Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy

2013 ◽  
Vol 31 (19) ◽  
pp. 2485-2492 ◽  
Author(s):  
George D. Demetri ◽  
Sant P. Chawla ◽  
Isabelle Ray-Coquard ◽  
Axel Le Cesne ◽  
Arthur P. Staddon ◽  
...  
Keyword(s):  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Study Drug ◽  
Progression Free Survival ◽  
Target Lesion ◽  
Phase Iii ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Phase Iii Trial ◽  
Prior Chemotherapy

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

scholarly journals Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206

2010 ◽  
Vol 28 (13) ◽  
pp. 2137-2143 ◽  
Author(s):  
Brian I. Rini ◽  
Susan Halabi ◽  
Jonathan E. Rosenberg ◽  
Walter M. Stadler ◽  
Daniel A. Vaena ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Interferon Alfa ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Grade 3

Purpose Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-α) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-α versus IFN-α monotherapy was conducted. Patients and Methods Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-α (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-α monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. Results Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-α and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-α monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-α. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-α. Patients who developed HTN on bevacizumab plus IFN-α had a significantly improved PFS and OS versus patients without HTN. Conclusion OS favored the bevacizumab plus IFN-α arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-α.

Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (≥ 24 months) overall survival results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10010-10010 ◽  
Author(s):  
Jean-Yves Blay ◽  
Sant P. Chawla ◽  
Isabelle Ray-Coquard ◽  
Axel Le Cesne ◽  
Arthur P. Staddon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Controlled Trial ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Phase Iii ◽  
Clinical Activity ◽  
Prior Chemotherapy

10010 Background: The mammalian target of rapamycin (mTOR) regulates cell growth and proliferation and is abnormally activated in many sarcomas. Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in previous nonrandomized trials in advanced sarcomas following failure of prior chemotherapy. Methods: An international, multicenter, placebo-controlled, phase 3 trial was conducted to evaluate maintenance therapy with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas who achieved disease control from prior chemotherapy. Patients were randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once daily for 5 days each week. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety and tolerability. For OS, patients were to be followed at 3-month intervals for at least 24 months and up to 60 months after randomization. Results: 702 of 711 randomized patients received treatment. At the time of the data cutoff for OS (386 deaths), patients in the study population had been followed for at least 15 months. Median OS was 93.3 weeks with ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]=0.88; 95% confidence interval [CI]: 0.72, 1.08; P=0.23). Ridaforolimus significantly improved PFS vs placebo (HR=0.72; 95% CI: 0.61, 0.85; P=0.0001; median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all prespecified baseline characteristics. As expected from the class of mTOR inhibitors, the most common adverse events with ridaforolimus were stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia, hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus was generally well-tolerated and significantly improved PFS in metastatic sarcoma patients with benefit from prior chemotherapy, offering an effective treatment alternative to surveillance alone. Results of a long-term OS analysis (prespecified to occur at 67% mortality, 24 months minimum follow-up) in the intent-to-treat population will be available in early 2012.

OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA5007-LBA5007 ◽  
Author(s):  
C. Aghajanian ◽  
N. J. Finkler ◽  
T. Rutherford ◽  
D. A. Smith ◽  
J. Yi ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Type I ◽  
Ecog Performance Status ◽  
Fallopian Tube Cancer ◽  
Phase Iii Trial ◽  
Platinum Sensitive

