APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Martin Bendszus ◽  
Jürgen Debus ◽  
Wolfgang Wick ◽  
Grigory Kobyakov ◽  
Tobias Martens ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Recurrent Glioblastoma ◽  
Tumor Diameter ◽  
Synergistic Activity ◽  
Open Label ◽  
Flat Dose ◽  
Pathway Inhibition

2034 Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblastoma. Methods: Patients with recurrent glioblastoma after prior standard radiochemotherapy with temozolomide (± 1 second-line chemotherapy) were considered for re-irradiation provided a tumor diameter 1-4 cm and time since the end radiotherapy ≥ 8 months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat dose to be continued until progression. Radiotherapy plans were centrally evaluated. Primary endpoint was 6-months progression free survival (PFS-6). MRIs were performed every 6-weeks and centrally read. Sample size of the investigational treatment arm according to a two-stage design of Simon required 55 patients. A control arm of 28 patients was implemented to validate the assumptions on PFS-6 in a cohort of patients treated with reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 centers were randomized and treated, preliminary data of the current report are available on 71 patients (49 APG01 + irradiation, 22 irradiation alone). Median age was 57 years, median KPS 90%. The maximal tumor diameter was ≤ 2-5 cm in 34 patients and > 2.5 cm in 37 patients. No SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is the first trial evaluating CD95-mediated pathway inhibition as a therapeutic strategy. This trial is also the prospective trial on reirradiation in glioblastoma. Side effects of the combination were minimal, and treatment could be delivered as planned. The experimental arm met the primary endpoint. The approach to block rather than stimulate the CD95 system is breaking a paradigm. Our data suggest that CD95 inhibition by APG101 should be evaluated in the management of newly diagnosed glioblastoma in combination with standard radiochemotherapy. Further molecular data and updated results will be presented.

scholarly journals Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx)

2020 ◽  
Vol 8 (2) ◽  
pp. e001146
Author(s):  
Gil Awada ◽  
Laila Ben Salama ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
Lydia Fischbuch ◽  
...  
Keyword(s):  
Adverse Events ◽  
Group Performance ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Synergistic Activity ◽  
Open Label ◽  
Corticosteroid Dose

BackgroundNo treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB.MethodsAdult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint.ResultsBetween June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0–1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events.ConclusionThe combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

A phase (Ph) 1b/2 study of ribociclib (R) in combination with docetaxel (D) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5043-5043
Author(s):  
Ivan de Kouchkovsky ◽  
Arpit Rao ◽  
Benedito A. Carneiro ◽  
Li Zhang ◽  
Catriona Lewis ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Single Agent ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Rank Test ◽  
Synergistic Activity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Increased Risk

5043 Background: The survival benefit of D in mCRPC is modest. CDK4/6 inhibitors such as R have shown synergistic activity with taxanes in pre-clinical cancer models. We sought to determine the safety and efficacy of R + D + P in mCRPC patients (pts). Methods: This was a Ph 1b/2 multicenter, open-label single arm trial of mCRPC pts with progression (PD) on ≥ 1 prior androgen receptor signaling inhibitor (ARSi) who had not previously received D for mCRPC (NCT02494921). Pts were treated with escalating doses of R in combination with D + P for 6-9 cycles, followed by single agent maintenance R until radiographic or clinical PD. The Ph 2 primary endpoint was 6-month (mo) radiographic progression-free survival (rPFS) rate by PCWG2 criteria, with a target rate of 55% and null hypothesis of 35%. Ph 2 pts underwent baseline circulating tumor cell (CTC) enumeration and genome sequencing (Epic Sciences). Cox proportional hazard model and log-rank test were used to test for associations between rPFS and CTC burden and copy number (CN) variants, respectively. Results: 43 pts were enrolled from 11/2015 to 6/2019. Median age was 68 (range 55-84). 20.9% of pts had visceral metastases. 33 (77%) had PD on prior abiraterone, 27 (63%) on enzalutamide, and 17 (40%) on both. In Ph 1b, 19 pts were enrolled. In the first cohort (D 75 mg/m2 day [d] 1, R 200 mg/d d2-14 of every 21d cycle), 2 pts experienced DLTs (febrile neutropenia [FN] and grade 4 neutropenia). With an alternative dosing schema of D 60 mg/m2 on d1, and R daily on d1-4 and 8-15 of cycle, with daily G-CSF support on d5-7, the MTD was not reached and D 60 mg/m2 + R 400 mg/d was chosen as the recommended Ph 2 dose (RP2D). In total, 30 pts were treated at RP2D; median number of D cycles was 8.5 and 60% went on to receive maintenance R. The Ph 2 primary endpoint was met with a 6-mo rPFS rate of 65% (95% CI 50-85%). Median rPFS was 8.0 mos (95% CI 4.1-10.0). PSA response rate (RR) defined as ≥50% reduction was 27.6% (95% CI 12.7-47.2%) and objective RR was 30.8% (95% CI 9.1-61.4%). Among pts treated at RP2D, the most common grade ≥3 treatment-related adverse events were neutropenia (n= 11, 36.7%), lymphocytopenia (n=3, 10%); no cases of FN were observed. Baseline CTC burden was associated with an increased risk of radiographic PD or death (HR 1.038, 95% CI 1.001-1.074, p = 0.038). Pts harboring CTCs without MYC (4/11 pts) or CDK6 CN gain (7/11 pts) had prolonged rPFS compared to those with gene amplification (median rPFS 10.76 vs 4.11 mos, p = 0.03, and 7.01 vs 1.92 mos, p = 0.053, respectively). Conclusions: The combination of R + D was well tolerated and showed promising activity in mCRPC pts who had progressed on an ARSi. The Ph 2 study met its primary endpoint, with an encouraging 6-mo rPFS rate of 65%. Lack of MYC or CDK6 amplification on CTC sequencing was associated with longer rPFS. Funding: Novartis Pharmaceuticals, PCF YIA. Managed by the PCCTC. Clinical trial information: NCT02494921.

