Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 181-181 ◽  
Author(s):  
Michael Khodadoust ◽  
Alain H. Rook ◽  
Pierluigi Porcu ◽  
Francine M. Foss ◽  
Alison J. Moskowitz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Clinical Activity ◽  
Phase 2 ◽  
Flare Reaction ◽  
Grade 3 ◽  
Experienced Grade

Abstract Background:PD-1 and PD-L1/PD-L2 are expressed by malignant T-cells in mycosis fungoides (MF) and Sézary syndrome (SS). PD-1 is additionally expressed by tumor-infiltrating cytotoxic T-cells and PD-L1 is expressed by macrophages and other stromal components of the tumor microenvironment in these diseases. Moreover, reports of 9p24.1/PD-L2 translocation and CTLA4-CD28 fusion events in MF/SS support a genomic basis for immune evasion. Here, we explore the clinical activity of pembrolizumab, an immune checkpoint inhibitor of the PD-1/PD-L1 axis, in MF/SS. Methods:Patients (pts) with MF/SS stages IB-IV treated with at least 1 prior systemic therapy were enrolled in this phase 2, single-arm study coordinated by the Cancer Immunotherapy Trials Network (CITN). A Simon two-stage design was applied where stage 2 is initiated if 1 of 9 pts had an objective response. An additional 15 pts were planned in stage 2. Pembrolizumab was administered at 2 mg/kg every 3 weeks and treatment was allowed up to 2 years. The primary endpoint was overall response rate (ORR) as determined by the consensus global response criteria. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative biomarker studies included immunohistochemistry (IHC) staining for PD-L1, PD-L2, and multiple immune subsets as well as serum analysis of 62 cytokines and chemokines. Phenotypic and functional profiling of malignant and non-malignant immune cells will be performed by flow cytometry and mass cytometry (CyTOF). Results: The study completed enrollment and all 24 patients received at least one dose of pembrolizumab. Median age was 67 (range 44-85); 18 were male. Patients were advanced stage with 23 patients (96%) stage IIB or higher, including 15 patients (63%) with stage IVA SS. Most pts were heavily treated with a median of 4 prior systemic therapies (range 1-11). The median follow-up time was 40 weeks (range 9-60 weeks). The objective response rate (ORR) was 38% with 1 complete response (CR) and 8 partial responses (PR). Of the responding pts, 6 pts had 90% or greater improvement in skin disease as measured by mSWAT. An additional 9 pts (38%) had stable disease (SD). The median TTR was 11 weeks (range 8-41 weeks). Responses were durable with 8 of 9 (89%) responses currently ongoing at a median of 32 weeks of duration (4-46). The median PFS has not yet been reached, and the one-year PFS was 69%. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), and number of prior therapies, nor with skin tissue expression of PD-1, PD-L1, PD-L2, or infiltrating CD8+ T-cells as determined by IHC. Planned additional correlatives including CyTOF profiling, gene expression profiling, T cell receptor high throughput sequencing, multiplexed ion beam imaging (MIBI), and whole exome sequencing will explore potential predictive biomarkers of response. Adverse events (AE) were consistent with those seen in prior studies of pembrolizumab with the exception of an immune-mediated skin flare reaction seen in 6 pts (2 grade 2 and 4 grade 3). Skin flares occurred exclusively in patients with SS (6/15; 40%) and were associated with lower serum levels of the cytokines IL-7 and SCF prior to pembrolizumab treatment (p=0.01 and p=0.02 respectively, n.s. by Bonferroni correction). Pts with the skin flare reaction experienced increases in serum IFN-gamma, IL-12p40, IL-15, LIF, G-CSF, and CCL4 following treatment. There were two treatment related serious adverse events (SAE), both immune related. One pt experienced grade 2 pneumonitis which resolved with systemic corticosteroids. Another patient experienced grade 3 diarrhea secondary to steroid-refractory duodenitis. Conclusions: Pembrolizumab has significant clinical activity in pts with previously treated MF/SS. Responses were durable and were not associated with any identifiable clinical or pathologic characteristics. Treatment was well tolerated with a toxicity profile consistent with prior pembrolizumab studies, though 40% of pts with SS developed a notable skin flare reaction. These findings support further study of PD-1 blockade in the treatment of MF and SS. A phase 2 trial of pembrolizumab in combination with interferon-gamma is being developed based on these results. Disclosures Porcu: Millenium: Other: investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Foss:Celgene: Consultancy, Research Funding, Speakers Bureau; Eisai: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Consultancy. Moskowitz:Bristol Myers Squibb: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding. Sokol:Seattle Genetics: Consultancy; Spectrum: Consultancy. Yearley:Merck: Employment. Chartash:Merck: Employment. Townson:Merck: Employment. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Kim:Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Neumedicine: Consultancy; Soligenix: Consultancy; Galderma: Consultancy; Genentech: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Millenium: Consultancy, Other: Investigator in a clinical trial; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; MiRagen: Consultancy; Horizon: Consultancy.

