A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 217-217 ◽  
Author(s):  
Eileen Mary O'Reilly ◽  
Do-Youn Oh ◽  
Neesha Dhani ◽  
Daniel John Renouf ◽  
Myung Ah Lee ◽  
...  
Keyword(s):  
Objective Response ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Controlled Study ◽  
Phase 2 ◽  
Intrinsic Resistance ◽  
Multiple Cancer ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Randomized Phase 2

217 Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) > 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.

A phase 2 trial of lenvatinib 18 mg versus 14 mg once daily (QD) in combination with everolimus (5 mg QD) in renal cell carcinoma (RCC) after 1 prior VEGF-targeted treatment.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS707-TPS707
Author(s):  
Hilary Glen ◽  
Javier Puente ◽  
Daniel Yick Chin Heng ◽  
Sun Young Rha ◽  
Di Li ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Final Analysis ◽  
The United States ◽  
Similar Efficacy ◽  
P Value ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Study ◽  
Grade 3

TPS707 Background: Based on findings from a randomized phase 2 study (Study 205), lenvatinib (LEN) + everolimus (EVE) was approved in the United States and European Union for patients (pts) with advanced RCC following 1 prior anti-angiogenic therapy. In that study, LEN 18 mg QD + EVE 5 mg QD significantly prolonged progression-free survival (PFS) compared with either monotherapy. In the LEN+EVE cohort, grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 71% of pts. We report the design of an ongoing, multicenter, randomized, double-blind, phase 2 study (Study 218) to evaluate if a lower LEN starting dosage regimen provides similar efficacy with a better safety profile than LEN 18 mg + EVE 5 mg (NCT03173560). Methods: Eligible pts are aged ≥ 18 years with advanced clear cell RCC, 1 prior anti-VEGF therapy, ≥ 1 measurable target lesion per RECIST 1.1, a KPS score of ≥ 70, and prior nivolumab is allowed. Pts will receive LEN 18 mg or 14 mg QD + EVE 5 mg QD in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The LEN 14-mg dose will be escalated to 18 mg if no intolerable grade 2, or any grade ≥ 3 TEAEs requiring dose reduction occur in cycle 1. The primary endpoints are objective response rate (ORR) at week 24 (ORR24W) and the proportion of pts with intolerable grade 2 and any grade ≥ 3 TEAEs within 24 wks after randomization. Secondary endpoints include PFS and ORR. An estimated 306 pts will be randomized. Sample size is based on detecting noninferiority (NI) of ORR24W and superiority of the primary safety endpoint. Two interim analyses (IA) will be performed when 150 and 200 pts have completed 24 wks of follow-up or discontinue earlier. Each analysis will test NI and futility of the LEN 14-mg arm ORR24W vs the 18-mg arm ORR24W. An O’Brien-Fleming boundary will be used for NI. If the 1-sided P-value is ≤ 0.005 at the first IA, ≤ 0.014 at the second IA, or ≤ 0.045 at the final analysis, then NI in ORR24W will be claimed. If the futility boundary is crossed (ie, 1-sided P-value is ≥ 0.776 at the first IA or ≥ 0.207 at the second IA), then futility will be claimed. Clinical trial information: NCT03173560.

Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9526-9526 ◽  
Author(s):  
Alexander David Guminski ◽  
Annette May Ling Lim ◽  
Nikhil I. Khushalani ◽  
Chrysalyne D. Schmults ◽  
Leonel Fernando Hernandez-Aya ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Median Duration ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase 2 ◽  
Primary Analysis ◽  
Phase 2 Study ◽  
Grade 3

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

First Clinical Results Of a Randomized Phase 2 Study Of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA), In Adult Patients With Acute Myeloid Leukemia (AML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 497-497 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Karen Yee ◽  
Patricia Kropf ◽  
Casey O'Connell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Research Funding ◽  
Remission Rate ◽  
Phase 2 ◽  
Elderly Aml ◽  
Phase 2 Study ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Randomized Phase 2 ◽  
Refractory Aml

Abstract Background SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding.

scholarly journals PEGPH20 improves pfs in patients with metastatic pancreatic ductal adenocarcinoma: A randomized phase 2 study in combination with nab-paclitaxel/gemcitabine

2017 ◽  
Vol 28 ◽  
pp. iii137-iii138 ◽  
Author(s):  
Sunil Hingorani ◽  
Andrea Bullock ◽  
Tara Seery ◽  
Lei Zheng ◽  
Darren Sigal ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Randomized Phase 2

scholarly journals Biweekly Oxaliplatin Plus S1 (SOX) As First Line Therapy For Advanced Or Metastatic Gastric Or Gastroesophageal Junction (G/GEJ) Caner In Chinese Elderly Patients: An Open-Label, Single-Arm, Phase 2 Study.

