TGR-1202, a Novel Once Daily PI3K-Delta Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile in Patients with CLL and B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4154-4154 ◽  
Author(s):  
Owen A. O'Connor ◽  
Ian W. Flinn ◽  
Manish R. Patel ◽  
Timothy S. Fenske ◽  
Changchun Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Safety Profile ◽  
Research Funding ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Tolerability Profile ◽  
Employment Equity ◽  
Once Daily ◽  
Equity Ownership ◽  
Pi3k Delta

Abstract Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor which exhibits a differentiated safety profile from other PI3Kδ inhibitors, both approved and in development, and has demonstrated activity in patients (pts) with advanced heme malignancies (ASH 2014). Herein we present updated safety and efficacy results from a Ph I study of TGR-1202 in pts with rel/ref CLL and lymphoma. Methods: TGR-1202 is administered orally once-daily (QD) following a 3+3 dose escalation design. Eligible pts have rel/ref non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other B-cell malignancy and an ECOG PS ≤ 2. Endpoints include safety, PK/PD, and efficacy. Results: As of August 2015, 75 pts are evaluable for safety including pts with CLL, FL, Hodgkin's (HL), DLBCL, MCL, and MZL. Patients had a median age of 65 yo (range: 22-85), 67% male, ECOG 0/1/2: 26/47/2, median prior Tx: 3 (range: 1-14), and 49% refractory to prior Tx. No Gr≥3 AEs were observed in ≥10% of pts. AEs (all grades, all causality) in >20% of pts were limited to nausea (44%, Gr3/4 0%), diarrhea (36%, Gr3/4 1%), and fatigue (31%, Gr3/4 3%). Notably, general tolerability and the incidence of hepatotoxicity and colitis appear significantly less than that reported with other agents in this class. Expansion cohorts are open at 800 mg, 1000 mg, and 1200 mg QD. Of 16 evaluable CLL pts, 15 (94%) achieved a nodal PR (median nodal ↓ of 76%), of which 10 (63%) achieved a PR per Hallek 2008 criteria. Among the 32 evaluable NHL patients, 10 achieved an objective response, including 3/11 evaluable patients with DLBCL, while responses have been limited in pts with MCL (1/5) and HL (1/9). Of the 16 evaluable indolent NHL (FL & MZL) pts, 14 (88%) have achieved reductions in tumor burden with 6 pts on study for over 12 cycles (and durations upwards of 29+ cycles), with 5/12 FL and 1/4 MZL pts achieving an objective response to date. Notably, a strong exposure-response relationship has been observed. Of the 24 patients starting TGR-1202 at 800 mg or 1200 mg of the micronized formulation, 19 (79%) remain on therapy, with 9/18 (50%) evaluable pts (6 too early to evaluate) achieving an objective response to date (range on study 3 - 49+ weeks). Conclusions: TGR-1202 is well tolerated in pts with rel/ref heme malignancies with a distinct safety and tolerability profile from other PI3K-delta inhibitors (with 43% of pts on study 6+ Cyc) and promising activity in CLL and NHL. Enrollment continues in expansion cohorts and registration directed Phase 3 studies are planned. Disclosures Flinn: Celgene Corporation: Research Funding. Fenske:Millennium/Takeda: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy; Otsuka American Pharmaceutical: Consultancy; Azaya Therapeutics: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership.

scholarly journals Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3929-3929 ◽  
Author(s):  
Paul A Hamlin ◽  
Ian Flinn ◽  
Nina wagner-Johnston ◽  
Jan A Burger ◽  
Glenn Michelson ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Once Daily ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone. Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (>80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state Cmin and Cmax concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more. Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. Disclosures Michelson: Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Pandey:Portola Pharmaceuticals Inc: Employment. Birrell:Portola Pharmaceuticals Inc: Employment. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leeds:Portola Pharmaceuticals Inc: Employment. Curnutte:Portola Pharmaceuticals Inc: Employment.

scholarly journals Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1741-1741 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andres Forero-Torres ◽  
Bijal D. Shah ◽  
Ranjana Advani ◽  
Paul Hamlin ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Objective Response ◽  
Antibody Drug Conjugate ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Grade 3