scholarly journals Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Wee-Joo Chng ◽  
Xinhua Li ◽  
Cindy Lin ◽  
Jin Seok Kim ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Prior Exposure ◽  
Phase 2 ◽  
Asian Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Phase Ib Study Of Combination Epigenetic Therapy With 5-Azacitidine and Vorinostat In Patients With Relapsed Or Refractory DLBCL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4339-4339
Author(s):  
Tiffany Tang ◽  
Peter Martin ◽  
Rebecca L. Elstrom ◽  
Jia Ruan ◽  
Richard R. Furman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Phase Ib ◽  
Grade 3 ◽  
Experienced Grade

Abstract Introduction Patients with chemorefractory DLBCL have a poor prognosis, rarely achieving durable responses to additional treatment with standard chemotherapy. Epigenetic dysregulation likely contributes to lymphomagenesis and chemoresistance. Distinct epigenetic signatures predicted response to the DNA methyltransferase inhibitor (MTI) azacitidine (Aza) and vorinostat (V), a histone deacytelase inhibitor (HDACi) in DLBCL cell lines. Preclinical studies suggested synergy between MTI and HDACi in chemoresistant DLBCL cell lines. We performed a phase Ib trial to evaluate the combination of Aza plus V in patients with relapsed or refractory DLBCL. Methods Subjects with relapsed or refractory DLBCL ineligible for (due to chemorefractory state or comorbidities) or relapsed after autologous stem cell transplant were treated with Aza and V at four different dose levels (DL). DL 1 consisted of Aza 55mg SC x 5 days plus V 300mg PO x 7 days. DL 2 consisted of Aza 75mg SC x 5 days plus V 200mg PO x 7 days. DL 3 and 4 used the same Aza doses as DL1 and 2 respectively but V was administered for 14 days. Treatment was administered on 28-day cycles. Subjects remained on treatment for a maximum of 6 cycles. Up to 8 subjects could be enrolled into each DL, depending on the toxicity and activity profile. If 2 patients developed dose-limiting toxicities (DLT), enrolment to that dose level was closed. Cycle 1 DLT was defined as any of the following treatment-related adverse events: Grade 3-4 non-hematologic toxicity excluding alopecia, nausea, or fatigue responding to maximal treatment; grade 4 neutropenia lasting longer than 7 days or failing to recover to > 1000 cells/mm3 within 14 days; grade 4 thrombocytopenia of any duration; grade 4 febrile neutropenia. Primary endpoints were safety and tolerability as well as overall response rates (ORR). Results A total of 18 patients were enrolled. The median age was 66 years old (range 26-82). Subjects had received a median of 3 prior lines of treatment, including 3 that had undergone autologous stem cell transplantation. Thirteen patients were refractory to their previous treatment. Eight subjects were treated at DL1, 5 at DL2, 4 at DL3 and 1 at DL4. DL2 was closed early due to limited efficacy demonstrated with the 7-day course of V; only 1 out of 13 patients treated at DL1 and DL2 achieved an objective response. DL3 and DL4 were closed early after 2 patients at DL3 required dose reductions. The following grade 1-2 non-hematologic toxicities, independent of relation to study drugs, were experienced by at least 2 subjects: nausea (11), diarrhea (8), hypoglycemia (7), vomiting (5), renal impairment (5), raised ALP (5), fatigue (4), hyperglycemia (4), fever (3) and hyperbilirubinemia (3). One patient experienced grade 3 thromboembolism (DL1), 1 experienced grade 3 diarrhea (DL2), and 1 experienced grade 4 ALP increase (DL4). Grade 3-4 hematologic toxicity included thrombocytopenia (8), anemia (3) and neutropenia (2). A median of 2 cycles of study regimen was administered (range 1-6). One patient completed 6 cycles of treatment and 17 patients stopped treatment due to PD. There was 1 DLT at DL1. Only one subject had an objective response (PR at DL2) and 3 subjects had stable disease. The trial was stopped prematurely because of low clinical activity and poor tolerability. Interestingly, 7 patients (2 with relapsed disease and 5 with disease refractory to prior pre-study therapy) received treatment post-study. Retrospective review of these cases demonstrated that 2 had CR (PEP-C and R-DICE) and 3 others appeared to have had a significant clinical response (bendamustine, radioimmunotherapy, and brentuximab vedotin-PEP-C), 1 had PD (PEP-C), and 1 was not formally evaluated (bendamustine). The median OS of these 7 patients was 501 days following Aza-V. Conclusions The combination of Aza and V was poorly tolerated and had minimal clinical activity at the doses/schedules tested in this study of refractory DLBCL patients. However, we observed that several heavily pre-treated and refractory patients appeared to go on to achieve better than expected responses to the next treatment following the study regimen, perhaps consistent with a chemosensitization effect (i.e., epigenetic priming) of Aza and V. Epigenetic priming in DLBCL warrants further investigation in less refractory patients and in combination with other agents. Epigenetic profiling of patient samples derived from this trial is ongoing. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Furman:Celgene: Research Funding.

