Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6012-6012
Author(s):  
Mansoor Raza Mirza ◽  
Gitte-Betina Nyvang ◽  
Bente Lund ◽  
Rene dePont Christensen ◽  
Theresa Louise Werner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Once Daily ◽  
Platinum Sensitive ◽  
Phase 2 Study ◽  
Patient Reported ◽  
Eortc Qlq

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. > 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P < 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 & TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.

Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5505-5505 ◽  
Author(s):  
Mansoor Raza Mirza ◽  
Elisabeth Avall-Lundqvist ◽  
Michael J. Birrer ◽  
Rene dePont Christensen ◽  
Gitte-Bettina Nyvang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Open Label ◽  
Once Daily ◽  
Platinum Sensitive ◽  
Patient Reported ◽  
Eortc Qlq

5505 Background: Standard treatment of platinum-sensitive recurrent ovarian cancer (PSROC) is platinum based combination chemotherapy ± bevacizumab. However, this treatment modality is hardly curative, and is associated with significant toxicity. Both bevacizumab (BEV) and PARP inhibitors (PARPi) have demonstrated efficacy in PSROC. There is preclinical evidence of enhanced activity of the combination. This is the proof-of-concept randomized trial of PARPi-BEV combination against PARPi monotherapy as treatment in PSROC, regardless of number of previous lines of therapies. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and BEV 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was progression-free survival (PFS). Stratification was according to homologous recombination-deficiency(HRD) status (MyChoice HRD) and chemotherapy-free-interval (CFI)(6-12months (mo) vs. >12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: median 11.9 vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.35; 95% confidence interval (CI),[0.21 to 0.57]; P<0.001. Pre-planned exploratory subgroup analyses: patients with HRD-positive tumors (n=54) HR 0.36 (CI, 0.18-0.69); HRD-negative disease (n=43) HR, 0.47 (CI, 0.24-0.95); g BRCAmut patients (n=34) HR 0.53 (CI, 0.23-1.21); non-g BRCAmut patients (n=63) HR 0.33; CI, 0.18-0.61); CFI of 6 to 12 mo (n=38) HR, 0.29 (CI, 0.14 to 0.62); CFI of ≥12 mo (n=59) HR, 0.42; (CI, 0.22 to 0.80). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (26.5% vs. 0%) and neutropenia (12.2% vs. 2.1%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Both niraparib alone and the combination had meaningful activity in PSROC. Compared to niraparib alone, the chemotherapy-free regimen of niraparib and BEV significantly improved PFS in women with PSROC,regardless of HRD status and duration of CFI. Clinical trial information: NCT02354131.

Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5535-5535 ◽  
Author(s):  
Joyce F. Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Free Survival ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

5535 Background: We previously reported that the combination of cediranib (ced) and olaparib (olap) improved progression-free survival (PFS) and overall response rates (ORR) in women with recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related ovarian cancer (OvCa) (NCT 01116648). We conducted an updated PFS and overall survival (OS) analysis. Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. PFS was defined as time from randomization to radiographic progression or death. OS was defined as time from randomization to death. Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). As of Dec 21, 2016, 67 pts had a PFS event, and 52 pts had an OS event. Updated median PFS was 8.2 mos for Olap and 16.5 mos for Ced/Olap (HR 0.50, 95% CI 0.30-0.83, p=0.007). Median OS was 33.3 mos for Olap and 44.2 mos for Ced/Olap (HR 0.64, 95% CI 0.36-1.11, p=0.11). Within known germline BRCA mut carriers, updated PFS was 16.5 vs 16.4 mos (HR 0.75, p=0.42), and OS was 40.1 vs 44.2 mos (HR 0.79, p=0.55) for Olap and Ced/Olap, respectively. In pts without known germline BRCA mut, updated PFS was 5.7 vs 23.7 mos (HR 0.32, p=0.002), and OS was 23.0 vs 37.8 mos (HR 0.48, p=0.074). Conclusions: Updated PFS results consistently demonstrated that Ced/Olap significantly extended PFS compared to Olap in the overall population of women with plat-sens OvCa. In this Phase 2 study not powered to detect OS diferences, there was a trend towards OS improvement with Ced/Olap, particularly in pts without a known germline BRCA mutation. Results from ongoing studies of this oral combination in OvCa are of clinical interest. Clinical trial information: NCT 01116648.