2021 ◽  
Author(s):  
Zhichao Jiang ◽  
Aiping Zhou ◽  
Yongkun Sun ◽  
Wen Zhang
Keyword(s):  
Cancer Patients ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Cancer Center ◽  
Phase 2 ◽  
First Line ◽  
Open Label ◽  
Weekly Chemotherapy ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: SOX (oxaliplatin and S1 every 3 weeks) is one of the most common used first line chemotherapy for advanced or metastatic G/GEJ cancer in Asia, but with significant hematological and neurological toxicity. In China, the majority of gastric cancer patients are the middle-aged and elderly with dissatisfactory tolerance to 3-weekly chemotherapy. Therefore, we aimed to assess efficacy and safety of biweekly SOX as first line treatment in patients 60 years old or older with advanced G/GEJ cancer in a single arm phase 2 study. Methods: Oxaliplatin was administered intravenously on day 1 at 85 mg/m2. S-1 was given at 80, 100, 120 mg/day depending on body surface area of <1.25 m2, 1.25 to <1.5 m2, or ≥1.5 m2 two times daily on days 1-10, every 2 weeks. Eligible patients were aged 60 years old or older with histological or cytological diagnosis of advanced G/GEJ adenocarcinoma, had measurable disease according to the RECIST v 1.1 without previous treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Results: Between May 2016 and Sep 2018, 42 patients were enrolled. Median follow-up time was 43.6 months. ORR and DCR were 52.4% and 85.7%, respectively. Median PFS was 4.6 months (95%CI 2.486-6.714). Median OS was 11.1 months (95%CI 8.001-14.199). The most common treatment-related adverse events (TRAEs) of any grade were thrombocytopenia (59.5%), neutropenia (57.1%), appetite loss (57.1%) and nausea (54.8%). Only two patients respectively suffered from grade 3 treatment-related neutropenia (1 patient, [2.4%]) and diarrhea (1 patient, [2.4%]). No other grade 3 or worse TRAEs occurred. Conclusions: First line biweekly SOX showed promising PFS and OS with a remarkable tolerance in advanced G/GEJ cancer patients 60 years old or older preliminary worth further evaluation.Trial registration: ClinicalTrials.gov ID: NCT04694404 (5/1/2021). This study was approved by the Ethical Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, (17-048/1303).

scholarly journals A Randomized Phase 2 Trial of Azacitidine ± Durvalumab as First-line Therapy for Higher-Risk Myelodysplastic Syndromes

2021 ◽  
Author(s):  
Amer M. Zeidan ◽  
Isaac Wayne Boss ◽  
CL Beach ◽  
Wilbert B. Copeland ◽  
Ethan Greene Thompson ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Surface Expression ◽  
Immune Recognition ◽  
Phase 2 ◽  
First Line ◽  
First Line Therapy ◽  
Phase 2 Trial ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Randomized Phase 2

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase inhibitory immune checkpoint (ICP) molecule expression. We conducted the first randomized phase 2 study of azacitidine plus the ICP inhibitor durvalumab versus azacitidine monotherapy as first-line treatment of higher-risk myelodysplastic syndromes (HR-MDS). Patients (N=84) received azacitidine 75 mg/m2 subcutaneously (days 1-7) with (Arm A) or without (Arm B) durvalumab 1500 mg intravenously on day 1 every 4 weeks. After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arms A and B received a median of 7.9 and 7.0 treatment cycles, respectively, with 73.7% and 65.9% completing ≥4 cycles. The overall response rate (primary endpoint) was 61.9% in Arm A (26/42) and 47.6% in Arm B (20/42; P=0.18), and median overall survival was 11.6 months (95% CI: 9.5, nonevaluable) versus 16.7 months (95% CI: 9.8, 23.5) (P=0.74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (A) and 81% (B). Grade 3 or 4 hematologic AEs were reported in (Arm A vs B) 89.5% vs 68.3% of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased PD-L1 (CD274) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining durvalumab and azacitidine in patients with HR-MDS was feasible, but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. ClinicalTrials.gov: NCT02775903

Phase 2 Study of Carfilzomib (CFZ) with or without Filanesib (FIL) in Patients with Advanced Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 728-728 ◽  
Author(s):  
Jeffrey A Zonder ◽  
Saad Usmani ◽  
Emma C. Scott ◽  
Craig C. Hofmeister ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): Updates from ALTA, a pivotal randomized phase 2 trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20503-e20503 ◽  
Author(s):  
Myung-Ju Ahn ◽  
D. Ross Camidge ◽  
Marcello Tiseo ◽  
Karen L. Reckamp ◽  
Karin Holmskov Hansen ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Best Response ◽  
Grade 3 ◽  
Nsclc Patients ◽  
To Receive ◽  
Randomized Phase 2

e20503 Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]

scholarly journals Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma

2020 ◽  
Vol 38 (27) ◽  
pp. 3185-3194 ◽  
Author(s):  
Eric Van Cutsem ◽  
Margaret A. Tempero ◽  
Darren Sigal ◽  
Do-Youn Oh ◽  
Nicola Fazio ◽  
...  
Keyword(s):  
Adverse Events ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Controlled Study ◽  
Double Blind ◽  
Intention To Treat ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Grade 3

PURPOSE To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA). PATIENTS AND METHODS HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1. RESULTS At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%). CONCLUSION The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.

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