scholarly journals 548 Phase 2 study of FLX475 in combination with ipilimumab in advanced melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A578-A578
Author(s):  
Rakesh Goyal ◽  
Nicole Nasrah ◽  
Dan Johnson ◽  
William Ho
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Antitumor Activity ◽  
Regulatory T Cells ◽  
Response Rate ◽  
Advanced Melanoma ◽  
Phase 2 ◽  
Car T Cells ◽  
Phase 2 Study ◽  
Car T

BackgroundRegulatory T cells (Treg) can dampen antitumor immune responses in the tumor microenvironment (TME) and have been shown to correlate with poor clinical outcome. Translational studies have demonstrated an accumulation of Treg in tumors after treatment with immunotherapies including CAR-T cells and anti-CTLA-4, which could potentially reflect a mechanism of adaptive immune resistance.1–2 CCR4, the receptor for the chemokines CCL17 and CCL22, is the predominant chemokine receptor on human Treg and is responsible for the migration and accumulation of Treg in the TME. Preclinical studies with orally available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and antitumor efficacy as a single agent and in combination with checkpoint inhibitors, including anti-CTLA-4.3 In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding pharmacokinetic and pharmacodynamic properties.4 An ongoing Phase 1/2 clinical trial of FLX475 is examining the safety and preliminary antitumor activity of FLX475 as monotherapy and in combination with pembrolizumab in subjects with several types of advanced cancer.5 Given the preclinical data demonstrating a significant enhancement of the antitumor activity of anti-CTLA-4 when combined with FLX475, a Phase 2 study investigating the combination of FLX475 and ipilimumab is now being conducted in subjects with advanced melanoma.MethodsThis clinical trial is a Phase 2, multicenter, open-label, single-arm study to determine the antitumor activity of FLX475 in combination with ipilimumab in subjects with advanced melanoma previously treated with an anti-PD-1 or anti-PD-L1 agent. The primary objectives of the study are to evaluate objective response rate, and the safety and tolerability of this combination. The study will first examine the safety of the combination of the 100 mg PO QD recommended Phase 2 dose of FLX475 and the approved 3 mg/kg IV Q3W dose of ipilimumab as part of a safety run-in phase, prior to examining the degree of antitumor activity in approximately 20 subjects. Evidence of an overall response rate (ORR) notably greater than the expected ORR of ipilimumab monotherapy alone in such subjects, which has been shown to be approximately 14%,6 would provide preliminary clinical evidence in support of the clinical hypothesis that CCR4 blockade by FLX475 can significantly enhance the antitumor activity of an anti-CTLA-4 checkpoint inhibitor.Trial RegistrationClinicalTrials.gov Identifier: NCT04894994ReferencesO’Rourke D, Nasrallah M, Desai A, Melenhorst J, Mansfield K, Morrissette J, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey S, Navenot J, Zheng Z, Levine B, Okada H, June C, Brogdon J, Maus M. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984. doi: 10.1126/scitranslmed.aaa0984.Sharma A, Subudhi S, Blando J, Vence L, Wargo J, Allison JP, Ribas A, Sharma P. Anti-CTLA-4 immunotherapy does not deplete FOXP3+ regulatory T cells (Tregs) in human cancers-Response. Clin Cancer Res 2019;25:1233–1238.Marshall L, Marubayashi S, Jorapur A, Jacobson S, Zibinsky M, Robles O, Hu D, Jackson J, Pookot D, Sanchez J, Brovarney M, Wadsworth A, Chian D, Wustrow D, Kassner P, Cutler G, Wong B, Brockstedt D, Talay O. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4. J Immunother Cancer 2020;8:e000764.van Marle S, van Hoogdalem E, Johnson D, Okal A, Kassner P, Wustrow D, Ho W, Smith S. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018; 6(Suppl 1):P484(SITC 2018).Powderly J, Chmielowski B, Brahmer J, Piha-Paul S, Bowyer S, LoRusso P, Catenacci D, Wu C, Barve M, Chisamore M, Nasrah N, Johnson D, Ho W. Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer. Journal of Clinical Oncology 2020;38(15_suppl): TPS3163 (ASCO 2020).Long G, Mortier L, Schachter J, Middleton M, Neyns B, Sznol M, Zhou H, Ebbinghaus S, Ibrahim N, Arance A, Ribas A, Blank C and Robert C. Society for Melanoma Research 2016 Congress. Pigment Cell & Melanoma Research 2017;30:76–156.Ethics ApprovalThis study has been approved by the Institutional Review Board at each investigational site.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Irinotecan plus temozolomide in children with recurrent or refractory neuroblastoma: A phase II Children's Oncology Group study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10011-10011
Author(s):  
R. Bagatell ◽  
L. M. Wagner ◽  
S. L. Cohn ◽  
J. M. Maris ◽  
C. P. Reynolds ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Bone Marrow Aspirate ◽  
Response Rate ◽  
Objective Response ◽  
Response Assessment ◽  
Stage Design ◽  
Combination Methods ◽  
Grade 3 ◽  
Experienced Grade

