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 .

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.

MK-6482, a hypoxia-inducible factor 2α inhibitor (HIF-2α), versus everolimus in heavily pretreated, immune checkpoint–inhibitor-resistant, advanced clear cell renal cell carcinoma (ccRCC): Phase III study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS368-TPS368
Author(s):  
Toni K. Choueiri ◽  
Laurence Albiges ◽  
Li Fan ◽  
Rodolfo F. Perini ◽  
Donna Vickery ◽  
...  
Keyword(s):  
Adverse Events ◽  
Objective Response Rate ◽  
Response Rate ◽  
Cox Regression ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Controlled Study ◽  
Patient Reported ◽  
Metastatic Rcc

TPS368 Background: In ccRCC, HIF-2α is involved in the activation of genes such as VEGFA, cyclin D1, and CXCR4, which are associated with angiogenesis, tumor progression, and metastasis. HIF-2α can accumulate and be overactivated due to the inactivation of the Von Hippel-Lindau ( VHL) tumor suppressor gene, which occurs in most RCC cases. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α that has shown antitumor activity in a phase I/II study in patients with pretreated, advanced ccRCC (NCT02974738). In the study, the objective response rate was 24%, the disease control rate was 80%, and the safety profile was acceptable. Methods: A phase III, open-label, multicenter, randomized, active-controlled study (NCT04195750) will evaluate the efficacy and safety of MK-6482 versus everolimus as second- to third-line therapy in advanced ccRCC. Eligibility criteria include age ≥18 years; unresectable, locally advanced, or metastatic ccRCC; measurable disease per RECIST v1.1; and a history 1 to 3 systemic regimens for locally advanced or metastatic RCC—including at least 2 doses of a PD-L1 inhibitor and a VEGF-targeted therapy alone or in combination, which resulted in progression. Exclusion criteria include diagnosis of hypoxia defined by pulse oximetry <92% at rest or requiring supplemental oxygen, prior HIF or mTOR inhibitor therapy, kinase inhibitors within 2 weeks of randomization and any systemic anticancer antibody within 4 weeks, and known central nervous system metastases and/or carcinomatous meningitis. The study will enroll approximately 736 patients, who will be randomly assigned 1:1 to MK-6482 120 mg or everolimus 10 mg, both orally once daily until documented disease progression, withdrawal of consent, or other discontinuation event. Stratification factors for this study are International Metastatic RCC Database prognostic scores (0 versus 1-2 versus 3-6) and the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 versus 2-3). The planned imaging (CT/MRI) for response evaluation per RECIST v1.1 by blinded independent central review is as follows: imaging at week 8 from the date of randomization, then every 8 weeks through week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). Progression-free survival per RECIST v1.1 and overall survival will be the dual primary endpoints. Objective response rate, duration of response, patient-reported outcomes, and safety will be secondary endpoints. Event rates over time will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. Stratified Miettinen and Nurminen method will be used for analysis of ORR. Recruitment began in December 2019. Clinical trial information: NCT04195750 .

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.

A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4693-TPS4693 ◽  
Author(s):  
Robert Dreicer ◽  
David B. Agus ◽  
Joaquim Bellmunt ◽  
Johann Sebastian De Bono ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fusion Gene ◽  
Phase 1 ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Double Blind ◽  
Investigational Agent ◽  
Patient Reported ◽  
To Receive

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).

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.

SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1119-TPS1119 ◽  
Author(s):  
Jose Baselga ◽  
Javier Cortés ◽  
Michelino DeLaurentiis ◽  
Susan Dent ◽  
Véronique Diéras ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Pik3ca Mutation ◽  
Pi3k Inhibitor ◽  
Phase Iii ◽  
Pik3ca Mutations ◽  
Patient Reported ◽  
Er Positive ◽  
Phase Iii Study

TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.

Phase III study of first-line pembrolizumab (pembro) plus lenvatinib (len) in patients (pts) with advanced urothelial carcinoma (UC) ineligible for platinum-based chemotherapy: LEAP-011.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS597-TPS597
Author(s):  
Yohann Loriot ◽  
Arjun Vasant Balar ◽  
Ronald De Wit ◽  
Jorge A. Garcia ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Previous Treatment ◽  
Phase Iii ◽  
End Points ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Ecog Ps ◽  
To Receive

