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.

scholarly journals Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4436-4438 ◽  
Author(s):  
Ruben A. Mesa ◽  
Xiaopan Yao ◽  
Larry D. Cripe ◽  
Chin Yang Li ◽  
Mark Litzow ◽  
...  
Keyword(s):  
Eastern Cooperative Oncology Group ◽  
Hematologic Toxicity ◽  
Cooperative Group ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Nonhematologic Toxicity ◽  
Grade 3 ◽  
Bone Marrow Analysis ◽  
Dose Prednisone

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)–defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Feasability and Toxicity After Induction Treatment with Rituximab-HCVAD and Metotrexate/Citarabine, Followed by Consolidation with Y-90 Ibritumomab Tiuxetan (Phase II GELTAMO–LCM 04-02 study).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1703-1703
Author(s):  
Reyes Arranz ◽  
Ana Garcia-Noblejas ◽  
Carlos Grande ◽  
José Terol ◽  
José Javier Sánchez ◽  
...  
Keyword(s):  
Haematological Toxicity ◽  
Induction Treatment ◽  
Ibritumomab Tiuxetan ◽  
Bulky Disease ◽  
Consolidation Treatment ◽  
Lower Stage ◽  
Ann Arbor ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 1703 Poster Board I-729 Abstract text Background Mantle Cell Lymphoma (MCL) is an entity with a median survival of 2- 4 years, so it is currently considered an aggressive tumour. Standard chemotherapies for other B cell lymphomas have yielded poor results. Better outcomes have been communicated with the use of up front intensive chemotherapy or of high doses schemas with stem cell support as consolidation of the response, although relapses frequently occur. Keeping in mind these considerations, we used the Hyper-CVAD/MTX-AraC squema in association with anti-CD20, followed by consolidation with Ibritumomab-tiuxetan (ZevalinR) with the aim of eradicating minimal residual disease and decrease the risk of relapse. Aims Evaluate the feasibility, safety and, efficacy for overall response, complete response and progression free survival (PFS) in newly diagnosed MCL patients with advanced Ann Arbor stage or with lower stage but with B symptoms or bulky disease. Methods All patients received: Anti-CD20/Hyper-CVAD therapy alternating with anti-CD20/MTX/Ara-C, supported with Peg- Filgastrim. Response was evaluated after 4 cycles and, treatment continued up to a median of 6 cycles if response (complete or partial) was achieved. Consolidation treatment consisted in a single dose of Y90-Ibritumomab-Tiuxetan (Zevalin) (RIT) administered 8 to 12 weeks after the last cycle. We started at a dose of 0.3 mCi/kg with a planned dose escalation to 0.4 mCi/kg if no unacceptable toxicity was observed in the 1st three patients treated. Results From February 2006 until July 2008, 30 patients were enrolled. Patients' characteristics: 77% male, median age of 59 years old (range 41-70), 93.3% Ann Arbor stage IV, 87% bone marrow infiltration, 62% gastrointestinal infiltration and 13%were blastic variant. Induction therapy: The main toxicities over 170 cycles were haematological and greater in the odd cycles (90% vs 53% grade 3-4 Neutropenia and 98% v. 33% grade 3-4 thrombocytopenia). Sixty five SAEs were reported during induction, mainly neutropenic fever and upper tract respiratory infection with 1 death due to sepsis (3.3%), and 5 non-related events (including 1 suicide). Response after induction: 20 patients (66,7%) were in CR, 5 (16,7%) in uRC, 1 (3,3%) progressed, and 4 patients (13,3%) were not evaluable due to early events (2 deaths and 2 toxicities). Consolidation with RIT: dose of RIT was fixed at 0.3 mCi/Kg after treatment of the first 6 patients and total of 18 patients (60%) have finally received it. Grade 3-4 neutropenia and thrombopenia was observed in 72% and 83% of the patients with a median duration of 3 and 8 weeks, respectively. Ten SAEs with no deaths were reported after consolidation. Twelve patients (40%) could not accomplish the whole treatment due to following reasons: 8 because of induction toxicity (5 infection with one death, 1 neurological, 3 delayed haematological recovery); 1 non related death, 1 progression and 1 withdrawal for personal reasons. Survival: With a median follow up of 25 months. Actuarial OS and PFS to 33 months is 90% and 75% respectively. Conclusion treatment of MCL with 6 cycles of Hyper-CVAD/MTX-AraC with anti-CD20 can be accomplished in 70% of the patients up to 70 years, although close follow-up and dose adjustments are frequently required mainly due to haematological toxicity. Consolidation with Ibritumomab-tiuxetan is safe and feasible at a dose of 0,3 mCi/Kg. Efficacy is high with an ORR and PFS of 83% and 75%, respectively although longer follow-up is needed to evaluate the role of consolidation treatment with RIT. Disclosures Salar: Amgen: Honoraria.