10011 Background: Treatment of children with relapsed or refractory neuroblastoma (NB) remains a challenge. Responses to irinotecan (IRN) + temozolomide (TEM) were seen in NB xenograft-bearing mice, and objective responses were observed in patients with NB treated on a phase I study of this combination. Methods: A phase II study of IRN (10 mg/m2/dose IV daily × 5 days times; 2 weeks) + TEM (100 mg/m2/dose PO daily × 5 days) for children with relapsed or refractory NB was conducted. A one-stage design (endpoint: best overall response) required 5 or more responders out of the first 25 evaluable patients on each of two strata: 1) patients with disease measurable by CT or MRI; and 2) patients with disease detected only by bone marrow aspirate/biopsy and/or MIBG scan. Patients with stable disease or better after 3 cycles could receive an additional 3 cycles of study therapy. International Neuroblastoma Response Criteria were used for response assessment. Radiographic responses were centrally reviewed. Results: Fifty-five eligible and evaluable patients were enrolled, 28 on stratum 1 and 27 on stratum 2. Four responses were observed in the first 25 evaluable stratum 1 patients, and five responses were observed in the first 25 evaluable stratum 2 patients. Three patients had complete responses, but the overall objective response rate (CR+PR) was 16% (9/55). Eleven (stratum 1) and 13 (stratum 2) patients had stable disease. Less than 5% of patients experienced Grade 3 or 4 diarrhea. Although 18% of patients on stratum 1 and 35% of patients on stratum 2 experienced Grade 3 or 4 neutropenia during the first 3 cycles of therapy, <10% of all patients developed evidence of infection while neutropenic. Thrombocytopenia (Grade 3 or 4) was observed in only 7% of patients on stratum 1 and 12% on stratum 2. Conclusions: The combination of IRN+TEM was well tolerated in patients with recurrent or refractory NB. There were 9 objective responses, including 3 complete responses. The minimum desired response rate was attained within stratum 2, but not stratum 1. IRN+TEM may be an appropriate backbone for further study in the relapse setting in combination with novel, targeted agents. No significant financial relationships to disclose.

