KEYLYNK-009: A phase II/III, open-label, randomized study of pembrolizumab (pembro) plus olaparib vs pembro plus chemotherapy after induction with first-line pembro plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS596-TPS596 ◽  
Author(s):  
Hope S. Rugo ◽  
Antonio Llombart-Cussac ◽  
Fabrice Andre ◽  
Mark E. Robson ◽  
Shigehira Saji ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase Ii ◽  
Induction Therapy ◽  
Randomized Study ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Metastatic Setting ◽  
Locally Recurrent ◽  
Unacceptable Toxicity

TPS596 Background: Combination therapy with immunotherapy + chemotherapy is a promising approach for first-line (1L) treatment of locally recurrent, inoperable TNBC or metastatic TNBC (mTNBC). However, an unmet need exists for effective and tolerable maintenance regimens in mTNBC to sustain clinical benefit after induction therapy and avoid potential toxicity or resistance in response to prolonged chemotherapy. The PARP inhibitor olaparib has demonstrated efficacy in the maintenance setting for multiple platinum-sensitive tumors, and the prevalence of BRCA mutations in TNBC may make these tumors particularly sensitive to DNA-damaging agents. Moreover, previous data suggest that combination therapy with olaparib and the PD-1 inhibitor pembro may have clinical benefits. KEYLYNK-009 (NCT04191135) is a phase II/III, open-label, randomized study of pembro + olaparib or pembro + chemotherapy after induction with 1L pembro + chemotherapy in patients with locally recurrent, inoperable TNBC or mTNBC. Methods: This 2-in-1 study design will enroll ~317 patients in phase II; if a planned efficacy boundary is met, ~615 additional patients will be enrolled in phase III. Patients eligible for induction therapy must have measurable, locally recurrent, inoperable TNBC that cannot be treated with curative intent or mTNBC previously untreated with chemotherapy in the metastatic setting. All patients will receive up to 6 cycles of induction therapy with pembro 200 mg every 3 wk (Q3W) + chemotherapy (carboplatin AUC 2 + gemcitabine 1000 mg/m2). Patients eligible for postinduction treatment must achieve complete or partial response or maintain stable disease during induction after 4-6 treatment cycles, with ECOG PS 0/1 and no grade >1 toxicities related to induction therapy (excluding alopecia, Hb ≥9.0 g/dL, grade 2 hyper-/hypothyroidism, or grade 2 hyperglycemia). These patients will be randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or continue pembro + chemotherapy (same as induction regimen). Olaparib and chemotherapy may continue until progression or unacceptable toxicity; pembro may continue for ≤35 cycles (including induction), unacceptable toxicity, or progression. Phase III dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints include OS and PFS in patients with BRCAm, health-related quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT04191135 .

Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 351-351 ◽  
Author(s):  
Elisa Giommoni ◽  
Evaristo Maiello ◽  
Vanja Vaccaro ◽  
Ermanno Rondini ◽  
Caterina Vivaldi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
First Line ◽  
Open Label ◽  
Grade 3

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.

A phase III, open-label, randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes: Subgroup analyses.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1049-1049 ◽  
Author(s):  
Peter Andrew Kaufman ◽  
Javier Cortes ◽  
Ahmad Awada ◽  
Louise Yelle ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Randomized Study ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Open Label ◽  
Eribulin Mesylate ◽  
Prior Chemotherapy ◽  
Metastatic Setting ◽  
Subgroup Analyses

1049^ Background: This phase III study, comparing eribulin versus capecitabine, showed a non-significant trend for superior overall survival (OS; hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.77, 1.00]; p = 0.056) but not progression-free survival (PFS; HR 1.08 [95% CI 0.93, 1.25]; p = 0.31). Pre-specified exploratory subgroup analyses previously presented showed that patients with triple-negative, ER-negative or HER2-negative disease may have a greater benefit in OS with eribulin compared with capecitabine. Here we present further pre-specified exploratory analyses of OS and PFS. Methods: Patients (eribulin n=554; capecitabine n=548) with locally advanced or MBC had received ≤3 prior chemotherapy regimens (≤2 for advanced disease), including an anthracycline and a taxane. Patients were randomized (stratified for geographic region and HER2 status) 1:1 to 21-day cycles of eribulin mesylate 1.4 mg/m2 i.v. on days 1 and 8 or capecitabine 1.25 g/m2BID orally on days 1-14. Further pre-specified exploratory subgroups included: age; receptor status; number and setting of prior chemotherapy regimen(s); sites of disease; number of organs involved; and time to progression after last chemotherapy. Results: From analyses for OS, patients with only non-visceral disease (HR 0.51; 95% CI 0.33, 0.80), with >2 organs involved (HR 0.75; 95% CI 0.62, 0.90), who had progressed >6 months after last chemotherapy (HR 0.70; 95% CI 0.52, 0.95), or who had received an anthracycline and/or a taxane in the metastatic setting (HR 0.84; 95% CI 0.72, 0.98), appeared to benefit more from treatment with eribulin compared with capecitabine. For OS, in no subgroup was a trend favoring capecitabine seen. Data for other pre-specified subgroups for both OS and PFS will be presented. Conclusions: In addition to patients with triple-, ER-, or HER2-negative disease, further pre-specified exploratory analyses suggest that other patient subgroups may particularly benefit from treatment with eribulin; further studies are warranted to address these hypotheses. Clinical trial information: NCT00337103.

