S748 Early PRO-2 Symptom Remission Following Guselkumab Induction Treatment: Results Through Week 12 of the Phase 2 GALAXI 1 Study

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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P463 Induction of endoscopic response: a network meta-analysis of induction studies comparing ontamalimab with other treatments for moderate-to-severe ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.592 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S410-S411

Author(s):

A Vickers ◽

A Nag ◽

B Devine ◽

B E Sands ◽

R Panaccione ◽

...

Keyword(s):

Ulcerative Colitis ◽

Large Scale ◽

Meta Analysis ◽

Placebo Response ◽

Study Data ◽

Induction Treatment ◽

Phase 2 ◽

Odds Ratios ◽

Phase 3 ◽

Random Effects Models

Abstract Background Clinicians, patients, payers and policymakers require relevant, high-quality evidence to support decision-making regarding the treatment of ulcerative colitis (UC). In the absence of head-to-head trials, network meta-analysis (NMA) can be used to compare treatments. We conducted an NMA to compare the efficacy of ontamalimab (anti-MAdCAM-1) using its phase 2 data, with all biologics and novel small molecules for which induction study data on endoscopic response were available. Methods A systematic literature review was conducted in November 2017 to identify published randomised controlled trials of induction treatment in patients with moderate-to-severe UC. An NMA of the identified studies was performed using random-effects models and methods based on NICE guidance. Odds ratios and 95% credible intervals were calculated to describe the relative differences between treatments and placebo in terms of efficacy in inducing endoscopic response. Results were examined by anti-TNF status (naïve vs. experienced). Results In total, 15 phase 2 and phase 3 induction studies of the following agents were available and included: adalimumab (160/80mg), etrolizumab (100mg and 300mg), golimumab (200/100mg), infliximab (5mg), ontamalimab (22.5mg and 75mg), ozanimod (0.5mg and 1mg), tofacitinib (10mg) and vedolizumab (300mg). The definition of endoscopic response (improvement) in all trials was a Mayo endoscopic subscore of ≤1. Homogeneity between studies was good, enabling pooling of results. Figure 1 shows odds ratios for induction of endoscopic response with treatments relative to placebo in anti-TNF-naïve and -experienced patients. All treatments performed significantly better than placebo in anti-TNF-naïve patients, with the exception of both doses of etrolizumab and ozanimod 0.5 mg. Significant differences between some treatments were observed; specifically, ontamalimab 22.5 mg (p = 0.0277), tofacitinib 10 mg (p = 0.0233) and infliximab 5 mg (p = 0.0047) were all superior to adalimumab 160/80 mg. Conclusion This study suggests that ontamalimab, infliximab and tofacitinib could be superior to adalimumab in inducing endoscopic healing, although it was conducted before any large-scale head-to-head trials of these drugs. Furthermore, large variances due to differing endpoint timings, the combination of phase 2 and phase 3 data, and lack of control for placebo response rates preclude firm conclusions being drawn.

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OP27 Long-term safety and efficacy of risankizumab treatment in patients with Crohn’s disease: Final results from the Phase 2 open-label extension study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.026 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S024-S025 ◽

Cited By ~ 3

Author(s):

M Ferrante ◽

B G Feagan ◽

J Panés ◽

F Baert ◽

E Louis ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Opportunistic Infections ◽

Activity Index ◽

Induction Treatment ◽

Phase 2 ◽

Open Label ◽

Safety And Efficacy ◽

Open Label Extension

Abstract Background Efficacy and safety of the IL-23 inhibitor risankizumab (RZB) have been assessed in patients with moderate-to-severe Crohn’s disease (CD) following induction/maintenance treatment.1,2 Responders to RZB in a Phase 2 induction/maintenance study2,3 could enrol in an open-label extension (OLE), NCT02513459.4 Final safety and efficacy results from this RZB OLE study are reported here. Methods Patients achieving clinical response (CResp) (decrease from baseline [BL] in CD Activity Index [CDAI] ≥100) without remission (CRem) (CDAI <150) after Period 2 (Week 26) or CResp/CRem after Period 3 (Week 52) of the preceding study1 received open-label 180 mg subcutaneous (SC) RZB every 8 weeks (Q8W) for up to 206 weeks. Patients who lost CResp/CRem at screening of the OLE were re-induced with open-label 600 mg IV RZB at Weeks 0, 4, and 8. Patients receiving re-induction treatment only received subsequent 180 mg SC RZB Q8W if they regained CResp/CRem following re-induction. A centrally read ileocolonoscopy was performed yearly. Treatment-emergent adverse events (AEs) were collected up to 20 weeks after the last RZB dose. CRem and endoscopic remission (ER [CD Endoscopic Index of Severity (CDEIS) ≤4 or CDEIS ≤2 for patients with isolated ileitis at BL]) were reported up to Week 152. Non-responder imputation (NRI) and observed case analysis were used for binary endpoints. Results Sixty-five patients with CD were enrolled in the OLE, with 4 patients re-induced. At BL of the preceding study, median (range) age was 34 (19–67) years and median (range) disease duration was 10 (2–38) years. Sixty patients (92%) were previously exposed to TNF antagonists. In the OLE, median (range) exposure to RZB was 1014.0 (114–1317) days. Twenty-one (32%) patients prematurely discontinued RZB, including 6 (9%) who had developed an AE. AEs were reported in 60 (92%) patients; 23 (35%) experienced serious AEs. The most common AEs were nasopharyngitis (31%), gastroenteritis (23%), and fatigue (20%). Serious infections were reported in 6 (9%) patients and opportunistic infections in 3 (5%) patients. No tuberculosis, malignancies, or deaths occurred. At Week 0 of the current study, 47 (72%) patients were in CRem and 27 (42%) patients had ER. Both CRem and ER were sustained up to Week 152 (Table). Conclusion In this final analysis of patients with CD receiving long-term open-label RZB treatment, the safety profile of RZB remained consistent with previous data² with no new safety signals. Clinical and endoscopic remissions were sustained. References