Abstract Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Table Best Clinical Response by Disease Status Relative to Most Recent Therapy, n (%) Relapsed N=17 Refractory N=26 Total N=43 CR 5 (29) 2 (8) 7 (16) PR 4 (24) 2 (8) 6(14) SD 4 (24) 9 (35) 13 (30) PD 4 (24) 13 (50) 17 (40) ORR (CR + PR), (95% CI) 53 (28, 77) 15 (4, 35) 30 (17, 46) Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

scholarly journals A Phase I Trial of TGR-1202, a Next Generation Once-Daily PI3Kδ Inhibitor, in Combination with Brentuximab Vedotin, in Patients with Relapsed/Refractory Hodgkins Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4146-4146 ◽  
Author(s):  
Radhakrishnan Ramchandren ◽  
Carolyn M. Mulroney ◽  
Manish R. Patel ◽  
Peter Sportelli ◽  
Hari P. Miskin ◽  
...  
Keyword(s):  
Research Funding ◽  
Complete Response ◽  
Brentuximab Vedotin ◽  
Hodgkin's Lymphoma ◽  
Tolerability Profile ◽  
Employment Equity ◽  
Once Daily ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Ecog Ps

Abstract Introduction: TGR-1202 is a once daily, oral PI3Kδ inhibitor that has demonstrated activity in patients (pts) with relapsed and refractory hematologic malignancies, with a favorable safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2016). Brentuximab vedotin (BV) is a CD30 specific antibody-drug conjugate, which is FDA approved for the treatment of Hodgkin's Lymphoma (HL) and Systemic Anaplastic Large-cell Lymphoma (sALCL). BV has demonstrated impressive response rates in pts with rel/ref disease, however the duration of response is short in pts not achieving a complete response (median PFS of ~6 months for non-CR pts; Gopal et al, Blood 2015). Marked synergy has been demonstrated pre-clinically with TGR + BV, with the combination demonstrating a 3-fold increase in cell death in-vitro and a 55% increase in tumor growth inhibition over either TGR or BV alone in an in-vivo xenograft model of HL (Locatelli et al, ASH 2014). As the combination of TGR + BV displays strong synergy pre-clinically and incorporates non-overlapping mechanisms of activity, a Phase 1 trial evaluating the combination of TGR + BV in pts with rel/ref HL was undertaken. Methods: Eligible pts have relapsed or refractory HL, have received prior ASCT or at least 2 prior regimens, and have an ECOG PS < 3. Prior BV exposure is allowed. Two dose cohorts for TGR are evaluated (400 and 600 mg) dosed once daily with a fixed dose of BV 1.8 mg/kg on day 1 of each cycle (Cycle = 21 days) until off study. Safety is the primary endpoint evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint with responses determined according to response criteria of the International Working Group (Cheson, JCO 2007). Results: Fourteen pts have been enrolled. Median age is 34 (range 21 - 81); 9 Male/5 Female; Median ECOG PS = 1; with a median of 3 prior therapies (range 2 - 6). Seven pts had prior ASCT. Six pts had previously received BV, and all 6 were refractory to prior BV therapy. All pts are evaluable for safety. The most common AEs regardless of causality were nausea (71%; 0% Gr. 3/4), diarrhea (57%; 7% Gr. 3/4), neutropenia (50%; 43% Gr. 3/4), and rash (43%; 7% Gr. 3/4), followed by cough, dyspnea, and vomiting (36% each, all grades). Peripheral neuropathy was reported in 4 pts (29%), and were all Grade 1/2. Eleven pts were evaluable for efficacy, with 3 discontinuing prior to first efficacy assessment (1 withdrew consent, and 2 due to AEs). The ORR was 64% (7/11), with 45% (5/11) achieving a complete response with a median TTR of 8 weeks. Notably, 50% (3/6) of BV refractory patients responded to TGR-1202 + BV combination therapy (2 CRs, 1 PR). Three responding patients proceeded to stem cell transplant. Of the remaining 4 patients achieving a response, 2 patients remain in CR, and 2 have progressed (at 13 and 16.5 mos respectively). Conclusions: The combination of TGR-1202 + brentuximab vedotin exhibits an acceptable tolerability profile and is clinically active. Responses were observed in patients with advanced Hodgkin's Lymphoma, including responses in 50% of patients previously refractory to brentuximab vedotin. Further studies evaluating this combination are warranted. Disclosures Sportelli: TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau.

Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 983-983 ◽  
Author(s):  
Susan O'Brien ◽  
Jan A. Burger ◽  
Kristie A. Blum ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Objective Response ◽  
Cellular Migration ◽  
Phase Iii ◽  
Employment Equity ◽  
Phase Ib ◽  
Btk Inhibitor ◽  
Equity Ownership

Abstract Abstract 983 Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial. Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report. Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2–10) and for the 840mg cohort was 5 (1–12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3). Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/SLL. Phase III trials of PCI-32765 in CLL/SLL are planned. Disclosures: O'Brien: Pharmacyclics, Inc: Research Funding. Burger:Pharmacyclics, Inc: Research Funding. Blum:Pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Coutre:Pharmacyclics, Inc: Research Funding. Sharman:Pharmacyclics, Inc: Research Funding. Flinn:Pharmacyclics, Inc: Research Funding. Grant:Pharmacyclics, Inc: Research Funding. Heerema:Pharmacyclics, Inc: Research Funding. Johnson:Pharmacyclics, Inc: Research Funding. Navarro:Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren:Pharmacyclics, Inc: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Byrd:Pharmacyclics, Inc: Research Funding.

scholarly journals The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37 Targeted Radioimmunotherapy in Activated B Cell like Diffuse Large B Cell Lymphoma Cell Lines

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2574-2574
Author(s):  
Gro Elise Rødland ◽  
Katrine Melhus ◽  
Roman Generalov ◽  
Sania Gilani ◽  
Francesco Bertoni ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin®) is currently being evaluated as monotherapy in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL), as well as in a phase 1b trial in combination with rituximab for patients with relapsed/refractory FL. Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines: U-2932 and RIVA. Both cell lines are representative for TP53 deficient Double Expressor (DE) DLBCL. Importantly, resistance was not a consequence of reduced binding of the radioimmunoconjugate to cell surface expressed CD37. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in both resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to radioimmunotherapy (RIT), alongside topoisomerase and histone deacetylases (HDAC) inhibitors. Kinetic studies of the effect of mono- and combination therapy of U-2932 and RIVA cells with JNJ-7706621 and 177Lu-lilotomab satetraxetan are suggestive of a model in which radiation damage induced G2-arrested lymphoma cells eventually enter mitosis (repair or escape) and mitotic entry, progression and exit are impaired by JNJ-7706621 mediated inhibition of CDK1/2 and AURKA/B. Extended residence-time of cells in mitosis due to chromosome condensation and congression defects as well as spindle and mid-spindle assembly failure is likely pivotal for the increased sensitivity to persistent 177Lu-lilotomab satetraxetan deposited DNA damage, ultimately promoting cytokinesis failure (multinucleation, aneuploidy, increased cell size) and cell death. In conclusion, CD37-targeting 177Lu-lilotomab satetraxetan RIT showed activity in several ABC-DLBCL lymphoma cell lines. CD37-independent RIT-resistance was identified in two cell lines representative of aggressive DE ABC-DLBCLs with inactive TP53, and reversed by subsequent inhibition of CDK1/2 and AURKA/B by JNJ-7706621. These findings may be of potential relevance for ongoing clinical trials of 177Lu-lilotomab satetraxetan in relapsed, ASCT-non-eligible DLBCL, and may also be more generally applicable to other 177Lu-based RITs and alternative radionuclide utilizing targeted therapies. Future pre-clinical investigations are required to elucidate the potential application of CDK1/2 and AURKA/B inhibitors as a strategy to revert RIT resistance in TP53 deficient cancers. Disclosures Rødland: Nordic Nanovector ASA: Patents & Royalties, Research Funding. Melhus:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Generalov:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Bertoni:Nordic Nanovector ASA: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants; Jazz Pharmaceuticals: Other: travel grants; NEOMED Therapeutics 1: Research Funding; Acerta: Research Funding; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Syljuåsen:Nordic Nanovector ASA: Patents & Royalties, Research Funding. Patzke:Nordic Nanovector ASA: Employment, Patents & Royalties.

