1239) was defined prospectively to try to account for a clinical hold by excluding pts randomized 6 months (m) before the hold. Arms were balanced for baseline characteristics. Median age was 61 y; 38.2% had stage IIIA and 61.3% IIIB; 65% had concurrent and 35% sequential CRT. Median OS was 25.6 m with L-BLP25 vs. 22.3 m with PBO (adjusted HR 0.88, 95% CI 0.75-1.03, p=0.123). Secondary endpoints time-to-progression and time-to-symptom-progression support consistency of results: HR 0.87 (95% CI 0.75-1.00, p=0.053) and 0.85 (95% CI 0.73-0.98, p=0.023). In predefined subgroup analyses, pts with concurrent CRT (n=806) had median OS of 30.8 m (L-BLP25) vs. 20.6 m (PBO; HR 0.78, 95% CI 0.64-0.95, p=0.016), while median OS with sequential CRT was 19.4 m (L-BLP25) vs. 24.6 m (PBO; HR 1.12, 95% CI 0.87-1.44, p=0.38; interaction p=0.032, Cox PH model). Sensitivity analyses revealed that there was no OS benefit in pts randomized 6 m before the hold (HR 1.09, CI 0.75-1.56, p=0.663). LEBLP25 was well tolerated with no safety concerns identified and no emergent evidence of immune related adverse events. Conclusions: L-BLP25 maintenance therapy in stage III NSCLC was well tolerated, but did not significantly prolong OS. Sensitivity analyses showed a smaller treatment effect due to the clinical hold, suggesting that longer uninterrupted treatment with L-BLP25 is required. Clinically meaningful prolongation of OS was observed in the predefined subgroup of pts with primary concurrent CRT. Clinical trial information: NCT00409188.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
M. H. Shah ◽  
T. Ito ◽  
C. Lombard-Bohas ◽  
E. M. Wolin ◽  
E. Van Cutsem ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Phase Ii Studies ◽  
The Impact ◽  
Patient Subgroups

158 Background: There is an unmet medical need for effective treatments for patients with advanced pNET. Systemic therapies for advanced pNET are limited both by toxicity and efficacy. Everolimus, an oral mTOR inhibitor, has shown promising antitumor activity in 2 phase II studies, leading to further investigation in the largest phase III randomized controlled trial completed in pNET patients. Methods: Patients with advanced low- or intermediate-grade pNET were randomly assigned to everolimus 10 mg/d orally + best supportive care (BSC; n = 207) or placebo + BSC (n = 203). Long-acting somatostatin analogs (SSAs) were permitted as BSC during the study. The primary endpoint was progression free survival (PFS). At progression (RECIST), patients could be unblinded and those randomly assigned to placebo were offered open-label everolimus. Results: Compared with placebo, everolimus reduced the risk of progression by 65% and increased median PFS by more than 6 months, from 4.6 to 11.0 months (HR = 0.35; 95% CI: 0.27-0.45; p < 0.0001), by investigator review (primary endpoint). Median PFS by central review was consistent (HR = 0.34; 95% CI: 0.26 to 0.44; p < 0.001] in favor of everolimus. Eighteen-month PFS estimates were 34% for everolimus (95% CI: 26-43) vs 9% (95% CI: 4-16) for placebo. Everolimus demonstrated a significant PFS benefit across all patient subgroups according to baseline characteristics and prior SSA use. Prior SSA use was 49% in the everolimus arm and 50% in the placebo arm. Updated analyses of the impact of concomitant SSA will be reported. The most common drug-related adverse events were stomatitis, rash, diarrhea, fatigue, and infections (primarily upper respiratory); most were grade 1 or 2. Stomatitis (6.9% vs 0%), anemia (6% vs 0%), and hyperglycemia (5% vs 2%) were the most common grade 3-4 events. Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups. Treatment resulted in a significant 6.4-month prolongation in median PFS. Everolimus had an acceptable and predictable safety profile. [Table: see text]

Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3515-3515 ◽  
Author(s):  
Christophe Tournigand ◽  
Benoist Chibaudel ◽  
Benoit Samson ◽  
Werner Scheithauer ◽  
Gérard Lledo ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Analysis ◽  
Phase Iii Trial ◽  
Kras Status ◽  
Secondary Endpoints ◽  
The Impact ◽  
Egfr Tki