LBA5007 Background: BEV, a humanized anti-VEGF monoclonal antibody, has shown a progression-free survival (PFS) benefit in 2 frontline phase III trials in patients with EOC, PPC and FTC. The therapeutic impact of BEV in combination with carboplatin (C) and gemcitabine (G) followed by single agent BEV to disease progression (PD) was evaluated in this phase III trial in the platinum-sensitive recurrent setting. Methods: Patients had recurrent, platinum-sensitive EOC, PPC or FTC, 1 prior regimen, no prior BEV, ECOG performance status 0-1, measurable disease. Subjects were randomized to: Arm A: [IV C (AUC 4, Day (D) 1) + G (1,000 mg/m2 D1 and 8) + placebo (PL) D1] q21D x 6 cycles (c) → PL q21D until PD or unacceptable toxicity (tox) Arm B: [CG + BEV (15 mg/kg) D1] q21D x 6 c → BEV q21D until PD or tox primary endpoint was investigator assessed PFS (RECIST). Secondary endpoints included objective response (OR), overall survival (OS), duration of response and safety. The design provided 80% power to detect a 27% reduction in the hazard of progression or death in Arm B vs A, limiting the overall type I error of 5%. Results: OCEANS enrolled 484 patients (242 per arm) from 4/07 - 1/10, median follow up of 24 months. BEV plus CG followed by single agent BEV to PD significantly increased PFS compared to CG alone (HR=0.484, p<0.0001). OR increased by 21% (p<0.0001). OS data is immature with only 29% of patients having had an event. The safety profile was consistent with other BEV trials. Conclusions: Results show a statistically significant and clinically relevant benefit when bevacizumab is added to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC. This is the first phase III trial of an antiangiogenic to demonstrate a clinical benefit to these patients. [Table: see text]

CA184-104: Randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) versus placebo with PC in patients (pts) with stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histology.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8117-TPS8117 ◽  
Author(s):  
Martin Reck ◽  
Pablo Gonzalez-Mella ◽  
Myung-Ju Ahn ◽  
Hassan H. Ghazal ◽  
Claus-Peter Schneider ◽  
...  
Keyword(s):  
Treatment Guidelines ◽  
Human Monoclonal Antibody ◽  
Specific Treatment ◽  
Stage Iv ◽  
Study Drug ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Immune Therapies

TPS8117 Background: Improved outcomes for squamous, advanced NSCLC—beyond standard platinum doublets—have not been demonstrated. Data suggestive of response to immune therapies in squamous NSCLC support investigation in this subtype. Ipi, a fully human monoclonal antibody which binds CTLA-4, augments antitumor immune responses. Ipi improved overall survival (OS) in advanced melanoma, with side effects managed using product-specific treatment guidelines. A randomized phase II study of phased Ipi/PC (Ipi started after 2 cycles of PC) in pts with stage IV NSCLC showed significant improvement in progression-free survival (PFS), as measured by mWHO or immune-related response criteria (irRC), with a trend toward prolonged OS, over chemotherapy alone; irRC were derived from WHO criteria to better capture response patterns observed with Ipi. Improvement in PFS and OS appeared greater in tumors of squamous histology. Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. This global (~253 sites among 34 countries) phase III trial (ClinicalTrials.gov identifier NCT01285609) is investigating whether phased Ipi/PC will prolong OS in first-line pts with squamous NSCLC. Methods: Stage IV/recurrent squamous NSCLC with ECOG 0-1 will be included; pts with CNS metastases or history of autoimmune disease will be excluded. Pts are randomized to 2 cycles of PC (175 mg/m2 and AUC=6, respectively; IV), followed by 4 cycles of study drug (Ipi in Arm A, placebo in Arm B; IV) with 4 additional cycles of PC (total 6 cycles). Pts without progressive disease (PD) after induction receive maintenance therapy with blinded study drug Q12W until PD per mWHO. The study will enroll an estimated 920 pts, randomized 1:1 between arms. The primary endpoint is OS; secondary endpoints include OS among pts who receive blinded therapy, PFS, and best overall response rate. Safety is an exploratory objective of the trial. Clinical trial information: NCT01285609.

Olaratumab plus anthracyline in advanced/metastatic soft tissue sarcoma: Data of real-world utilization in Austria.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e22550-e22550
Author(s):  
Florian Kocher ◽  
Andreas Seeber ◽  
Lukas Weiss ◽  
Franz Romeder ◽  
Joanna Szkandera ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Real World ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Metastatic Soft Tissue Sarcoma ◽  
Third Line

e22550 Background: Olaratumab is a humanized monoclonal anti platelet-derived growth factor receptor α antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria. Methods: Retrospectively collected, longitudinal data from patients treated between November 2016 and September 2018 at 9 Austrian centers were obtained from respective medical charts. Eligible patients were all patients who received at least one dose of olaratumab. Parameters of most interest collected were response rates, progression-free survival (PFS) and overall survival (OS). Results: Altogether 55 patients were included into analysis. Median age was 58 years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first-, second- or ≥ third-line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); 1 patient received olaratumab as upfront monotherapy. Median PFS and OS were 2.6 and 11.4 months. The objective response rate was 11.4 % and the disease control rate was 40.9 %. Conclusions: In this real-world analysis outcome was less pronounced compared to the results of the Phase Ib/II approval trial ( Tap WD et al. Lancet 2016). Thus, the results of the ongoing phase III trial (NCT02451943) are urgently needed to confirm the efficacy of the combination of olaratumab and doxorubicin in STS patients.