CC-122 Dosing on a Novel Intermittent Schedule Mitigates Neutropenia and Maintains Clinical Activity in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1494-1494 ◽  
Author(s):  
Cecilia Carpio ◽  
Loïc Ysebaert ◽  
Raúl Cordoba ◽  
Armando Santoro ◽  
José Antonio López-Martín ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: CC-122, a first in class PPM™ pleiotropic pathway modifier, has anti-tumor activity against B cell lymphomas. The molecular target of CC-122 is cereblon (CRBN) and CC-122 promotes ubiquitination of lymphoid transcription factor Aiolos in a CRBN-dependent manner, leading to its degradation in Diffuse Large B Cell Lymphoma (DLBCL) tumor tissue and immune cells. CC-122 also depletes Ikaros, which is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Blood 101:2219 2003). Following establishment of CC-122 3mg daily (QD) as the maximum tolerated dose (MTD) on a continuous schedule (Blood 122:2905 2013), subjects with advanced lymphoma, myeloma, and select solid tumors were enrolled in parallel expansion. In DLBCL subjects, CC-122 treatment demonstrated promising clinical efficacy, however, dose reductions due to neutropenia were frequent with the QD schedule (Blood 124:3500 2014). Therefore, a second cohort of DLBCL subjects was enrolled to evaluate the tolerability and clinical activity of intermittent schedules. Methods: Subjects with relapsed/refractory DLBCL were enrolled in parallel dose escalation of CC-122 given orally at 4mg or 5mg on two intermittent schedules. CC-122 given 21/28 days was tested based on lenalidomide experience. In order to model a second schedule, human bone marrow CD34+ cells were cultured for two weeks in SCF, Flt3L and G-CSF for expansion towards granulocytic lineage followed by 6 days with media plus G-CSF for neutrophil maturation.CC-122 0.5 uM was added continuously or on a 5 out of 7 day (5/7d) schedule. Myeloid maturation stages were measured 14 days later by CD34, CD33 and CD11b flow cytometry. Continuous exposure to CC-122 led to reversible myeloid maturation arrest and 90% decreased mature neutrophils compared to vehicle, whereas, CC-122 exposure for 5/7d resulted in only 50% decreased mature neutrophils. Based on this rationale, CC-122 given 5/7d was selected as the second intermittent schedule tested in DLBCL. Results: As of June 25, 2015, 22 subjects with relapsed/refractory DLBCL were enrolled in the 2nd cohort; all were evaluable for safety, 16 were efficacy evaluable (EE) as of the cutoff date. The median age was 60 years and 54% were male. The median time since diagnosis was 14 months and all subjects were ECOG 0-1. For subjects treated with CC-122 4mg 21/28 days (N=3), there were no dose limiting toxicities (DLTs) in cycle 1, however, all subjects required dose reduction due to neutropenia and therefore this dose level was considered a non-tolerated dose (NTD). For subjects treated with CC-122 on a 5/7 days schedule, the NTD was at 5mg due to 2 DLTs in 2 of 5 subjects (grade 3 febrile neutropenia and grade 3 pneumonitis). CC-122 4mg was the MTD on 5/7d and was selected for ongoing expansion in up to 50 subjects (N=14 as of cutoff date). There were no DLTs in 12 DLT-evaluable subjects. Median relative dose intensity achieved for 4mg 5/7d vs 3mg QD was 99% vs 79%. The most common (≥ 10%) related adverse events (AEs) were neutropenia (36%), constipation (29%), asthenia (21%) and grade 3/4 related AEs were neutropenia (36%) and lipase elevation (14%). In addition, drug-related serious AEs included pneumonia, neck pain, and respiratory failure. AEs were an uncommon cause of discontinuation (7%, n=14). Response rates for the EE DLBCL subjects treated at 5mg 5/7d (N=3), 4mg 5/7d (N=10), and 3mg QD (N=22) was 67% (2 PR), 30% (1CR, 2 PR) and 23% (1CR, 4PR), respectively. Aiolos protein levels in peripheral T cells was measured by flow cytometry pre (baseline) and 5 hours post dosing on C1D1, C1D10 and C1D22. The median % change Aiolos levels at each of these visits were -47, -28 and -52%, respectively, indicating that Aiolos degradation occurs throughout the cycle. In addition, the median increase from baseline in cytotoxic memory T cells and helper memory T cells at cycle 1 day 22 in peripheral blood samples was 580% and 76%, respectively. Conclusion: In an in vitro myeloid differentiation assay, myeloid maturation arrest by CC-122, possibly due to Ikaros degradation, can be partially bypassed with a 2 day drug holiday. From a clinical standpoint, exploration of intermittent dosing confirmed that 5/7d schedule mitigates neutropenia-related dose reductions and improves CC-122 clinical activity in relapse/refractory DLBCL patients. Of note, the immunomodulatory effects of CC-122 are maintained on the 5/7d schedule. Disclosures Carpio: Celgene: Research Funding. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with anti-tumor activity against B cell lymphomas.. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Santoro:Celgene: Research Funding. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Celgene: Research Funding; Roche: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Gharibo:Celgene: Research Funding. Rasco:Asana BioSciences, LLC: Research Funding; Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Damian:Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Carrancio:Celgene: Research Funding. Gandhi:Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment, Equity Ownership. Ribrag:Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 182-182 ◽  
Author(s):  
Craig H Moskowitz ◽  
Michelle A Fanale ◽  
Bijal D Shah ◽  
Ranjana H Advani ◽  
Robert Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership

Abstract Background Denintuzumab mafodotin (SGN-CD19A) is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B-cell-specific marker expressed in the vast majority of patients (pts) with B-cell non-Hodgkin lymphoma (NHL). Methods An ongoing phase 1, dose-escalation study is investigating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-cell NHL (NCT 01786135). Eligible pts were ≥12 yrs of age and were R/R to ≥1 prior systemic regimens; pts with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FL3) also received intensive salvage therapy ± autologous stem cell transplant (ASCT), unless they refused or were ineligible. Denintuzumab mafodotin was administered IV every 3 weeks (q3wk; 0.5-6 mg/kg) for dose escalation and every 6 weeks (q6wk; 3 mg/kg) in a subsequent expansion cohort. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation in the q3wk dosing schedule. Archived tissue was collected to assess potential biomarkers of response. Results To date, 62 pts have been treated, including 53 pts (85%) with DLBCL (of whom 16 had transformed DLBCL), 5 (8%) with mantle cell lymphoma, and 3 (5%) with FL3. Median age was 65 yrs (range, 28-81). Pts had received a median of 2 prior systemic therapies (range, 1-6); 15 pts (24%) had prior ASCT. Thirty-seven pts (60%) were refractory to the most recent prior therapy. Fifty-two pts were treated in the q3wk schedule (0.5-6 mg/kg), and 10 pts were treated with 3 mg/kg q6wk. Five pts remain on treatment (2 q3wk pts, 3 q6wk pts). Overall, 20 (33%) of 60 efficacy-evaluable pts achieved objective responses, including 13 (22%) with CRs. Eighteen of the 20 objective responses were achieved by the end of Cycle 2 (15 q3wk pts, 3 q6wk pts). Table.Q3wk Dosing (N=51)Q6wk Dosing (N=9)RelapsedaN=22RefractorybN=29RelapsedaN=3RefractorybN=6Best clinical response, n (%)Complete remission (CR)7 (32)3 (10)3 (100)-Partial remission (PR)4 (18)3 (10)--Stable disease (SD)6 (27)7 (24)-3 (50)Progression5 (23)16 (55)-3 (50)ORR (CR+PR), % (95% CI)50 (28, 72)21 (8, 40)100 (29, 100)-CR rate, % (95% CI)32 (14,55)10 (2, 27)100 (29, 100)-ORR=objective response rateaBest response of CR/PR with most recent prior therapybBest response of SD/PD with most recent prior therapy Median duration of objective response in the q3wk schedule was 39 wks for relapsed pts (95% CI: 11.6, - [range, 0.1+ to 73+ wks]) and 41 wks for refractory pts (95% CI: 13.7, 67 [range, 13.7 to 67 wks]); this included 2 pts who maintained their responses for >15 mos. Data for the q6wk schedule are not yet mature. The MTD was not reached at 0.5-6 mg/kg q3wk, and only 1 DLT was observed (G3 keratopathy at 3 mg/kg). Toxicity profiles were similar across both dosing schedules; the most frequently reported adverse events (AEs) were blurry vision (65%), dry eye (52%), fatigue and keratopathy (35% each), constipation (29%), photophobia (27%), and nausea (26%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 52 pts (84%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~5 wks (range, 1-17) in pts for whom there was sufficient follow-up. ADC PK demonstrated a mean terminal half-life of ~2 wks, and accumulation was observed following multiple dose administrations in both schedules. Conclusions Denintuzumab mafodotin is generally well tolerated and demonstrates encouraging activity with durable responses in heavily pre-treated pts with B-cell NHL. In relapsed pts, 56% achieved objective responses with a CR rate of 40% across both the q3wk and q6wk schedules. The low rate of myelosuppression and neuropathy suggests that denintuzumab mafodotin could be incorporated into novel combination regimens in earlier lines of therapy. A randomized phase 2 trial is being initiated to evaluate RICE (rituximab, ifosfamide, carboplatin, etoposide) ± denintuzumab mafodotin pre-ASCT as second-line treatment for pts with DLBCL. Disclosures Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding. Off Label Use: Denintuzumab mafodotin (SGN-CD19A) is not approved for use.. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Shah:Janssen: Speakers Bureau; Seattle Genetics: Research Funding; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Plexus Communications: Honoraria; Spectrum: Speakers Bureau; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SWOG: Consultancy; NCCN: Consultancy. Chen:Genentech: Consultancy, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Liu:Seattle Genetics, Inc.: Employment, Equity Ownership, Other: Travel expenses. Peng:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics, Inc.: Research Funding.