scholarly journals Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Linda T. Vahdat ◽  
Peter Schmid ◽  
Andres Forero-Torres ◽  
Kimberly Blackwell ◽  
Melinda L. Telli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Primary Endpoint ◽  
Triple Negative ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

AbstractThe METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

CTIM-14. RANDOMIZED PHASE II OPEN LABEL STUDY OF NIVOLUMAB PLUS STANDARD DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM). NIVOLUMAB BENEFITS OLDER POPULATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi52-vi52
Author(s):  
Manmeet Ahluwalia ◽  
David Peereboom ◽  
Yasmeen Rauf ◽  
Patrick Wen ◽  
David Reardon
Keyword(s):  
Overall Survival ◽  
Low Dose ◽  
Standard Dose ◽  
Performance Status ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Dose Effect ◽  
Open Label ◽  
Anti Vegf

Abstract BACKGROUND Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. VEGF is upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF may be a promising approach in rGBM. METHODS 90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance status and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared between two arms. RESULTS 90 patients (Median age 60.6 years ranged 27.4-86.4, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall Survival was not significantly different between arm A and arm B (1 year: 41.1 vs 37.7%, p=0.14), while OS was better for arm A in age > 60 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P=0.90). Most frequent toxicities ( >20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function. CONCLUSIONS Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.

A phase 1b multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients (pts) with metastatic or unresectable gastric and gastroesophageal adenocarcinoma (mGEC) after at least one line of treatment with a fluoropyrimidine and platinum (FP) containing regimen.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16006-e16006
Author(s):  
Farshid Dayyani ◽  
Kit Wah Tam ◽  
Edward Jae-Hoon Kim ◽  
Samuel Ejadi ◽  
Fa Chyi Lee ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Meaningful Improvement ◽  
Best Response ◽  
Previously Treated ◽  
Phase 1B

e16006 Background: FTD/TPI, an antimetabolite, is approved for treatment of refractory mGEC. This study sought to determine whether the combination of FTD/TPI with IRI (“TASIRI”) was safe and effective in mGEC previously treated with FP. Methods: This investigator‐initiated, multicenter, open‐label, single-dose level, single‐arm phase 1b study enrolled pts with mGEC previously treated with at least one line of FP containing regimen. FTD/TPI was given at 25 mg/m2 twice daily on days 1 to 5 with 180 mg/m2 IRI on day 1 of a 14‐day cycle. The primary endpoint was progression-free survival at six months (mo) (PFS-6). The aim was to show an improvement of PFS-6 from 15% to at least 30% based on historical controls. Results: At the time of data-cutoff (03Feb2021), 23 pts were screened and ultimately 20 pts were treated. The study met its primary endpoint. With a median follow-up of 9.8 mo (range 0.7 – 17), 8 pts are still on treatment and 4 pts have died. PFS-6 is 53.9% (lower limit of 95% CI: 28%). Median PFS and overall survival are 6.9 mo and not reached, respectively. At the time of data-cutoff, data were available for 13 pts with measurable disease by RECIST criteria and at least 1 on-treatment scan. Of those, 11 had stable disease and 2 had progressive disease as best response (5 pts had tumor shrinkage < 30%), therefore the disease control rate was 84.6%. The most common any grade (G) treatment related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (17%) and neutropenia (9%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. Conclusions: The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls. TASIRI was well tolerated and no new safety signals were seen. TASIRI warrants further investigation for patients with refractory mGEC and limited treatment options. Updated results with longer follow-up will be presented at the meeting. Clinical trial information: NCT04074343.