PROPEL: A randomized, phase III trial evaluating the efficacy and safety of olaparib combined with abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS340-TPS340 ◽  
Author(s):  
Noel W. Clarke ◽  
Andrew J. Armstrong ◽  
Antoine Thiery-Vuillemin ◽  
Mototsugu Oya ◽  
Dingwei Ye ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Metastatic Setting

TPS340 Background: A Phase II trial showed olaparib (tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; hazard ratio 0.65, 95% CI 0.44–0.97, P=0.034) in patients (pts) with mCRPC in the second-line metastatic setting who received prior docetaxel (Clarke et al. Lancet Oncol 2018). Treatment benefits were achieved irrespective of homologous recombination repair (HRR) mutation status, suggesting potential synergy between the two treatments that could impact a broader patient population. PROpel (EudraCT: 2018-002011-10) is the follow-on study to this, and the first Phase III trial to assess a PARP inhibitor in combination with abiraterone as first-line treatment in a genetically unselected mCRPC pt population. Methods: PROpel is a double-blind, placebo-controlled, international, multicenter study of pts randomized (1:1), as for the Phase II trial, to abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) plus either olaparib (tablets, 300 mg bid) or placebo. Pts must not have received prior chemotherapy, new hormonal agents or other systemic treatment at mCRPC stage (except docetaxel at metastatic hormone-sensitive prostate cancer stage [mHSPC]). Randomization is stratified according to site of metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes, no). The primary endpoint is investigator-assessed rPFS (RECIST v1.1 [soft tissue] and Prostate Working Cancer Group 3 [PCWG-3 criteria; bone]). Secondary objectives include time to first subsequent therapy or death, time to pain progression, overall survival, and health-related quality of life. Safety and tolerability will also be described. Exploratory endpoints include HRR subgroup analyses to confirm that efficacy is independent of HRR status. Screening across ~200 sites in 20 countries is being conducted to identify a target sample of ~720 pts. Enrollment is expected to begin in October 2018. (Study 8, NCT01972217). Clinical trial information: NCT03732820.

Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: The phase-II FIRE-4.5 study (AIO KRK-0116).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3502-3502
Author(s):  
Sebastian Stintzing ◽  
Kathrin Heinrich ◽  
David Tougeron ◽  
Dominik Paul Modest ◽  
Ingo Schwaner ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Randomized Study ◽  
Braf V600e ◽  
Comparable Efficacy ◽  
Line Treatment ◽  
First Line ◽  
Open Label ◽  
Primary Tumors ◽  
First Line Treatment

3502 Background: FIRE-4.5 (AIO KRK-0116) compared FOLFOXIRI plus either cetuximab or bevacizumab in BRAF V600E-mutant metastatic colorectal cancer (mCRC) patients not treated for metastatic disease before. Methods: Within this 1:2 randomized, controlled, open-label phase-II study, patients received FOLFOXIRI every two weeks at the following schedule: irinotecan 150mg/m² (30-90min, day 1), folinic acid 400mg/m² (120min, day 1), oxaliplatin 85mg/m² (120 min, day 1), followed by 5-fluorouracil 3,000 mg/m², 48h. FOLFOXIRI was combined with either bevacizumab (arm A) at a dose of 5mg/kg body weight, every 2 weeks or cetuximab (arm B) at a loading dose of 400mg/m² and subsequent weekly doses of 250mg/m². FOLFOXIRI was applied for a maximum of 12 cycles before maintenance treatment was recommended. Primary endpoint was superiority of Arm B with respect to overall response rate (ORR) according to RECIST 1.1 criterions. Secondary endpoints included PFS, OS, and tolerability. Results: From November 2016 to December 2020 108 patients were randomized in 90 German and 10 French centers (35 arm A and 73 in arm B). No new or unexpected toxicities were observed. Primary endpoint was not met with an ORR of 66.7% and 52.0% (p =0.23) in the respective arms. Median PFS was significantly longer in arm A vs arm B (8.3 months vs 5.9 months; logrank p = 0.03; HR 1.8). While OS data is still immature, median OS time are comparable at the time of analysis. Patients with left-sided primary tumors had comparable results with either bevacizumab or cetuximab, whereas those with right-sided primary tumors showed a trend towards better efficacy of the bevacizumab combination. Updated results will be presented at the annual meeting. Conclusions: FIRE-4.5 is the first prospective and randomized study investigating efficacy of FOLFOXIRI combined with targeted therapy in the first-line treatment of BRAF V600E-mutant mCRC. FOLFOXIRI plus either bevacizumab or cetuximab have comparable efficacy with differential effects according to primary tumor sidedness supporting the heterogeneity of BRAF V600E-mutant subpopulation of mCRC. Clinical trial information: NCT04034459.