scholarly journals Data from the First CD20-Targeted Immunotoxin, MT-3724, in a Phase I/Ib Study in Relapsed/Refractory (R/R) Non-Hodgkin's B-Cell Lymphoma (NHL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4200-4200 ◽  
Author(s):  
Paul A Hamlin ◽  
Michelle A. Fanale ◽  
Steven I. Park ◽  
David J. Valacer ◽  
Jack Higgins ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Cd20 Antibodies

Abstract Background Novel mechanisms of action (MOA) are needed for the treatment of NHL. Because of the ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop novel MOAs targeting CD20. However, CD20's non-internalizing nature has impeded the development of novel MOAs against this target.. MT-3724 is a recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to the ribosomal inhibitory protein Shiga-like toxin-I A1 subunit (SLT-I A1). Upon scFv binding to surface CD20, SLT-I A1 forces MT-3724 internalization and irreversibly inactivates cell ribosomes triggering cell death. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro and in in vivo animal models. Data from the first eighteen subjects evaluable for efficacy in the on-going Phase I/Ib monotherapy dose-escalation study of MT-3724 are presented. Methods MT-3724 is being tested in a first-in-human, open label, ascending dose study (3 + 3 design) in cohorts of 5, 10, 20, 50, 100, and 75 mcg/kg/dose. Eligible subjects who previously responded to a CD20 MAb containing therapy followed by relapse/recurrence of NHL receive 6 infusions over 2 hours in the first 12 days of a 28 day cycle (first cycle). With continued safety, tolerability and lack of tumor progression, subjects may receive 4 additional 6-dose cycles (21 days) with tumor assessments after cycles 2, 4 and 5. Dose escalation is based on < 33% dose limiting toxicities (DLTs) observed during the first 28 day cycle. Results To date, 18 R/R NHL subjects (mean number of prior therapies >4) have enrolled and completed at least one cycle in either the 5, 10, 20, 50, 100, or 75 mcg/kg/dose cohort. Two DLTs were identified in the 100 mcg/kg cohort considered possibly consistent with early signs/symptoms of capillary leak syndrome, a known side effect of immunotoxins. These adverse events (AEs) were non-life threatening and reversible upon drug withdrawal. The most common non-DLT AEs have been reversible hypoproteinemia (≤ Grade 2) with or without transient peripheral edema (≤ Grade 2). A summary of AEs and pharmacodynamic results will be presented. Anti-drug antibodies (ADA) have been observed with MT-3724 but the advent of ADA in subjects has not precluded deepening tumor responses. These data are consistent with the clinical experience of denileukin diftitox, the only approved toxin-based oncology therapeutic. Consistent signs of efficacy including responses were seen in subjects without recent exposure to CD20 antibodies (see table). Conversely, progression by cycle 2 was seen in all subjects who had recent CD20 antibody exposure. CD20 antibodies compete with MT-3724 for target binding and high tissue levels of CD20 antibodies likely inhibit MT-3724 activity. Conclusions Targeting CD20 with antibodies has substantially improved survival in NHL, but unmet need remains and there is strong rationale for agents with new MOAs. MT-3724 is the first CD20 targeted immunotoxin to enter clinic trials. Encouraging clinical activity has been seen; safety, efficacy, PK, and ADA data will be presented. Ribosome inhibition represents a novel mechanism of action for the treatment of R/R NHL and continued development of MT-3724 is warranted. *both Drs. Hamlin and Fanale contributed equally to this work Table Table. Disclosures Hamlin: Molecular Templates: Research Funding; Novartis: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Fanale:molecular templates: Research Funding. Valacer:Molecular Templates: Employment, Equity Ownership. Higgins:Molecular Templates: Employment, Equity Ownership. Younes:Molecular Templates: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals CD19-Loss with Preservation of Other B Cell Lineage Features in Patients with Large B Cell Lymphoma Who Relapsed Post-Axi-Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 203-203 ◽  
Author(s):  
Sattva S Neelapu ◽  
John M. Rossi ◽  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
David B. Miklos ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Cell Lineage ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Cd19 Expression ◽  
Large B Cell