A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 16-16 ◽  
Author(s):  
Marcia S. Brose ◽  
Nicholas J. Vogelzang ◽  
Christopher DiSimone ◽  
Sharad K. Jain ◽  
Donald A. Richards ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Small Cell ◽  
Clinical Activity ◽  
Phase 2 ◽  
Small Cell Lung ◽  
Previously Treated ◽  
Grade 3

16 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is an approved monotherapy for previously treated patients (pts) with PD-L1 (+) (tumor proportion score ≥1%) metastatic non-small cell lung cancer (mNSCLC; objective response rate [ORR] 18%). We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in pts with solid tumors, focusing on the mNSCLC cohort. Methods: In this multicenter, open-label study (NCT02501096), pts with measurable, confirmed mNSCLC, ECOG PS ≤1, ≤ 2 prior systemic therapies (phase 2 only) received oral LEN (20 mg/day) and PEM (200 mg Q3W, IV). Pts were not preselected by PD-L1 status. The phase 2 primary end point was ORR at 24 weeks (ORRWK24) by investigator-assessed immune-related RECIST (irRECIST). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 9 (43%) PD-L1(+), 5 (24%) PD-L1(-), and 7 (33%) not tested. Pts were treatment-naïve (14%); or had 1 (33%), 2 (48%), or ≥3 (5%) prior lines of systemic therapy. ORRWK24 was 33.3% (95% CI, 14.6–57.0); other efficacy outcomes are summarized in the table. Grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 48% and 5% (increased aspartate aminotransferase) of pts. There was 1 fatal TRAE (exsanguination; “possibly related” to study treatment). The most common grade 3 TRAEs were hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%). Conclusions: LEN + PEM showed promising clinical activity and a manageable safety profile in previously treated pts with mNSCLC who were not preselected for PD-L1 status. Further study is warranted.[Table: see text]

scholarly journals Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3376-3376
Author(s):  
Olga Salamero ◽  
Tim C.P Somervaille ◽  
Antonieta Molero ◽  
Evelyn Acuña-Cruz ◽  
Jose Pérez-Simón ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Therapeutic Options ◽  
Dose Finding ◽  
Open Label ◽  
Advisory Committees ◽  
Platelet Recovery

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

scholarly journals Deep and Durable Remissions of Relapsed Multiple Myeloma on a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptor (CAR) with a Fully-Human Heavy-Chain-Only Antigen Recognition Domain

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-51
Author(s):  
Lekha Mikkilineni ◽  
Elisabet E. Manasanch ◽  
Danielle Vanasse ◽  
Jennifer N. Brudno ◽  
Jennifer Mann ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Research Funding ◽  
Cord Compression ◽  
Cell Maturation ◽  
Car T Cells ◽  
B Cell Maturation ◽  
Car T ◽  
Grade 3 ◽  
B Cell Maturation Antigen