A combination of pertuzumab, trastuzumab, and vinorelbine for first-line treatment of patients with HER2-positive metastatic breast cancer: An open-label, two-cohort, phase II study (VELVET).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS653-TPS653 ◽  
Author(s):  
Edith A. Perez ◽  
Jose Manuel Lopez-Vega ◽  
Lucia Del Mastro ◽  
Thierry Petit ◽  
Lada Mitchell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Metastatic Breast ◽  
Observation Time ◽  
Comparable Efficacy ◽  
Loading Dose ◽  
First Line ◽  
Dimerization Domain ◽  
Her2 Positive ◽  
Open Label ◽  
Metastatic Setting

TPS653 Background: Pertuzumab (P) is a humanized monoclonal antibody directed against the dimerization domain of HER2: it prevents HER2 heterodimerization and thus activation of downstream signaling. Since P targets a different epitope than trastuzumab (H), a more comprehensive HER2 blockade is achieved by combining the two agents. Data from CLEOPATRA showed improved efficacy for P and H plus docetaxel. The combination of P and H has not yet been assessed with other chemotherapy partners in the metastatic setting. H plus vinorelbine (V) has shown comparable efficacy to H plus docetaxel but with a superior safety profile. VELVET will assess the overall response rate (ORR) of P with H+V in first-line patients (pts) with HER2-positive MBC. Co-administration of P and H within the same infusion bag will also be investigated as this could increase pt convenience by reducing administration and observation time. Methods: VELVET is a multicenter, open-label, two-cohort, Phase II trial. Pts with HER2-positive LABC or MBC not previously treated in the metastatic setting with non-hormonal anticancer therapy are eligible. Pts must have an LVEF >55% at baseline and an ECOG PS of 0 or 1. Study enrollment started in January 2012. A total of 210 pts will be included. Based on statistical assumptions, 95 pts must be evaluable per cohort, which assumes a withdrawal rate around 10%. Pts in Cohort 1 (the first 105 pts enrolled) will receive P and H sequentially and pts in Cohort 2 (the next 105 pts) will receive P and H in the same infusion bag at Cycle 2 onwards if drug administration in Cycle 1 was well tolerated. V will be given in both cohorts. Treatment duration is until disease progression or unacceptable toxicity. Study dose: P: 840 mg loading dose, 420 mg q3w (iv); H: 8 mg/kg loading dose, 6 mg/kg q3w (iv), and V: 25 mg/m2 Day 1 and 8 (first cycle) then 30−35 mg/m2 Day 1 and 8 q3w (iv) (dose escalation at investigator’s discretion). The primary endpoint is ORR by independent assessment. Secondary endpoints include investigator assessment of ORR, time to response, duration of response, PFS, time to progression, overall survival, safety and tolerability, and QoL.

Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 337-337 ◽  
Author(s):  
David Cunningham ◽  
Istvan Lang ◽  
Vito Lorusso ◽  
Janja Ocvirk ◽  
Dongbok Shin ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Statistical Significance ◽  
Performance Status ◽  
Randomized Study ◽  
Single Agent ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
First Line ◽  
Open Label ◽  
Phase Iii Trial

337 Background: Elderly patients (pts) comprise the majority of pts diagnosed with mCRC, although they are in general underrepresented in clinical trials. AVEX, an open-label phase III trial, evaluated the efficacy and safety of cape ± bev in elderly pts with previously untreated mCRC. Methods: Pts ≥70 years with mCRC, for whom single-agent chemotherapy was deemed appropriate, were randomized 1:1 to receive first-line cape (1000 mg/m2 bid days 1–14) as monotherapy or in combination with bev (7.5 mg/kg) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety. The study was powered to show a difference in PFS, but not OS, between treatment arms. PFS and OS estimates were calculated using Kaplan-Meier methods. Results: 280 pts across 10 countries were randomized to cape + bev (n=140) and cape alone (n=140). Median age at enrollment was 76 years (range, 70–87), and 91.1% of pts had an ECOG performance status of 0–1. Baseline pt and disease characteristics were well balanced between arms. Bev + cape was associated with significantly prolonged PFS compared with cape alone (median of 9.1 vs 5.1 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41–0.69; p<0.001). The ORR was also significantly improved in the bev + cape arm (19.3% vs 10.0%; p=0.042). OS was longer in pts treated with bev + cape vs cape alone, although this difference did not reach statistical significance (median of 20.7 vs 16.8 months; HR, 0.79; 95% CI, 0.57–1.09; p=0.182). Grade ≥3 adverse events occurred in 59.0% vs 44.1% of pts in the bev + cape and cape arm, respectively. Treatment was in general well tolerated and the safety profile consistent with previously reported data for bev + cape. Conclusions: This is the first randomized study prospectively evaluating bev specifically in elderly pts with mCRC. Based on the efficacy and safety results, bev plus cape might be an optimal treatment approach to improve outcomes in elderly pts. Clinical trial information: NCT00484939.

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