scholarly journals A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3458-3464 ◽  
Author(s):  
Paul G. Richardson ◽  
Emily Blood ◽  
Constantine S. Mitsiades ◽  
Sundar Jagannath ◽  
Steven R. Zeldenrust ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Once Daily ◽  
Vein Thrombosis ◽  
Phase 2 Study ◽  
First Occurrence ◽  
Clinically Significant ◽  
Grade 3 ◽  
Randomized Phase 2

Abstract This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

scholarly journals Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

2014 ◽  
Vol 15 (11) ◽  
pp. 1207-1214 ◽  
Author(s):  
Joyce F Liu ◽  
William T Barry ◽  
Michael Birrer ◽  
Jung-Min Lee ◽  
Ronald J Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase 2 ◽  
Platinum Sensitive ◽  
Phase 2 Study

TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9637-TPS9637
Author(s):  
Robert Charles Doebele ◽  
Jessica Jiyeong Lin ◽  
Misako Nagasaka ◽  
Viola Weijia Zhu ◽  
Nashat Y. Gabrail ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Resistance Mutations ◽  
Open Label ◽  
Phase 2 Study

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]

A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA5500-LBA5500 ◽  
Author(s):  
Joyce Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Open Label ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.

L-MOCA: An open-label study of olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17526-e17526
Author(s):  
Qing-lei Gao ◽  
Jianqing Zhu ◽  
Weidong Zhao ◽  
Yi Huang ◽  
Ruifang An ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Disease Progression ◽  
Brca Mutation ◽  
Progression Free Survival ◽  
Primary Analysis ◽  
Open Label ◽  
Platinum Sensitive ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Full Analysis

e17526 Background: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib, significantly improves progression-free survival (PFS) versus placebo. This is the first study to evaluate the efficacy and tolerability of the olaparib (Lynparza), an oral PARPi, in patients with platinum-sensitive relapsed (PSR) ovarian cancer, carried out exclusively in Asia. Methods: In this open-label, single arm trial, patients with PSR high grade epithelial ovarian cancer who had received ≥2 previous lines of platinum-based chemotherapy with a response, were enrolled from 28 centres in China and Malaysia. All patients received oral olaparib (300 mg) tablet twice daily until disease progression or unacceptable toxicity. The primary endpoint was PFS assessed by investigator according to RECIST 1.1 criteria. Secondary endpoints included time to TFST, PFS2, TSST, OS, and safety endpoints included adverse events (AEs). Subgroup analysis of PFS was examined by BRCA status. Data were summarized by descriptive statistics; time-to-event endpoints were analyzed using Kaplan-Meier method. Primary analysis was performed when 60% of PFS events had been achieved. Results: Between 2018 and 2020, the 224 patients recruited into this study received oral olaparib (full analysis set). 224 patients (91.5% from China and 8.5% from Malaysia) provided BRCA mutation status by blood and tissue testing. 47.3% patients were BRCAm, 41.1% patients were gBRCAm,52.2% patients were BRCAwt and 0.4% patients were BRCA unknown. 35.7% patients had received ＞2 lines of chemotherapy. At data cut-off (Dec 25th, 2020), 139 patients had disease progression; median PFS (mPFS) was 16.1 (95% CI 13.3-18.3) m in all patients. The mPFS was 21.2m, 21.4m and 11.0m in BRCAm, gBRCA and BRCAwt subgroups, respectively. The overall incidence of any AE and SAE was 99.1% and 25.4%, respectively. There were 9.4% patients who discontinued therapy due to the treatment related AE. The most common AEs were anemia, nausea and vomiting. Conclusions: The L-MOCA study demonstrates olaparib maintenance treatment is effective and well tolerated in Asian PSR ovarian cancer patients regardless of BRCA status. Clinical trial information: NCT03534453. [Table: see text]

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