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.

Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9075-9075 ◽  
Author(s):  
David Planchard ◽  
Benjamin Besse ◽  
Tae Min Kim ◽  
Elisabeth A. Quoix ◽  
Pierre Jean Souquet ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Braf V600e ◽  
Phase 2 ◽  
Primary Analysis ◽  
Durable Response ◽  
Phase 2 Trial ◽  
Duration Of Response ◽  
Independent Review ◽  
Previously Treated

9075 Background: BRAF V600E mutations occur in 1% to 2% of lung adenocarcinomas and act as oncogenic drivers. Initial cohorts of the BRF113928 (NCT01336634) trial evaluated efficacy and safety of D monotherapy (cohort A; n = 78) or D + T (cohort B; n = 57) in pts with previously treated BRAFV600E–mutant metastatic NSCLC. At primary analysis, overall response rates (ORRs) were 33.3% and 63.2% in pts who received D or D + T, respectively. Furthermore, durable response (median duration of response [DOR], 9.0 mo) was observed in D + T pts. Here, we present an updated survival analysis based on additional follow-up. Methods: In this phase 2 trial, 2 cohorts (A and B) of pts with previously treated metastatic BRAFV600E–mutant NSCLC were enrolled sequentially. The primary endpoint was investigator-assessed ORR. Secondary efficacy endpoints included progression-free survival (PFS), DOR, and overall survival (OS). D and T were dosed orally at the established phase 2 dose of D 150 mg twice daily and T 2 mg once daily. Results: This updated analysis had a median follow-up of 16.2 mo, which represented an additional 10 mo of follow-up. Median OS was 12.7 mo (95% CI, 7.3-16.3) with 57 deaths reported for pts treated with D monotherapy and 18.2 mo (95% CI, 14.3-not estimable [NE]) with 33 deaths reported for pts treated with D + T. Detailed efficacy results are presented in the table. Investigator-assessed ORR, DOR, and PFS were supported by independent review committee assessments. No new safety signals were observed for D + T. Conclusions: This update of the BRF113928 study confirms that durable responses and encouraging survival were achieved with combination D + T in pts with BRAFV600E–mutant NSCLC. Clinical trial information: NCT01336634. [Table: see text]

Interim analysis of STARTAR: A phase II salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 90-90
Author(s):  
Tian Zhang ◽  
Bridget F. Koontz ◽  
Scott T. Tagawa ◽  
Himanshu Nagar ◽  
Rhonda L. Bitting ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Interim Analysis ◽  
Salvage Treatment ◽  
Research Network ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Psa Recurrence ◽  
Grade 3