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DOP46 Extended induction treatment with mirikizumab in patients with moderately to severely active ulcerative colitis: results from a Phase 2 trial

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy222.080 ◽

2019 ◽

Vol 13 (Supplement_1) ◽

pp. S054-S054

Author(s):

W J Sandborn ◽

M Ferrante ◽

B R Bhandari ◽

E Berliba ◽

T Hibi ◽

...

Keyword(s):

Ulcerative Colitis ◽

Induction Treatment ◽

Active Ulcerative Colitis ◽

Phase 2 ◽

Phase 2 Trial

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A randomized Phase 2 study comparing different dosing approaches of induction treatment (first cycle) of regorafenib in metastatic colorectal cancer (mCRC) patients

Annals of Oncology ◽

10.1093/annonc/mdx393.135 ◽

2017 ◽

Vol 28 ◽

pp. v206-v207

Author(s):

G. Argilés Martinez ◽

E. Sanz-Garcia ◽

M. Valladares-Ayerbes ◽

J.M. Viéitez ◽

P. Garcia-Alfonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Induction Treatment ◽

Phase 2 ◽

Phase 2 Study ◽

Randomized Phase 2

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HOVON 50/GMMG-HD3-Trial: Phase III Study on the Effect of Thalidomide Combined with High Dose Melphalan in Myeloma Patients up to 65 Years.

Blood ◽

10.1182/blood.v106.11.424.424 ◽

2005 ◽

Vol 106 (11) ◽

pp. 424-424 ◽

Cited By ~ 21

Author(s):

Hartmut Goldschmidt ◽

Pieter Sonneveld ◽

Iris Breitkreuz ◽

Bronno van der Holt ◽

Axel Benner ◽

...

Keyword(s):

Stem Cell ◽

Interferon Alpha ◽

Median Number ◽

Drop Out ◽

Phase Iii ◽

Induction Treatment ◽

P Value ◽

High Dose ◽

Treatment Results ◽

High Dose Melphalan

Abstract The joint phase-III HOVON50/GMMG-HD3 trial was designed to assess the effect of thalidomide in induction treatment and as maintenance after high-dose therapy (HDT) and autologous stem cell transplantation (SCT) for multiple myeloma (MM). The standard treatment arm comprised 3 cycles of VAD, mobilisation with CAD+G-CSF (cyclophosphamide 1000 mg/m2, day 1; adriamycin 15 mg/m2, days 1–4; dexamethasone 40 mg, days 1–4; G-CSF until end of harvest), HDT with 1 or 2 cycles of melphalan 200 mg/m2, followed by autologous peripheral blood SCT (PBSCT), and maintenance with interferon-alpha (9 mio. U per week). In the experimental arm, TAD (thalidomide, 200 mg for HOVON / 400 mg for GMMG; adriamycin 9 mg/m2, days 1–4; dexamethasone 40 mg, days 1–4, 9–12, 17–21) was used for induction treatment. Mobilisation and HDT were identical to the standard arm. Experimental maintenance was thalidomide (50 mg per day). A first group of 406 patients (of 1050 included) are evaluable for the comparison of VAD vs. TAD and response after 1st HDT. A trend for a higher toxicity was observed in the TAD- compared with the VAD-arm (drop out: 15% vs. 8%, p= 0.10). Low molecular weight heparin was effective in the prevention of deep venous thrombosis during TAD-treatment (DVT-incidence 8% vs. 4% p= 0.15). The median number of stem cell collections to harvest at least one autograft was 1 in both arms (p= n.s.). Treatment-results are presented in table 1. In a subgroup of 90 GMMG-patients, 78% and 74% compared with 62% and 54% still received thalidomide compared with interferon-alpha at 12 and 24 months after start of maintenance. In summary, thalidomide+AD induce a significantly higher response rate, but this effect is completely offset by HDM. Therefore, results on EFS/PFS are necessary before thalidomide containing regimens can be defined as a standard for induction treatment before HDT. The maintenance treatment with thalidomide is better tolerated compared with interferon-alpha. Treatment results (n=406) after VAD/TAD and after first HDT After VAD After TAD p-value PR 60% 73% <0.001 CR 3% 7% 0.11 PR/CR 63% 80% 0.001 After VAD/HDT After TAD/HDT p-value PR 75% 72% 0.8 CR 13% 19% 0.3 PR/CR 88% 91% 0.4

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SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model

Advances in Therapy ◽

10.1007/s12325-015-0274-5 ◽

2016 ◽

Vol 33 (1) ◽

pp. 96-115 ◽

Cited By ~ 36

Author(s):

Anton Petrov ◽

Natalia Perekhvatova ◽

Maxim Skulachev ◽

Linda Stein ◽

George Ousler

Keyword(s):

Clinical Study ◽

Dry Eye ◽

Ophthalmic Solution ◽

Phase 2 ◽

Treatment Results ◽

Safety And Efficacy ◽

Environment Model

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7503 ◽

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.

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