Phase III randomized, placebo-controlled trial of carboplatin (C) and paclitaxel (P) with/without veliparib (ABT-888) in HER2- BRCA-associated locally advanced or metastatic breast cancer (BC).

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 155-155 ◽  
Author(s):  
Shannon Leigh Huggins-Puhalla ◽  
Hyo S. Han ◽  
Véronique Diéras ◽  
Michael Friedlander ◽  
George Somlo ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Receptor Expression ◽  
Phase Iii ◽  
Double Blind

155 Background: BRCA-mutated tumors are more susceptible to platinum therapy and PARP inhibitors due to underlying defects in homologous recombination repair of DNA damage. In preclinical models the potent oral PARP1/2 inhibitor veliparib was shown to enhance sensitivity to C and to have single-agent activity in BRCA+ cell lines. Phase 1 trials suggest promising antitumor activity and acceptable toxicity of veliparib plus C/P in triple-negative BC (Puhalla et al. Cancer Res 2012;72:PD09-06) and single-agent activity of veliparib in BRCA+ BC (Somlo et al. J Clin Oncol 2014;32:abstr. 1021). This phase III trial assesses efficacy and toxicity of veliparib plus C/P vs C/P alone in patients with HER2− BRCA-associated locally advanced or metastatic BC (NCT02163694). Methods: Phase III randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients (female or male; ≥ 18 years) have HER2−metastatic/locally advanced unresectable BC with (suspected) deleterious BRCA1/2 germline mutations and received 2 or fewer prior lines of DNA-damaging chemotherapy for metastatic BC. In addition, patients must have received ≤ 1 prior line of platinum therapy (any setting) without progression within 12 months of completing treatment. Patients are randomized 2:1 to C/P with veliparib or C/P with placebo, stratified by estrogen and/or progesterone receptor expression, prior platinum therapy, and central nervous system metastases. Veliparib (120 mg p.o. BID) or placebo will be given on Days −2 to 5, C (AUC 6 mg/mL/min i.v.) on Day 1, and P (80 mg/m2i.v.) on Days 1, 8, and 15 (21-day cycles). Treatment continues until unacceptable toxicity or progressive disease (PD). Patients in the placebo arm who discontinue due to PD are eligible for crossover to veliparib monotherapy. The primary objective is to assess if the addition of veliparib to C/P increases progression-free survival; additional objectives include evaluation of overall survival, clinical benefit rate, objective response rate, quality of life, and safety. Enrollment began in July 2014 with a planned sample size of 270 patients. Clinical trial information: NCT02163694.

Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.

2018 ◽  
Vol 36 (18_suppl) ◽  
pp. LBA1006-LBA1006 ◽  
Author(s):  
Jose Baselga ◽  
Susan Faye Dent ◽  
Javier Cortés ◽  
Young-Hyuck Im ◽  
Véronique Diéras ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Primary Analysis ◽  
Double Blind ◽  
Er Positive ◽  
Phase Iii Study

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

RILOMET-1: An international phase III multicenter, randomized, double-blind, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin, and capecitabine (ECX) as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4153-TPS4153 ◽  
Author(s):  
David Cunningham ◽  
Salah-Eddin Al-Batran ◽  
Irina Davidenko ◽  
David H. Ilson ◽  
André M. Murad ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Double Blind ◽  
Disease Extent

TPS4153 Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor that inhibits signaling through the MET receptor. In a randomized phase II study in patients with advanced G/GEJ adenocarcinoma, addition of rilotumumab every 3 weeks (Q3W) to ECX showed trends toward improved overall survival (OS) and progression-free survival (PFS) compared with ECX alone. In patients with high tumor MET expression and high rilotumumab exposure, the treatment effect of rilotumumab combined with ECX was significantly enhanced. Methods: In this phase III study, patients (planned N=450) are randomized 1:1 to ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral capecitabine 625 mg/m2 twice daily on days 1−21) plus double-blind rilotumumab 15 mg/kg or placebo IV Q3W. Randomization is stratified by disease extent (locally advanced vs metastatic) and Eastern Cooperative Oncology Group (ECOG) score (0 vs 1). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma; ECOG score 0 or 1; ≥18 years old; MET-positive by centralized immunohistochemistry; HER2-negative; adequate organ function; and ≥6 months since neoadjuvant/adjuvant therapy. The primary endpoint is OS. Key secondary endpoints include PFS, 12-month survival rate, objective response, OS in MET expression tertiles, safety, and pharmacokinetics. An exploratory objective is to assess associations between outcomes and tumor and circulating biomarkers. Enrollment began in November 2012, and the trial continues to accrue. An independent data monitoring committee will conduct planned interim reviews for safety and efficacy. Status: recruiting participants. Sponsored by Amgen Inc. Clinical trial information: NCT01697072.

Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4148-TPS4148 ◽  
Author(s):  
Eric Van Cutsem ◽  
Robert J. Fram ◽  
Michael Schlichting ◽  
David P. Ryan
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
Treatment Discontinuation ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Double Blind

TPS4148 Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m2+ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.

Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5094-TPS5094 ◽  
Author(s):  
Toni K. Choueiri ◽  
Laurence Albiges ◽  
Li Fan ◽  
Rodolfo F. Perini ◽  
Naseem J. Zojwalla ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Phase Iii ◽  
Once Daily ◽  
Patient Reported ◽  
Previously Treated ◽  
Metastatic Rcc

TPS5094 Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .

An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5508-5508 ◽  
Author(s):  
Patrick Schoffski ◽  
Rossella Elisei ◽  
Stefan Müller ◽  
Marcia S. Brose ◽  
Manisha H. Shah ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Double Blind ◽  
Efficacy Measure ◽  
Independent Review ◽  
Phase Iii Study ◽  
Grade 3

5508 Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.

BOLERO-1: A randomized, phase III, double-blind, placebo-controlled multicenter trial of everolimus in combination with trastuzumab and paclitaxel as first-line therapy in women with HER2-positive (HER2+), locally advanced or metastatic breast cancer (BC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS648-TPS648 ◽  
Author(s):  
Sara A. Hurvitz ◽  
Fabrice Andre ◽  
Howard A. Burris ◽  
Masakazu Toi ◽  
Marc E. Buyse ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Trastuzumab Resistance ◽  
First Line ◽  
Double Blind ◽  
Good Tolerability

TPS648 Background: Up to 25% of BCs overexpress human epidermal growth factor receptor 2 (HER2). Patients with HER2+ disease have a higher rate of relapse and shorter overall survival (OS). Trastuzumab, a monoclonal antibody targeting HER2, is the standard of care and improves OS for HER2+ BC, but acquired resistance is common. The combination of trastuzumab and paclitaxel has shown good tolerability and excellent objective response rates (ORR) in up to 84% of patients with HER2+ metastatic BC (MBC) (Gasparini G, et al. BCRT. 2007;101:355-65). Everolimus is an orally bioavailable inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to multiple protein synthesis pathways and implicated in trastuzumab resistance. Everolimus-containing regimens have shown promising results in patients with ER+, HER2– advanced BC in phase II/III trials; everolimus plus trastuzumab/paclitaxel or vinorelbine has shown encouraging ORR with an acceptable safety profile in phase I/II trials in patients with HER2+ MBC. The present phase III study was undertaken to assess the effectiveness of adding everolimus to first-line standard therapy in HER2+ advanced BC. Methods: Women with HER2+, locally advanced or metastatic BC who have received no prior systemic therapy (except endocrine) are eligible. Local disease must not be amenable to resection with curative intent. Women with a history of central nervous system metastasis are excluded. Patients are randomized 2:1 (everolimus vs control) to receive standard therapy (paclitaxel and trastuzumab) plus everolimus (10 mg daily) or placebo. The primary endpoint is progression-free survival. Secondary endpoints include OS, ORR, and clinical benefit rate. Additional endpoints are safety, performance status, and biomarkers. This trial is sponsored by Novartis Pharmaceuticals and is registered (ClinicalTrials.gov: NCT00876395). Enrollment began September 2009, with a planned accrual of 717. The current accrual is 719, and the estimated primary completion date is October 2012.