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA5002-LBA5002 ◽  
Author(s):  
Eric Pujade-Lauraine ◽  
Felix Hilpert ◽  
Béatrice Weber ◽  
Alexander Reuss ◽  
Andres Poveda ◽  
...  
Keyword(s):  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Phase Iii ◽  
Rank Test ◽  
Meaningful Improvement ◽  
Phase Iii Trial ◽  
Phase Iii Trials ◽  
History Of

LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. Results: Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. Conclusions: In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text]

Analysis of overall survival (OS) based on early tumor shrinkage in the phase III METEOR study of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 550-550 ◽  
Author(s):  
Ignacio Duran ◽  
Pablo Maroto ◽  
Cristina Suárez ◽  
Daniel E. Castellano ◽  
Xavier Garcia del Muro ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Lesion Size ◽  
Target Lesion ◽  
Phase Iii ◽  
Early Tumor Shrinkage ◽  
Tumour Shrinkage ◽  
Mri Scans ◽  
Previously Treated ◽  
Early Tumor

550 Background: In the phase 3 METEOR study (NCT01865747), cabo improved OS (median 21.4 vs 16.5 mo; HR, 0.66; 95% CI, 0.53–0.83), progression-free survival and objective response rate compared with eve in patients (pts) with previously treated advanced RCC (Choueiri 2016). Retrospective studies have shown that early tumour shrinkage (eTS), based on target lesion reduction from baseline to first post-baseline scan, has predictive value for targeted therapies in RCC (Grunwald 2015; Grunwald 2016); here we evaluate its impact on OS in METEOR. Methods: In total, 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd), stratified by MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed by independent radiology review using CT/MRI scans at baseline, every 8 wk for the first 12 mo and every 12 wk thereafter. Median OS was estimated for pts with ≥30% eTS, any eTS or no eTS at first post-baseline scan (week 8); data cutoff, 2 October 2016 (Motzer 2018). Results: Median follow-up was 28 mo (IQR 25, 30). Median (range) time to objective response was 1.91 (1.6, 11.0) mo with cabo and 2.14 (1.9, 9.2) mo with eve, and corresponded to the time to the first post-baseline scan. A greater proportion of pts had ≥30% eTS with cabo (20%) than with eve (5%) and the rate of any eTS was higher in the cabo arm (73%) than with eve (47%; Table). Median OS with cabo vs eve for pts with ≥30% eTS was not reached (NR; 95% CI, 23.7–NR) vs 10.2 mo (95% CI, 3.9–NE), respectively (stratified HR, 0.45; 95% CI, 0.21–0.95; p<0.05). Median OS with cabo vs eve for pts with any eTS was 23.7 (95% CI, 21.7–27.7) vs 17.3 mo (95% CI, 15.4–20.8), respectively; (stratified HR, 0.62; 95% CI, 0.48–0.80; p<0.05). OS was similar for cabo and eve for pts with no eTS. Conclusions: Cabo demonstrated a higher rate and greater magnitude of eTS at first post-baseline scan compared with eve, and eTS was associated with prolonged OS in pts treated with cabo. Clinical trial information: NCT01865747. [Table: see text]

scholarly journals Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09)

2018 ◽  
Vol 10 ◽  
pp. 175883591880733 ◽  
Author(s):  
Sara Hurvitz ◽  
Rashi Singh ◽  
Brad Adams ◽  
Julie A. Taguchi ◽  
David Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Metastatic Breast ◽  
Study Drug ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Breast Cancer Brain Metastasis

Background: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease. Methods: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1–14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR. Results: A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0–11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2 due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively. Conclusions: This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen. Trial registration: ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756

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