T cells expressing chimeric antigen receptors (CAR) that target B-cell maturation antigen (BCMA) recognize and eliminate multiple myeloma (MM). BCMA is expressed by nearly all cases of MM. BCMA has a restricted expression pattern on normal cells. To reduce the risk of recipient immune responses against CAR T cells, we used a novel, fully-human, heavy-chain-only anti-BCMA binding domain designated FHVH33 instead of a traditional single-chain variable fragment (scFv). The FHVH33 binding domain lacks the light chain, artificial linker sequence, and 2 associated junctions of a scFv. We constructed a CAR designated FHVH33-CD8BBZ. FHVH33-CD8BBZ was encoded by a γ-retroviral vector and incorporated FHVH33, CD8α hinge and transmembrane domains, a 4-1BB costimulatory domain, and a CD3ζ domain. T cells expressing FHVH33-CD8BBZ are designated FHVH-BCMA-T. On this clinical trial, patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5 to -3 followed by infusion of FHVH-BCMA-T on day 0. Twenty-one FHVH-BCMA-T infusions have been administered on 5 dose levels (DL), 0.75x106, 1.5x106, 3x106, 6x106 and 12 x106 CAR+ T cells/kg of bodyweight. DL4 (6 x 106 CAR+ T cells/kg) was identified as the maximum feasible dose (MFD) after weighing toxicity, efficacy and manufacturing factors. Patients are now being enrolled on an expansion phase to test the MFD. One patient (Patient 11) received 2 treatments. Four patients have been enrolled who were not ultimately treated. The median age of the patients enrolled is 64 (range 41-72). Patients received a median of 6 prior lines of therapy (range 3-12). Of the 20 FHVH-BCMA-T treatments evaluable for response, 18 (90%) resulted in objective responses (OR). Twelve treatments resulted in VGPR, complete remission (CR) or stringent complete remission (sCR). Ten patients (50%) have ongoing responses that range between 0-80 weeks (6 sCR/CRs, 3 VGPRs, 1 PR). At the highest two DLs (8 patients), 7 patients (88%) have ongoing responses (median duration 20 weeks, range 0+ to 35+ weeks); progressive MM occurred in only 1 patient who had evidence of spinal cord compression on day +5 due to a rapidly expanding plasmacytoma, which required early intervention with high-dose corticosteroid and radiation therapy. Of the 8 patients evaluated for response who had high-risk cytogenetics at baseline, 7 had ORs. Responses are ongoing in 2 patients with TP53 mutations and 1 patient with t(4;14) translocation. Ten treated patients came off study due to progressive MM (9 patients) or death from other causes (1 patient, influenza). Two of 4 patients who had plasmacytomas evaluated for BCMA expression at relapse had evidence of BCMA-negative MM. Four patients had bone marrow aspirates evaluated for BCMA-expression before treatment and at the time of relapse; 3 of these patients had evidence of loss of BCMA expression at relapse. Of 21 FHVH-BCMA-T treatments administered, 20 (95%) were followed by cytokine release syndrome (CRS) with 16 (76%) cases of grade 1 or 2 CRS, 4 cases (19%) of grade 3 CRS, and no cases of grade 4 CRS. Three patients received tocilizumab. The median peak C-reactive protein after all 21 treatments was 196.9 mg/L. Of 21 total treatments, 8 (38%) were followed by neurologic toxicity; there were 5 cases of grade 1-2 neurologic toxicity (headache, dysarthria, confusion, delirium), 2 cases of grade 3 neurologic toxicity (confusion), and 1 patient with grade 4 spinal cord compression due to progressive MM. Two patients received corticosteroids to manage neurologic toxicities. A median of 3.0% (range 0-95%) of bone marrow T cells were CAR+ when assessed by flow cytometry 14 days after FHVH-BCMA-T infusion. We assessed blood CAR+ cells by quantitative PCR. The median peak level of CAR+ cells was 121 cells/µl (range 3-359 cells/µl) and the median day post-infusion of peak blood CAR+ cell levels was 12 (range 7-14). The results from this phase 1 trial demonstrate that FHVH-BCMA-T cells can induce deep and durable responses of relapsed MM with manageable toxicities. Assessment of durability of responses at the maximum feasible dose is a critical future plan. Accrual to the expansion cohort continues. Table Disclosures Manasanch: Novartis: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; JW Pharma: Research Funding; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Sanofi: Research Funding. Rosenberg:Kite, A Gilead Company: Consultancy, Patents & Royalties, Research Funding. Kochenderfer:Kite, a Gilead company: Patents & Royalties, Research Funding; Celgene: Patents & Royalties, Research Funding; bluebird, bio: Patents & Royalties. OffLabel Disclosure: cyclophosphamide 300 mg/m2 fludarabine 30 mg/m2 Conditioning chemotherapy prior to CAR T-cell infusion

scholarly journals Results of a Phase 2 Study of MEDI-551 and Bendamustine Vs Rituximab and Bendamustine in Relapsed or Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4472-4472
Author(s):  
Douglas Gladstone ◽  
Marc Andre ◽  
Jan Zaucha ◽  
Sarit Assouline ◽  
Naresh Bellam ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Micro Rna ◽  
Lymphocytic Leukemia ◽  
Stock Ownership ◽  
Clinical Activity ◽  
Phase 2 ◽  
Mirna Signature ◽  
Grade 3 ◽  
All Treatment

