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.

Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6015-6015 ◽  
Author(s):  
Michael Robert Migden ◽  
Nikhil I. Khushalani ◽  
Anne Lynn S. Chang ◽  
Danny Rischin ◽  
Chrysalyne D. Schmults ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Phase 2 ◽  
Primary Analysis ◽  
Curative Surgery ◽  
Grade 3

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC 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: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

scholarly journals Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing

2020 ◽  
Vol 8 (1) ◽  
pp. e000775 ◽  
Author(s):  
Danny Rischin ◽  
Michael R Migden ◽  
Annette M Lim ◽  
Chrysalyne D Schmults ◽  
Nikhil I Khushalani ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Antitumor Activity ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Phase 2 ◽  
Primary Analysis ◽  
Link Type ◽  
Phase 2 Study ◽  
Group 3 ◽  
Group 1

BackgroundCemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).MethodsThe primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.ResultsFor Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).ConclusionIn patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.Trial registration numberClinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498

Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3229-3229 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Francis Giles ◽  
Andreas Hochhaus ◽  
Jane F. Apperley ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Time To Progression ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4048-4048
Author(s):  
Kensei Yamaguchi ◽  
Yung-Jue Bang ◽  
Satoru Iwasa ◽  
Naotoshi Sugimoto ◽  
Min-Hee Ryu ◽  
...  
Keyword(s):  
Median Survival ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Phase 2 ◽  
Standard Chemotherapy ◽  
Primary Analysis ◽  
Her2 Positive ◽  
Open Label ◽  
Grade 3

4048 Background: T-DXd is an antibody–drug conjugate comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. DESTINY-Gastric01 (DS8201-A-J202; ClinicalTrials.gov, NCT03329690) is an open-label, multicenter, randomized, phase 2 trial of T-DXd in patients with HER2-positive advanced gastric cancer (GC) or GEJ adenocarcinoma. In the primary analysis (101 OS events; median survival follow-up, 12.3 mo), T-DXd showed statistically significant benefit vs standard chemotherapy in objective response rate (ORR) and OS (Shitara K, et al. N Engl J Med. 2020;382:2419-2430); here, we present the final OS analysis as well as updated efficacy and safety. Methods: Patients (pts) with locally advanced or metastatic, centrally confirmed HER2-positive (IHC3+ or IHC2+/ISH+ on archival tissue) GC or GEJ cancer that had progressed after ≥2 previous lines of therapy including trastuzumab were randomly assigned 2:1 (T-DXd 6.4 mg/kg Q3W or physician’s choice [PC] irinotecan [I] or paclitaxel [P]). Pts were stratified by country, ECOG performance status (0, 1), and HER2 status. Primary end point was ORR by independent central review. Key secondary end points were OS, duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), confirmed ORR, and safety. Final OS analysis was performed at 133 OS events. Results: 187 pts received T-DXd (n = 125) or PC (n = 62 [55 I; 7 P]); 79.7% of pts were Japanese and 20.3% were Korean. Pts had a median of 2 prior lines of therapy, and 44.4% had ≥3. At data cutoff (June 3, 2020), 8% of T-DXd and 0% of PC pts remained on treatment (median survival follow-up, 18.5 mo). OS was improved with T-DXd vs PC (median OS, 12.5 vs 8.9 mo; hazard ratio [HR], 0.60 [95% CI, 0.42-0.86]); 12-month OS, 52.2% vs 29.7%. ORR was 51.3% (61/119; 11 CR; 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < 0.0001); confirmed ORR, 42.0% (50/119; 10 CR; 40 PR) vs 12.5% (7/56; all PR) ( P = 0.0001); DCR, 86.6% vs 62.5% ( P = 0.0003); confirmed median DOR, 12.5 vs 3.9 mo; median PFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = 0.0003). Grade ≥3 AEs occurred in 85.6% of T-DXd pts vs 56.5% with PC; the most common were neutrophil count decreased (49.6%, 22.6%), anemia (38.4%, 22.6%), and white blood cell count decreased (20.8%, 11.3%). 16 pts (12.8%) had T-DXd–related interstitial lung disease (ILD; 13 grade 1/2, 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. As reported in the primary analysis, there was 1 T-DXd–related death from pneumonia (non-ILD). Conclusions: With additional follow-up after the primary analysis, T-DXd continued to demonstrate OS benefit and clinically relevant improvement in ORR compared with standard chemotherapy, and a manageable safety profile, in HER2-positive advanced GC or GEJ adenocarcinoma. Clinical trial information: NCT03329690.

Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 272-272
Author(s):  
Toni K. Choueiri ◽  
Todd Michael Bauer ◽  
David F. McDermott ◽  
Edward Arrowsmith ◽  
Ananya Roy ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Preliminary Analysis ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Cell Renal Cell Carcinoma ◽  
Hand Foot Syndrome ◽  
Previously Treated ◽  
Grade 3

272 Background: Belzutifan (MK-6482) inhibits HIF-2α and demonstrated antitumor activity and favorable safety as monotherapy in a phase 1 study of patients (pts) with metastatic ccRCC. Current study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced ccRCC who were either treatment naive (cohort 1) or previously treated, including immunotherapy and TKIs (cohort 2). This preliminary analysis presents data from cohort 2. Methods: Pts had metastatic ccRCC and received no more than 2 prior systemic treatment regimens. Initially, 6 pts in either cohort 1 or 2 were treated with belzutifan 120 mg and cabozantinib 60 mg orally once daily for 21 days and a safety review committee performed an initial evaluation. For purpose of this preliminary analysis, efficacy was evaluated in pts who received ≥1 dose of treatment and had an opportunity of ≥6 mo of follow-up. Primary end point: objective response rate (ORR; RECIST v1.1 by investigator review). Secondary end points: progression free survival (PFS), overall survival (OS), and duration of response (DOR). Safety was evaluated for all cohort participants. Results: Evaluation of safety and tolerability of belzutifan 120 mg plus cabozantinib 60 mg was performed in the first 6 pts. Only 1 participant experienced a dose-limiting toxicity of hand-foot syndrome, therefore belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended phase 2 dose. 53 pts were included in the safety analysis population. Median age was 64 yrs, 73.6% were male, 54.7% had ECOG PS 1. Twenty-eight (52.8%) received prior first-line and 24 (45.2%) prior second-line therapies. Median (range) time from enrollment to data cutoff was 11.3 mo (5.6-24.0) for pts with ≥6 mo of follow-up (n=41). The confirmed ORR was 22.0% (9 PRs) and 90.2% had any tumor shrinkage. Disease control rate (CR+PR+SD) was 92.7%. Median (range) DOR was not reached (3.7+ to 14.8+ mo); all responses were ongoing. Median (95% CI) PFS was 16.8 mo (9.2-not reached); PFS rate at 6 mo was 78.3%. OS rate at 6 mo was 95.0%. While 52 of 53 (98.1%) pts experienced a treatment-related adverse event (TRAE), 92% of events were grade 1 and 2. Most common (≥30%) TRAEs were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%), and ALT/AST increase (32-34%). Incidence of grade 3 TRAEs >5% were hypertension (22.4%), anemia (11.3%), fatigue (11.3%), and ALT increase (5.7%). 2 pts experienced grade 3 hypoxia (3.8%). There were no grade 4 TRAEs or deaths. Discontinuations due to TRAEs occurred in 6 pts (11.3%) for belzutifan and 8 pts (15.1%) for cabozantinib. Conclusions: In this preliminary analysis, belzutifan in combination with cabozantinib demonstrated promising antitumor activity in previously treated pts with metastatic ccRCC. Safety was consistent with individual profiles of each agent. Clinical trial information: NCT03634540 .

Phase 2 study of zolbetuximab plus mFOLFOX6 in claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ): ILUSTRO cohort 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16063-e16063
Author(s):  
Samuel J Klempner ◽  
Keun-Wook Lee ◽  
Jean-Philippe Metges ◽  
Daniel V.T. Catenacci ◽  
Fotios Loupakis ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Treatment Options ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase 2 ◽  
Cancer Cell Death ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Junction Protein ◽  
Grade 3

e16063 Background: One accepted treatment for patients (pts) with advanced HER2-negative G/GEJ is mFOLFOX6 (5-FU, folinic acid, oxaliplatin). Despite treatment options, 5-year survival is poor, and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a tight junction protein normally confined to gastric mucosa of healthy tissue, is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Nonclinical results showed that cytotoxic chemotherapy increased CLDN18.2 expression, improving ADCC/CDC activity of zolbetuximab. Phase 2 results (NCT01630083, FAST) showed prolonged survival with zolbetuximab+EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. This study assessed antitumor activity and safety/tolerability of first-line zolbetuximab+mFOLFOX6 (Cohort 2 in NCT03505320) in G/GEJ with high CLDN18.2 expression. Methods: Cohort 2 of this multicohort study enrolled adult pts with metastatic or locally advanced unresectable G/GEJ. Patients had measurable disease (RECIST v1.1), HER2-negative disease, and high CLDN18.2 expression (≥75% of tumor cells demonstrating moderate-to-strong membranous staining by central IHC testing). Patients received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 3 then 600 mg/m2 Q3W. Zolbetuximab and mFOLFOX (Q2W from Cycle 1 Day 1) were administered in 42-day cycles. Key endpoints were safety/tolerability and objective response rate by independent central review (ORRICR RECIST v1.1). Results: As of Jan 26, 2021, Cohort 2 had enrolled 21 pts; median age was 63 years (range, 36-74), 57% were male, 43% were Asian, and 38% were white. Of 19 evaluable pts, 12 had confirmed partial responses; ORRICR was 63.2% (95% CI: 38.4-83.7) (Table). Median PFS was 13.7 months (95% CI: 7.4-not estimable); 12-month PFS rate was 58%. Common adverse events (AEs) were nausea (90.5%; grade 3, 4.8%) and vomiting (61.9%; grade 3, 9.5%). Common grade 3/4 AEs were decreased neutrophil count (33.3%) and neutropenia (28.6%). There were no fatal AEs. Conclusions: Results suggest promising antitumor activity with zolbetuximab+mFOLFOX6 in metastatic or locally advanced G/GEJ. The safety profile was manageable and no new safety signals were identified. Clinical trial information: NCT03505320. [Table: see text]

Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CMLCP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3238-3238 ◽  
Author(s):  
Hagop M Kantarjian ◽  
Francis Giles ◽  
Kapil N. Bhalla ◽  
Richard A. Larson ◽  
Norbert Gattermann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Prior Therapy ◽  
Imatinib Resistant ◽  
Phase 2 Study ◽  
Biochemical Laboratory ◽  
Grade 3

Abstract Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR, survival, and safety. Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151–1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinibintolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.

Atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory indolent non-Hodgkin’s lymphoma (R/R iNHL): Primary analysis of a phase 2 trial from LYSA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7544-7544
Author(s):  
Charles Herbaux ◽  
Herve Ghesquieres ◽  
Reda Bouabdallah ◽  
Stephanie Guidez ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
Tumor Lysis Syndrome ◽  
Safety Data ◽  
Induction Treatment ◽  
Phase 2 ◽  
Primary Analysis ◽  
Phase 2 Trial ◽  
Ann Arbor ◽  
Baseline Characteristics ◽  
Grade 3

7544 Background: R/R iNHL treatment remains challenging. Atezolizumab (ATE) and obinutuzumab (OBI) are monoclonal antibodies acting respectively to inhibit T-lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity, whereas venetoclax (VEN) is a small molecule inhibiting BCL-2. Combining tumor-targeted therapies with agents that enhance anti-tumor immunity represents an attractive treatment paradigm. This LYSA sponsored multicenter phase 2 trial (NCT03276468) evaluated ATE, OBI and VEN combination in R/R B-cell lymphomas. Herein, we present primary efficacy and safety data from the iNHL cohort including Follicular Lymphoma (FL) and Marginal Zone Lymphomas (MZL). Methods: Patients ≥18 years with biopsy-confirmed R/R FL and MZL who failed at least one line of therapy were eligible. OBI was given IV at 1 g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every 3 weeks. ATE was given IV, 1.2 g every 3 weeks, started at D2 of C1, then administered at D2 of each cycle for 24 cycles. VEN was given orally at 800 mg/D at full dose, starting on D8C1 for 24 cycles. The primary endpoint was the Overall Response Rate (ORR) evaluated by Lugano criteria at the end of induction (EOI) after 8 cycles of ATE, OBI and VEN (M6) or at premature treatment discontinuation. Results: At the time of the primary analysis (08 Jan 2021), 78 patients were enrolled. FL cohort (n = 58): the median follow-up was 14.5 months. Main baseline characteristics were: Ann Arbor Stage III/IV, 85.7%; FLIPI HR, 47.3%; > 2 prior lines of therapy, 32.1%; and exposed to ASCT, 30.4%. The ORR on PET scan at EOI was measured at 53.6% [41.8%-65.1%], including 30.4% of CMR. 37 patients (63%) received the full induction treatment. MZL cohort (n = 20; 13 nMZL, 5 eMZL, 2 sMZL): the median follow-up was 11.9 months. Main baseline characteristics were: Ann Arbor Stage IV, 100%; bone marrow infiltration, 38.9%; ≥ 2 extra-nodal sites, 50%; and > 2 prior lines of therapy, 22.2%. The ORR on CT scan at EOI was measured at 66.76% [44.6%-84.4%], including 16.7% of CR and 50.0% PR. 11 patients (55%) received the full induction treatment. At time of the present analysis, responses in the 2 cohorts seem durable with only 21,4% of responders who have reported relapse/progression. Out of the 78 pts, a total of 55 (70.5%) pts experienced grade 3–4 adverse event (AE) and 1 patient experienced an AE that led to discontinuation of any drug. Main AE of grade 3 or more were hematologic cytopenias, with only one febrile neutropenia (1.3%). Three pts experienced immune-related AE (1 grade 2 myositis and 2 grade 3 colitis), no tumor lysis syndrome was observed. Conclusions: ATE, OBI and VEN triplet appears to be well tolerated, with no unexpected toxicity brought by the combination. The ORR at EOI seems to be comparable to other innovative regiments in this setting, with durable responses to date. Clinical trial information: NCT03276468.

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