TPS597 Background: KEYNOTE-052 (NCT02335424) results led to pembro, a PD-1 inhibitor, to become the standard of care for cisplatin-ineligible pts with locally advanced or metastatic UC with tumors expressing PD-L1 and for pts unable to receive platinum-based chemotherapy regardless of PD-L1 status. Len, a potent, multiple-receptor, tyrosine kinase inhibitor has activity in multiple solid tumors. KEYNOTE-146 (NCT02501096) results showed promising efficacy and manageable safety with pembro+len in previously treated pts with advanced UC, regardless of PD-L1 status. Methods: LEAP-011 (NCT03898180) is a randomized phase 3 study to assess efficacy and safety of pembro+len, compared with pembro+placebo, in pts with advanced UC. An estimated 694 pts will be enrolled. Adults (≥18 years) with histologically confirmed locally advanced unresectable or metastatic UC who are either cisplatin-ineligible with tumors expressing PD-L1 (combined positive score [CPS] ≥10) or ineligible to receive any platinum-based chemotherapy are eligible. Pts are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 analysis. Previous treatment with systemic chemotherapy for advanced UC is not permitted, except in cases of recurrence after 1 year of platinum-based chemotherapy for either muscle-invasive bladder cancer (neoadjuvant) or after radical cystectomy (adjuvant). Pts will be randomly assigned 1:1 to receive pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 y) plus either len 20 mg or placebo orally once daily. Pts will be stratified as follows: ineligible for any platinum containing chemotherapy and ECOG PS 2 (CPS ≥10 vs <10); cisplatin ineligibility and CPS ≥10 (ECOG 0-1 vs 2). Radiologic assessment will include CT/MRI of the chest, abdomen, and pelvis, and bone imaging. Responses will be assessed per RECIST v1.1 by blinded independent central review (BICR). Coprimary end points are PFS and OS. Secondary end points are objective response rate, duration of response, and disease control rate per RECIST v1.1 by BICR; patient-reported outcomes; and safety. Tissue-and blood-based biomarkers will be explored. Accrual began May 6, 2019. Clinical trial information: NCT03898180.

Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9013-9013
Author(s):  
Shun Lu ◽  
Xiaorong Dong ◽  
Hong Jian ◽  
Jianhua Chen ◽  
Gongyan Chen ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
P Value ◽  
Low Grade ◽  
First Line ◽  
Once Daily ◽  
Phase Iii Trial ◽  
Exon 19

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value <0.0001). DoR was also significantly prolonged with Au. Median OS has not been reached. Efficacy and relevant safety results are summarized in Table. Despite a significantly longer duration of treatment (median 463 vs 254 days), Au was associated with a lower incidence of rash, diarrhea, AST/ALT increase, and treatment related serious adverse events (SAEs) (4.2% vs 11.2%). Au was associated with more frequent events of CPK increased, platelet count decreased, and neutrophil count decreased, which were predominantly low grade. Conclusions: Au significantly prolonged PFS and DoR compared to G as first-line therapy in pts with advanced NSCLC with EGFRm. Au demonstrated a favorable safety profile, especially regarding toxicities mediated by wild-type EGFR. These results establish Au as a promising option for advanced NSCLC with EGFRm. Clinical trial information: NCT03849768. [Table: see text]

scholarly journals Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study

2021 ◽  
pp. JCO.21.00217
Author(s):  
Yoon-Koo Kang ◽  
Suzanne George ◽  
Robin L. Jones ◽  
Piotr Rutkowski ◽  
Lin Shen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Disease Control ◽  
Survival Data ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Once Daily ◽  
End Point ◽  
Significant Difference ◽  
Phase Iii Study

PURPOSE Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha ( PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study ( NCT02508532 ), avapritinib showed clinical activity against PDGFRA D842V–mutant and later-line KIT-mutant GIST. VOYAGER ( NCT03465722 ), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.

A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4135-TPS4135 ◽  
Author(s):  
Charles S. Fuchs ◽  
Sergio Jobim Azevedo ◽  
Alfredo Carrato ◽  
Vincent Haddad ◽  
Lara Rachel Lipton ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Rank Test ◽  
Metastatic Adenocarcinoma ◽  
Double Blind ◽  
Patient Reported ◽  
Adenocarcinoma Of The Pancreas

TPS4135 Background: Ganitumab (AMG 479) is an investigational, fully human, monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study in patients with metastatic pancreatic cancer, addition of ganitumab 12 mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS) and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposure-efficacy analysis showed that patients with higher ganitumab exposure levels (AUCss at or above median) had longer PFS and OS (Lu. JCO. 2011;29:4049). Methods: In this phase III study, patients are randomized 2:2:1 to placebo + G, ganitumab 12 mg/kg + G, or ganitumab 20 mg/kg + G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas; ECOG score 0 or 1; ≥ 18 years old; adequate organ function; and fasting (or non-fasting) glucose ≤ 160 mg/dL. The primary endpoint is OS. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab + G vs placebo + G. Key secondary endpoints include PFS, objective response, safety, and patient-reported outcomes. An additional objective is to define a subpopulation with improved OS based upon baseline levels of circulating biomarkers. Enrollment began in April 2011. As of January 23, 2012, 463 of 825 patients have been enrolled. The study is overseen by an independent data monitoring committee. Status: open. Supported by Amgen Inc. in collaboration with Takeda Global Research & Development Center, Inc.; ClinicalTrials.gov: NCT01231347.

Sign in / Sign up

Export Citation Format

Share Document