Abstract Background: In patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), novel therapies are needed to prolong disease control. MEDI-551, an afucoslylated, affinity-optimized, anti-CD19 antibody, functions by antibody-dependent cellular cytotoxicity, with a 30% monotherapy response rate in CLL. A phase 2 randomized, open-label study (NCT01466153) is evaluating the clinical activity, efficacy, and safety of combination therapy with MEDI-551 + bendamustine compared with rituximab + bendamustine in R/R CLL patients. Methods: Patients were initially randomized to receive bendamustine 70 mg/m2 intravenously (IV) on days 1, 2 with either MEDI-551 2 or 4 mg/kg on days 2, 8 of cycle 1 (on day 1 of subsequent cycles) or rituximab 375 mg/m2 IV on day 1 of cycle 1 (then 500 mg/m2 IV on day 2 of subsequent cycles), for up to six 28-day cycles. The 4-mg/kg dose of MEDI-551 was selected for the final efficacy analysis against rituximab. Safety assessments included adverse events (AEs) and laboratory parameters. Disease response was determined using 2008 International Working Group criteria. Exploratory objectives included micro RNA (miRNA) expression levels before and after treatment. Results: As of March 2014, the safety population comprised 147 patients across all treatment arms. The median age was 66 years (range 41–81), with 11% of patients with deletion (del) (17p), 20% with del (11q), 30% with del (13q), 12% with trisomy 12, and 39% with unmutated immunoglobulin heavy chains (IgVH). The median number of treatment cycles was 4 (range 1–6). Treatment-related AEs observed in ≥20% of patients included nausea, infusion-related reactions (IRRs), nausea, fatigue, pyrexia, neutropenia, and cough in the MEDI-551 arm vs nausea, fatigue, constipation, asthenia, pyrexia, and neutropenia in the rituximab arm. Grade 3/4 treatment-related AEs are listed in the table. Table. Treatment-Related Grade 3/4 AEs (≥5% of patients in any treatment group) Parameter, n (%) MEDI-551 + Bendamustine Rituximab + Bendamustine 2 mg/kg (n=32) 4 mg/kg (n=56) (n=59) Patients reporting ≥1 event 20 (63) 25 (45) 29 (49) Neutropenia 8 (25) 9 (16) 20 (34) IRR* 6 (19) 4 (7) 1 (2) Thrombocytopenia 2 (6) 1 (2) 5 (9) Lymphopenia 2 (6) 1 (2) 4 (7) Anemia 1 (3) 0 3 (5) Fatigue 0 0 3 (5) *Note: After 42 patients were enrolled in the study (all treatment groups), corticosteroid prophylaxis was recommended before patients receiving the initial dose of MEDI-551. Discontinuation of study treatment because of AEs occurred in 26% of patients receiving MEDI-551/bendamustine (including neutropenia, thrombocytopenia, bradycardia, abdominal pain, asthenia, fatigue, cytokine release syndrome, hypersensitivity, pneumonia, infusion-related reactions, elevated liver function tests, dehydration, hyponatremia, headache, depression, epistaxis, hypoxia, rash, and hypotension) and in 20% of those receiving rituximab/bendamustine (including febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, cardiac failure, uveitis, small intestine obstruction, upper gastrointestinal hemorrhage, asthenia, fatigue, and systemic inflammatory response syndrome). No treatment-related deaths occurred in any treatment arm. Clinical activity was observed in both the MEDI-551 and rituximab arms, and a biomarker has been identified that may predict for MEDI-551 responders. Expression of a miRNA signature is specifically elevated in NHL patient samples. Low pretreatment levels of this miRNA signature in whole blood may predict for responders to MEDI-551. Three-fold lower levels (P<.0001) in pretreatment samples from MEDI-551 responders vs nonresponders were noted, but no differences in miRNA signature expression were noted between responders and nonresponders in the rituximab arm. Conclusions: Data show evidence of clinical activity in R/R CLL patients, with comparable safety observed between the MEDI-551 and rituximab arms. Expression level of a miRNA signature is able to predict for those more likely to respond to MEDI-551, with MEDI-551 responders having low pretreatment miRNA signature expression. Disclosures Gladstone: MedImmune: Research Funding. Andre:MedImmune: Research Funding. Zaucha:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Bellam:Genentech: Research Funding; Janssen: Research Funding; MedImmune: Research Funding; Facet: Research Funding. Cascavilla:MedImmune: Research Funding. Jourdan:MedImmune: Research Funding; Roche: Research Funding. Panwalkar:MedImmune: Research Funding. Patti:MedImmune: Research Funding. Zaja:MedImmune: Research Funding. Goswami:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Elgeioushi:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Streicher:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Bao:MedImmune: Employment; MedImmune: Stock ownership, Stock ownership Other. Spaner:MedImmune: Research Funding.