Phase I results from the phase 1/3 FIGHT study evaluating bemarituzumab and mFOLFOX6 in advanced gastric/GEJ cancer (GC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 91-91 ◽  
Author(s):  
Mohamedtaki Abdulaziz Tejani ◽  
Eric Cheung ◽  
Peter D. Eisenberg ◽  
Aaron James Scott ◽  
Anteneh A. Tesfaye ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Single Agent ◽  
Locally Advanced ◽  
Underlying Disease ◽  
Phase Iii ◽  
Duration Of Treatment ◽  
Double Blind ◽  
Combination Methods ◽  
Favorable Safety

91 Background: GC with FGFR2b overexpression or FGFR2 amplification is associated with a poor prognosis. Bemarituzumab (bema, FPA144) is a first-in-class humanized monoclonal IgG1 antibody that selectively blocks FGFR2b and triggers antibody-dependent cell-mediated cytotoxicity. With favorable safety and activity as a single agent in 2L+ patients with FGFR2b+ GC, the global, randomized, double-blind, placebo-controlled FIGHT study (NCT03343301) is evaluating the front-line combination of bema with mFOLFOX6. We report here the results from the phase I evaluation of the combination. Methods: Patients (pts) with unresectable, locally advanced or metastatic gastrointestinal malignancy (irrespective of FGFR2b status) for whom mFOLFOX6 would be appropriate were eligible for enrollment in the phase I. Her2+ disease or prior treatment with FGF-FGFR inhibitors was not allowed. All pts in the Phase 1 received mFOLFOX6 combined with bema in Q2W cycles. Cohort 1 (3+3) began with bema 6 mg/kg and cohort 2 (Rolling-6) bema 15 mg/kg with one dose of 7.5 mg/kg on C1D8. A dose-limiting toxicity (DLT) evaluation window of 28 days was used for both cohorts. Results: Cohorts 1 and 2 treated 3 pts and 9 pts respectively with a median of 4 and 2 prior lines of therapy. As of the iDMC data-cut on July 24, 2018, the median duration of treatment was 15 wks for cohort 1 and 4 wks for cohort 2; 6/9 pts in cohort 2 continue on treatment. No DLTs were identified. No adverse events (AEs) led to treatment discontinuation. There were no newly identified bema-related toxicities and the only ≥ Gr 2 AE attributable to bema in cohort 2 was fatigue (1 pt/Gr 2). The most common AEs overall were fatigue (6 pts/50%), nausea, vomiting and diarrhea (5 pts/42% each) and were generally attributed to FOLFOX or underlying disease. The ≥ Gr 3 AEs present in ≥ 1 pt were fatigue and neutropenia (2 pts/Gr 3 each). mFOLFOX6 did not affect bema exposure and all evaluable pts in cohort 2 achieved the target ≥ 60 µg/mL trough concentration by day 15. 2/7 pts at the data-cut had FGFR2b+ GC. Conclusions: Bema in combination with mFOLFOX6 has acceptable safety to proceed with the cohort 2 dose to the phase III portion of the FIGHT trial in previously untreated patients with FGFR2b+ GC. Clinical trial information: NCT03343301.

Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment

2007 ◽  
Vol 25 (33) ◽  
pp. 5210-5217 ◽  
Author(s):  
Eva S. Thomas ◽  
Henry L. Gomez ◽  
Rubi K. Li ◽  
Hyun-Cheol Chung ◽  
Luis E. Fein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Treatment Options ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival

PurposeEffective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.Patients and MethodsSeven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m2intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m2orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m2on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.ResultsIxabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [≥ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.ConclusionIxabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

2013 ◽  
Vol 31 (28) ◽  
pp. 3509-3516 ◽  
Author(s):  
Josep M. Llovet ◽  
Thomas Decaens ◽  
Jean-Luc Raoul ◽  
Eveline Boucher ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Controlled Trial ◽  
Objective Response ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Time To Progression ◽  
Fibroblast Growth Factor Receptors ◽  
Double Blind ◽  
Dual Inhibitor

Purpose Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. Patients and Methods In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Results Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). Conclusion In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS498-TPS498
Author(s):  
Petros Grivas ◽  
Scott T. Tagawa ◽  
Joaquim Bellmunt ◽  
Maria De Santis ◽  
Ignacio Duran ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Topoisomerase I ◽  
Progressive Disease ◽  
Group Performance ◽  
Checkpoint Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii

TPS498 Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.

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