90 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. Current standard duration of ADT for high risk PSA recurrence is up to 2 years with RT; therefore shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo of enzalutamide added to ADT/RT had a 3-year progression free survival (PFS) of 53% in high risk patients including lymph node (LN) positive. Given that docetaxel improves survival in men with mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide and docetaxel in this setting. Methods: STARTAR is a multicenter phase 2 trial for salvage treatment of PSA recurrent PC following RP conducted within the US Dept. of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). Key inclusion criteria included PC with Gleason 7 with T3/positive margin/1-4 positive LNs or Gleason 8-10 disease and PSA relapse within 4 years of RP (min PSA 0.2 ng/mL to max PSA 4 ng/mL). Men with up to 4 positive resected LNs were eligible. Men started ADT with apalutamide, continued with RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 weeks), and finally completed docetaxel 75mg/m2 IV q3 weeks for 6 cycles. Men were treated with ADT and apalutamide for approximately 9 months. The primary endpoint was PSA PFS at 36 months. This interim analysis evaluated secondary endpoints of 1-year PSA recurrence, testosterone recovery, and safety of this treatment sequence. Results: From 3/2018 to 12/2019, 39 men were enrolled at Duke, Wake Forest, Cornell, and the GU Research Network. With a data cutoff in 9/2020, median follow up from enrollment was 14 months. Baseline patient characteristics included Gleason 4+3 = 7 in 54% and Gleason 8-10 in 46%, and 23% LN positive; median PSA at the time of enrollment was 0.58 ng/mL (range 0.21-3.40) and the median time from RP to enrollment was 7 mo (range 2-98). At 1 year, there have been no progression events with 38% (12/31) of men with post-treatment testosterone recovery into normal range (recovery time median 10 mos [1-17 mos]). Common adverse events (AEs) of any-grade at least possibly related to the regimen were 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with neutropenia as the most common grade 3/4 AE (27/39 men, 70%) with two grade 3 febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apalutamide, radiation, and 6 cycles docetaxel in the salvage setting for high risk PSA recurrence, short term outcomes are excellent with no recurrences at 12 months of follow-up. This salvage treatment was well tolerated in the majority of men with the exception of a high rate of drug rashes and neutropenia related to the course of treatment, in line with known safety profiles of the study agents. Clinical trial information: NCT03311555.

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.

A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 369-369 ◽  
Author(s):  
Armando Lopez-Guillermo ◽  
Miguel A. Canales ◽  
Ivan Dlouhy ◽  
Javier Briones ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Initial Therapy ◽  
Phase 2 ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Phase 2 Trial ◽  
Number Of Patients ◽  
Grade 3 ◽  
Randomized Phase 2

Abstract Patients with FL can have long time of survival, but disease progression typically occurs 3-5 years after initial treatment. Consolidation with Z after initial therapy has shown to improve progression-free survival (PFS) mainly in the pre-R era, whereas maintenance with R also has demonstrated a substantial benefit in terms of PFS in patients treated with immunochemotherapy. In this setting, the Spanish intergroup PETHEMA/GELTAMO/GELCAB started a randomized phase 2 trial in order to compare the use of consolidation with Z vs. R maintenance in patients with FL responding to R-CHOP. From June 2008 to July 2010, 146 patients (66M/80F; median age, 55 years) were enrolled from 25 Spanish institutions in the randomized phase 2 trial ZAR2007 (ClinicalTrials.gov, number NCT00662948). Main inclusion criteria were: FL grade 1, 2 or 3a, age 18-75 years, stages II-IV and need of treatment according to modified GELF criteria. Patients with FL grade 3b or transformed to DLBCL were excluded. In addition, patients with platelet count <150x109/L or bone marrow infiltration>25% before randomization were also excluded. Main end-point of the trial was PFS from randomization. The distribution according to the FLIPI score was as follows: low-risk 14%, intermediate 47%, and high 39%. After R-CHOP, 124 patients in CR (n=56), CR[u] (13) or PR (55) were randomized 1:1 (stratified by response) to arm A (90Y ibritumomab tiuxetan 0.4 mCi/kg IV; total dose of 90Y was capped at 32 mCi) vs. arm B (1 infusion of R 375 mg/m2 every 8 weeks for 2 years). Sixty three (51%) patients were assigned to arm A (Z) and 61 (49%) to arm B (R). Twenty two patients were not randomized due to response <PR, low neutrophil or platelets counts or patient decision. After a median follow-up of 37 months from randomization (range, 26 to 56), 31 patients eventually progressed/relapsed with a 36-month PFS of 64% (95% confidence interval [CI] 52-76) for patients in arm A (consolidation with Z) (22 events) and 86% (95% CI 77-95) for patients in the R maintenance (9 events) (p=0.01; HR=0.38, 95%CI 0.17-0.83) as shown in the figure. The number of patients in PR after R-CHOP who reached CR during maintenance were 14 of 28 (50%) and 12 of 26 (46%) for arms A and B, respectively. Two patients developed transformation to DLBCL at 8 (arm A) and 39 months (arm B) after randomization. During the maintenance period, patients receiving Z showed grade 3-4 neutropenia in 6 of 63 cases and grade 3-4 thrombocytopenia in 5 of 63, whereas these figures were 1 of 61 and 0 of 61 (p=0.05) for patients in arm B, respectively. No unexpected late toxicities have been reported. Five patients have died during the follow-up due to the progression of lymphoma in all cases, with no differences between the arms (36-month OS, 98% vs. 95% for arms A and B, respectively). In conclusion, in patients with FL in response after R-CHOP, maintenance with R was superior to consolidation with Z in terms of PFS, with no differences in OS with the current follow-up. Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees. Briones:F. Hoffmann-La Roche: Honoraria.

ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for Mantle cell lymphoma: Effect of adding bortezomib to front-line BR induction on PFS.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7503-7503
Author(s):  
Mitchell Reed Smith ◽  
Opeyemi Jegede ◽  
Peter Martin ◽  
Brian G. Till ◽  
Samir S. Parekh ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
Induction Treatment ◽  
Phase 2 ◽  
Mantle Cell ◽  
Grade 3 ◽  
Ecog Ps ◽  
Randomized Phase 2

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

Atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory diffuse large B-cell Lymphomas (R/R DLBCL): Primary analysis of a phase II trial from LYSA.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8053-8053 ◽  
Author(s):  
Charles Herbaux ◽  
Olivier Casasnovas ◽  
Pierre Feugier ◽  
Gandhi Damaj ◽  
Reda Bouabdallah ◽  
...  
Keyword(s):  
Metabolic Response ◽  
Treatment Options ◽  
Safety Data ◽  
Stage Iv ◽  
Tumor Burden ◽  
Primary Analysis ◽  
Phase 2 Trial ◽  
Treatment Paradigm ◽  
Grade 3 ◽  
Line Of Therapy

8053 Background: R/R DLBCL 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) evaluate the combination of ATE, OBI and VEN in R/R B lymphomas, we present here primary efficacy and safety data fromthe DLBCL cohort. Methods: Patients ≥18 years with biopsy-confirmed R/R DLBCL who failed at least one line of therapy were eligible. OBI was given IV at the dose of 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, started on D8C1 for 24 cycles. The primary endpoint wasthe Overall Metabolic Response Rate (OMRR) 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 (03 Jan 2020), 58 pts were enrolled and the median follow-up was 9 months [6.9-11.8]. Baseline characteristics were: median age, 70 years; male, 53.4%; Ann Arbor Stage IV, 84.5%; aaIPI (≥2), 63.2%; > 2 prior lines of therapy, 83.6%; and refractory to last line of prior regimen, 63.6%. The OMRR at EOI was measured at 23.6% [14.58%-34.93%], including 18% of CMR. To date, these responses seem durable with only 3 reported relapses. According to the highest diameter mass, OMRR was 38.5% versus 10.3%, < 5cm and > 5cm respectively; P = 0,02. All three treatments were stopped in 78% of patients, mostly for progressive disease. At the time of analysis, a median of 4 cycles [1-8] has been administered. A total of 48 (84.2%) pts experienced grade 3–4 adverse event (AE) and 6 (10.5%) had an AE that led to discontinuation of any drug.AE of grade 3 or more reported in at least 20% of patients were neutropenia (33.3%) and lymphopenia (35.1%). Of note, a grade 3 autoimmune colitis and a grade 1 hypothyroidism were reported during induction. Conclusions: The ATE, OBI and VEN combinationappears to be well tolerated. The OMRR rate at EOI is comparable with currently available treatment options in this population, with durable responses. The OMRR seems better in patients with a low tumor burden. Clinical trial information: NCT03276468 .

scholarly journals CA180-372: An International Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 98-98 ◽  
Author(s):  
Stephen P. Hunger ◽  
Vaskar Saha ◽  
Meenakshi Devidas ◽  
Maria Grazia Valsecchi ◽  
Julie Gastier Foster ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Research Funding ◽  
Study Endpoint ◽  
Primary Study ◽  
Intensive Chemotherapy ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children's Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor. Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (&gt;1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR - ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up. Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in &gt;10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented. Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial. Disclosures Hunger: Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership. Saha: Shire: Research Funding. Gastier Foster: Bristol-Myers Squibb: Research Funding. Cazzaniga: Italian Association for Cancer Research: Research Funding; Fondazione Tettamanti onlus: Employment. Borowitz: Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Gramatges: Bristol Meyer Squibb: Research Funding. Sun: Baxalta: Consultancy. Swanink: Bristol-Myers Squibb: Employment. Schrappe: Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Healey: Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Equity Ownership.

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