scholarly journals Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Romain Guieze ◽  
Loic Ysebaert ◽  
Lysiane Molina ◽  
Damien Roos-Weil ◽  
Anne-Sophie Michallet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Phase 2 ◽  
Grade 3

Background Richter syndrome (RS) refers as to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with chronic lymphocytic leukemia (CLL). The outcome of RS pts is usually very poor with both low response rates to chemoimmunotherapy and short survival, except for the minority of them whose tumor cells are clonally unrelated to the underlying CLL. While BCR and BCL2 inhibitors have transformed the management of CLL pts, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of pts with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. More recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in pts with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS pts failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a currently ongoing phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for pts with untreated RS of DLBCL histology (NCT03931642). The pts achieving complete remission (CR) after 2 cycles of R-CHOP21 discontinued study while those with persisting (PR, SD) or progressive disease (PD) were eligible to receive an 8-week course of blinatumomab induction. An additional 4-week consolidation cycle was optional and might be proposed according to the treating-physician decision, especially in pts who were ineligible for stem-cell transplantation. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. Interim analysis (Simon two-stage design) was planned after completion of blinatumomab induction in 10 pts. Results A total of 15 pts out of 35 has already been enrolled in the trial to date. Median age was 67 years (range, 38-80) andsex ratioM/F was 12/3. CLL features at baseline were as follows: 9/15 (60%) pts hadTP53alterations and 10/13 (77%) unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-4): 10 (67%) pts previously received chemo-immunotherapy, 10 (67%) pts were exposed to BCR inhibitors and 3 (20%) to venetoclax. As of the data cut-off of July 1st, 2020, the blinatumomab induction course has been completed for 5 pts while it is still on-going in 3 others. Three pts are still on R-CHOP debulking. Four pts discontinued study before receiving blinatumomab for the following reasons: 2 pts achieved CR after R-CHOP, 1 patient died because of febrile neutropenia after R-CHOP and 1 patient discontinued study before starting R-CHOP (no RS criteria after pathology review). Regarding toxicity during blinatumomab, data are available for the 5 pts having completed the blinatumomab induction to date. Four pts had at least one grade 1 adverse event (AE), 2 had grade ≥3 AE. The most common AE, regardless of relationship to blinatumomab, were grade 1 fever (2 pts) and grade 2 leukopenia (2 pts). Other grade &gt;1 AE were observed in 1 pt only (grade 3 anxiety, grade 2 anemia, grade 2 neutropenia, grade 3 lymphopenia). In terms of neurologic event, 1 pt had grade 1 AE (paresthesia, myoclonus and muscle contraction) and another one presented grade 4 confusion while on first 9 μg/d dose leading to permanent discontinuation of blinatumomab. In terms of efficacy, after R-CHOP debulking therapy (n=10 evaluable pts), 2 pts achieved CR (and did not pursuit on study), 5 pts were in PR and 3 pts were progressive. At evaluation after the blinatumomab induction (n=5 evaluable pts), 2 pts achieved CR, 1 patient PR and 2 pts were progressive. Conclusions Our preliminary data suggest that blinatumomab shows encouraging anti-tumor activity and acceptable toxicity in pts with RS. Further analyses are warranted to validate these conclusions. Updated efficacy/safety in the remaining pts enrolled in the trial will be presented at the meeting. Disclosures Guieze: astrazanecka:Honoraria, Other: advisory board;gilead:Honoraria, Other: travel funds;janssen cilag:Honoraria, Other: advisory board, travel funds;roche:Other: travle funds;abbvie:Honoraria, Other: advisory board, travel funds.Ysebaert:AbbVie:Consultancy;Janssen:Consultancy;Roche:Consultancy.Fornecker:Roche:Consultancy;Takeda:Consultancy.Broséus:Gilead:Honoraria;AstraZeneca:Consultancy, Honoraria;Janssen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Feugier:astrazeneca:Consultancy, Honoraria, Research Funding;abbvie:Consultancy, Honoraria, Research Funding;roche:Consultancy, Honoraria, Research Funding;gilead:Consultancy, Honoraria, Research Funding;janssen:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells. It has been approved as a second line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.

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