3515 Background: The primary analysis of DREAM demonstrated that a maintenance therapy (MT) with bevacizumab (Bev) + EGFR TKI erlotinib (E) significantly improved progression-free survival (PFS) after a 1st-line Bev-based induction therapy (IT) in patients (pts) with unresectable mCRC. Methods: Pts were randomized to MT after an IT with FOLFOX-bev or XELOX-bev or FOLFIRI-bev between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/d ; arm B) until PD or unacceptable toxicity. Primary endpoint was PFS on MT. Secondary endpoints included PFS from inclusion, overall survival (OS) and safety. The impact of KRAS tumor status on treatment efficacy was evaluated in an exploratory analysis. Results: 700 pts were registered and 452 pts were randomized (228 in arm A, 224 in arm B). KRAS status was available for 413/452 (91%) pts. The median duration of MT was 3.6 m. Results for MT are presented below (Table). In the registered population, median OS was 24.9m (22.5 – 27.3). Conclusions: Maintenance treatment with bev + erlotinib increases PFS over maintenance with bev alone in pts with mCRC but does not prolong OS. Further follow-up will determine the impact of 2nd or 3rd line anti-EGFR Mabs in this study. Contrasting with anti-EGFR Mabs, KRAS tumor status is not mandatory to select pts with mCRC for treatment with erlotinib. Clinical trial information: NCT00265824. [Table: see text]

POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 412-412
Author(s):  
Lawrence Howard Schwartz ◽  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pancreatic Disease ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Free Survival ◽  
Radiologic Assessment ◽  
The Impact

412 Background: The phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195. [Table: see text]

Centralized independent disease status adjudication for maintenance treatment evaluation in advanced ovarian cancer setting: A critical analysis of the MIMOSA trial experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16510-e16510
Author(s):  
Simona Scartoni ◽  
Jacobus Pfisterer ◽  
Paul Sabbatini ◽  
Jonathan S. Berek ◽  
Monica Bertolotti ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Data ◽  
Maintenance Treatment ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Double Blind ◽  
Abdomen Ct

e16510^ Background: Progression free survival (PFS) is an accepted surrogate of Overall Survival (OS) often used as the primary endpoint in phase III trials evaluating maintenance treatment in advanced ovarian cancer (AOC). Methods: We compare the centrally assessed PFS (PFS-CA) vsthe locally assessed PFS (PFS-LA) data collected in the Mimosa Trial, a randomized, double blind, placebo controlled, Phase III study of Abagovomab maintenance therapy in AOC patients in complete response after standard chemotherapy. PFS was assessed at pre-fixed time points by pelvis/abdomen CT scan, which were centrally and blinded reviewed by trained radiologists for radiological assessment (RA) of recurrence status and date (PFS-RA). An independent blinded committee, including one radiologist and one oncologist, reviewed all the CT scans and any additional imaging records AND/OR clinical data (when locally required for patients’management) to adjudicate the recurrence status and date (PFS-CA). PFS-CA was used for the primary analysis; sensitivity analyses were carried out on PFS-LA as well as on the strictly defined PFS-RA data. Results: 888 patients were randomized 2:1 to receive Abagovomab or placebo. In the ITT population (n = 886) time to PFS-CA was 403 and 402 days in Abagovomab and placebo group, respectively; in the sensitivity analyses time to PFS-LA was 407 and 409, and finally time to PFS-RA was 414- 487 days respectively, without any statistically significant differences between groups or PFS assessments. Conclusions: No differences were seen in PFS assessed centrally or locally when RA and clinical data are considered, whereas a slightly longer PFS was observed when it was assessed exclusively by the independent radiological review although this is not statistically different. The centralised independent assessment of recurrence status for ovarian cancer patients treated in the remission setting appears not to add value to the local blinded assessment. Clinical trial information: NCT00418574.

POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16800-e16800
Author(s):  
Lawrence Howard Schwartz ◽  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pancreatic Disease ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Free Survival ◽  
Radiologic Assessment ◽  
The Impact

e16800 Background: The Phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195 . [Table: see text]

Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4033-4033 ◽  
Author(s):  
C. Kohne ◽  
E. Bajetta ◽  
E. Lin ◽  
J. W. Valle ◽  
E. Van Cutsem ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Final Analysis ◽  
Serum Lactate ◽  
Phase Iii ◽  
Serum Lactate Dehydrogenase ◽  
Double Blind ◽  
Strong Activity ◽  
Baseline Serum ◽  
Secondary Endpoints ◽  
Pre Treatment

4033 Background: PTK/ZK, a novel, oral, anti-angiogenic compound that inhibits all VEGF receptors has been investigated in two multinational randomized phase 3 studies in 1st (CONFIRM 1) and 2nd line (CONFIRM 2) mCRC. Interim analyses (IA) have been presented at ASCO 2005 and 2006, respectively. Methods: In CONFIRM 2, 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically documented mCRC, pre-treatment for metastatic disease with irinotecan-/fluoropyrimidine- based therapy, measurable disease by RECIST, PS of 0–2 and adequate organ function. Pts were stratified based on PS (0 vs. 1–2) and baseline serum Lactate Dehydrogenase (LDH = vs. >1.5 × ULN). The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (LDH > 1.5 × ULN). Results: At the time of IA in July 2005, OS was 12.1 mo in the PTK/ZK and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, a marker for poor prognosis in mCRC, is predictive of the outcome in the PTK/ZK arm. When treated with PTK/ZK, high LDH pts showed a strong improvement in PFS (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and in OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial. Final analysis for OS, PFS and safety is planned for Feb. 2007 after 732 events (compared to 413 in the IA) and will be presented at the meeting. Conclusions: While the primary endpoint for OS was not met in the IA, PTK/ZK improves PFS significantly in the overall population, and shows strong activity (improved PFS and OS) in patients with high baseline serum LDH. Final results of the study will be presented at the meeting. No significant financial relationships to disclose.

Baseline demographics of the randomized, placebo-controlled, double-blind, phase III RADIANT-4 study of everolimus in nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NET).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 276-276 ◽  
Author(s):  
James C. Yao ◽  
Roberto Buzzoni ◽  
Carlo Carnaghi ◽  
Nicola Fazio ◽  
Simron Singh ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Performance Status ◽  
Progression Free Survival ◽  
The Body ◽  
Neuroendocrine Cells ◽  
Phase Iii ◽  
Somatostatin Analogue ◽  
Primary Analysis ◽  
Open Label ◽  
Double Blind

276 Background: NET are malignant tumors arising from neuroendocrine cells throughout the body. Everolimus (EVE), a mammalian target of rapamycin inhibitor, is approved for the treatment of advanced, well-differentiated pancreatic NET. There is an unmet medical need in GI and lung NET; targeted therapies, such as everolimus, are of particular interest. Methods: Patients with advanced nonfunctional NET of GI or lung origin with progressive disease (PD) within the past 6 months were randomized (2:1) to EVE 10 mg/d or placebo, both with best supportive care. Concomitant use of somatostatin analogue (SSA) was not allowed during the study, except for control of emergent carcinoid symptoms not manageable by standard therapy. Patients were stratified based on tumor sites, prior SSA exposure, and WHO performance status (PS) at baseline. Primary endpoint was progression-free survival (PFS) as assessed by central radiology review using modified RECIST 1.0 criteria. Primary analysis is planned after ~176 PFS events. Crossover to open label EVE after progression would not be allowed prior to the primary analysis. Overall survival was the key secondary endpoint. Results: Recruitment is completed. Of 388 patients screened, 302 were randomized (planned, 285). Median age was 63 years, 53% were females, and majority of them (76.2%) were white. The most common tumor sites were lung (29.8%), ileum (23.5%), and rectum (13.2%). WHO PS was 0 in 219 (72.5%) patients and 1 in 82 (27.2%) patients; 52% had received SSA prior to study entry. As of Sep 16, 2013, 173 (57.3%) patients remain on treatment, 127 (42.1%) discontinued treatment and 2 (0.7%) were not treated. PD (24.2%) and adverse events (10.6%) were the most common reasons for treatment discontinuation. Results of primary analysis are expected by early 2015. Conclusions: RADIANT-4 is the first phase III study to assess the efficacy and safety of EVE in patients with nonfunctional NET of GI or lung origin. Non-crossover design and prospective stratification of the population based on known prognostic factors should minimize confounding in the estimation of the treatment effect. Clinical trial information: NCT01524783.

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