Phase II study of ifosfamide, carboplatin and etoposide (ICE) in recurrent glioblastoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2066-2066
Author(s):  
T. Aoki ◽  
K. Nojima ◽  
T. Mizutani ◽  
M. Ishikawa ◽  
A. Takasu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
First Line ◽  
Open Label ◽  
Free Survival ◽  
Secondary Endpoints

2066 Background: To evaluate the efficacy and tolerability of ifosfamide, carboplatin and etoposide ( ICE ) in patients with recurrent glioblastoma. Methods: This was an open-label, single-center phase II trial. Forty-two patients with first recurrent glioblastoma after surgery, standard radiotherapy and a first-line temozolomide-based or ACNU-based chemotherapy, were enrolled.The primary endpoint was progression-free survival at 6 months ( PFS-6 ), and secondary endpoints were response rate, toxicity, and survival. Chemotherapy consisted of Ifosfamide ( 700 mg / m2 on day 1, 2 and 3 ), carbopaltin ( 100 mg / m2 on day 1 ), etoposide ( 70 mg / m2 on day 1, 2, and 3 ), every 6 weeks. Results: PFS-6 was 37 %. The median PFS was 17 weeks. Response rate was 27 %. Adverse events were generally mild ( grade 1 or 2 ) and consisted mainly of alopecia. Conclusions: This regimen is well tolerated and has activity in patients with recurrent glioblastoma. No significant financial relationships to disclose.

Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 478-478 ◽  
Author(s):  
J. C. Bendell ◽  
C. Tournigand ◽  
M. Bednarczyk ◽  
A. Swieboda-Sadlej ◽  
I. Chung ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Performance Status ◽  
Progression Free Survival ◽  
Second Line ◽  
Open Label ◽  
Vegf Inhibitors ◽  
Multiple Tumor ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Line Chemotherapy

478 Background: Axitinib (AG-013736,AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy. Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS). Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table). Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev. [Table: see text] [Table: see text]

A phase II, multicenter, open-label study of YM155 plus docetaxel in subjects with stage III (unresectable) or stage IV melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8587-8587 ◽  
Author(s):  
Joyce Leta Steinberg ◽  
Agop Y. Bedikian ◽  
D. Scott Ernst ◽  
Bartosz Chmielowski ◽  
Bruce Redman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Continuous Infusion ◽  
Primary Endpoint ◽  
Clinical Benefit ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Open Label ◽  
Clinical Benefit Rate

8587 Background: Survivin is a microtubule-associated protein implicated in both preservation of cell viability and regulation of mitosis in tumor cells. It is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: Part 1 established the dose of docetaxel that was tolerable in combination withYM155 at 5 mg/m2/day continuous infusion over 168 hours q 3 weeks. Part 2 utilized the dose of docetaxel established in Part 1 to further evaluate the tolerability and activity of the combination. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were overall response rate, 1-year overall survival (OS), time from first response to progression, clinical benefit rate, time to response, and safety. Results: 64 patients with metastatic melanoma were treated with docetaxel followed by continuous infusion YM155. 7 patients were treated with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of docetaxel. Median age was 59, with 44 men and 20 women treated. 6-month PFS per Independent Review Committee (IRC) was 34.8% (95% CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with no complete responses (CR) and 8 patients with partial responses (PR). The Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR + PR + SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities occurring in greater than 5% of patients treated included neutropenia (59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all attributable to disease progression. Conclusions: YM155 is a novel agent that shows modest activity when combined with docetaxel in patients with melanoma. YM155 was generally well tolerated, but the pre-determined primary endpoint for efficacy was not achieved.

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA10008-LBA10008 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

A phase II trial of trabectedin (T) in patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to xeroderma pigmentosum gene (XPG) expression.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS652-TPS652
Author(s):  
Ahmad Awada ◽  
Javier Cortes ◽  
Miguel Martin ◽  
Philippe Aftimos ◽  
Mafalda Oliveira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Hormone Receptor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Metastatic Setting

TPS652 Background: Hormone receptor-positive, HER2-negative breast cancer (BC) is currently associated with 3-4 years overall survival in the metastatic setting and, after ≥2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T is a cytotoxic agent that forms a complex with the XPG, inducing cell apoptosis. As a single agent, T has shown anti-tumor activity in patients with poor prognosis BC, and a better response to T in BC patients with XPG RNA overexpression has been observed. Methods: This is an open-label, phase II study of T (1.3 mg/m2 in 3-hour intravenous infusion every 3 weeks) in patients with hormone receptor-positive, HER2-negative advanced BC, according to their primary tumor’s XPG expression. Primary endpoint: to evaluate the efficacy of T in terms of progression free survival rate at 4 months (PFS4) according to the patient’s XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety profile in XPG-high and XPG-low patients. Assignment: BC patients who have previously received anthracyclins and/or taxanes and who progressed after 2-5 chemotherapy lines will be assigned according to their XPG expression from paraffin embedded tumor samples to stratum A (XPG-high [>3]) or to stratum B (XPG-low [≤3]) (threshold was selected from median XPG expression values observed in a previous trial). Statistical methods: A two-stage design was chosen: at a first stage 20 patients will be enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint (PFS4) will be conducted once 40 evaluable patients have been recruited. If ≥ 7 out of 20 patients achieve PFS4, recruitment will continue to a maximum sample size of 50 evaluable patients per stratum. If ≥ 22 out of 50 patients achieve PFS4, T will be considered active in this group (alpha error: 0.025, power: 80%). To date, 35 patients (16 XPG-high and 15 XPG-low) have been enrolled from three countries and five centers. Recruitment is ongoing.

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