Background: Axi-cel is the first, personalized autologous anti-CD19 CAR T cell therapy approved for the treatment of patients with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies (YESCARTA. Prescribing Information. 2017). With a median follow-up of 27.1 months in ZUMA-1, the overall response rate was 83%, and 39% of the treated patients had ongoing response (Locke et al. Lancet Oncol. 2019). To gain insights into the mechanism of secondary treatment failure post-axi-cel, as well as define alternative targets and product optimization approaches, we analyzed tumor biopsies obtained prior to axi-cel therapy and at relapse. Methods: Tumor tissue samples from patients in Cohorts 1 and 2 of ZUMA-1 who had responded and subsequently relapsed were assessed in a post-hoc analysis for protein expression of B cell linage markers (CD19, CD20, PAX5, CD79a, and CD22) by multiplex immunohistochemistry (IHC), followed by multiplex immunofluorescence (IF) staining and confocal microscopy in representative cases. Pretreatment tissue samples were available from 96 patients, and 21 were available post-relapse. Paired pretreatment and post-relapse samples were available for 16 patients. CD19 and CD20 H-scores were derived based on proportion and intensity of antigen expression. Scores of 0 - 5 were considered negative, and scores of 6 - 300 were considered positive. CD19 splice variants were assessed by RNA sequencing. Results: Among all patients with available post-relapse samples, 7/21 (33%) showed loss of CD19 expression. Analysis of the 16 paired pretreatment and post-treatment samples showed loss of CD19 expression in 4 patients (25%) who relapsed post-axi-cel (Figure). Nineteen post-relapse tumor samples were evaluable for other B cell lineage markers and showed preservation of CD20, CD22 and CD79a, and the B cell lineage transcription factor PAX5, even in samples with loss or substantial reduction of CD19 expression. Multiplex IF showed that CD19 and CD20 were expressed on the cell membrane, and analysis uncovered the presence of malignant cells with different relative expression levels of these two antigens within a given biopsy. Interestingly, among the 96 pretreatment tumor samples, IHC analysis demonstrated that CD20 was robustly expressed in nearly all samples, alongside CD19, despite all patients having previously relapsed after receiving rituximab-based regimens. The CD19 and CD20 expression levels in these tumor biopsies obtained pre-axi-cel did not correlate with each other. RNA sequencing showed alternative splicing of CD19 with loss of exon 2 and/or exons 5/6 in diffuse large B cell lymphoma tumors at baseline and/or relapse, similar to what has been described previously in B cell acute lymphoblastic leukemia (Sotillo et al. Cancer Discov. 2015). In addition, several novel splice junctions have been identified. Data on the correlation between H-scores and CD19 splice forms and clinical outcomes, including response and progression-free survival, will be presented. Conclusions: In this cohort of patients relapsing after axi-cel, loss of CD19 expression was common by IHC as compared to pretreatment, likely due to alternative splicing and selection of variants devoid of target epitope. Additionally, the data showed that expression of alternate B cell lineage antigens was largely preserved. In particular, CD20 cell surface expression was strong in most tumors despite prior rituximab-based treatments. Altogether, these data point to strategies to improve efficacy of anti-CD19 CAR T cell products through co-targeting or sequential targeting of alternate B cell antigens. Disclosures Neelapu: Novartis: Consultancy; Cell Medica: Consultancy; Poseida: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; BMS: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding; Karus: Research Funding; Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Jacobson:Celgene: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor. Miklos:AlloGene: Consultancy; Celgene-Juno: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Becton Dickinson: Consultancy; Miltenyi: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Rodig:Kite, a Gilead Company: Research Funding; Bristol Myers Squib: Consultancy, Honoraria, Other: Travel Expenses, Speakers Bureau; Merck: Research Funding; Affirmed: Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Milletti:Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Chang:Kite, a Gilead Company: Employment, Equity Ownership. Xue:Kite, a Gilead Company: Employment. Plaks:Gilead: Equity Ownership. Kim:Kite, a Gilead Company: Employment. Bot:Kite, a Gilead Company: Employment, Equity Ownership.

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