Post ASH speaker abstracts 2018

High Grade Lymphoma

Abstracts to support presentations from Andy Davies and Graham Collins

Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Result Type: Paper
Number: 577
Presenter: Stephen Schuster
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Immune-Based Therapeutic Approaches

Stephen J. Schuster, MD1, Michael R. Bishop, MD2, Constantine S. Tam, MBBS, MD, FRACP, FRCPA3, Edmund K. Waller, MD 4, Peter Borchmann, MD5, Joseph P. McGuirk, DO6, Ulrich Jaeger, MD7*, Samantha Jaglowski, MD8*, Charalambos Andreadis, MD9, Jason R. Westin, MD10, Isabelle Fleury, MD, MSc, FRCP11, Veronika Bachanova, MD, PhD12, Stephen Ronan Foley, MD, FRCPC13, P. Joy Ho, MBBS, DPhil, FRACP, FRCPA, FFSc(RCPA)14*, Stephan Mielke, MD15, John M. Magenau, MD16*, Harald Holte17, Koen Van Besien, MD, PhD18, Marie Jose Kersten, MD, PhD19, Takanori Teshima, MD, PhD20, Kensei Tobinai, MD, PhD21, Paolo Corradini, MD22, Oezlem Anak, MD23*, Lida Bubuteishvili Pacaud, MD23*, Christopher del Corral, PharmaD24*, Rakesh Awasthi25*, Feng Tai, PhD25*, Gilles Andre Salles, MD, PhD26 and Richard Thomas Maziarz, MD27

1Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
2Hematopoietic Stem Cell Transplantation Program, The University of Chicago Medicine, Chicago, IL
3Peter MacCallum Cancer Centre, Melbourne, Australia
4Bone Marrow and Stem Cell Transplant Center, Winship Cancer Institute of Emory University, Atlanta, GA
5Department of Haematology and Oncology, University Hospital of Cologne, Cologne, Germany
6Department of Blood and Bone Marrow Transplant, The University of Kansas Medical Center, Kansas City, KS
7Department of Medicine I, Division of Hematology and Hemostaseology, and Comprehensive Cancer Center, Medical University of Vienna, Medical University of Vienna, Vienna, Austria
8The James Cancer Hospital and Solove Research Institute of The Ohio State University Comprehensive Cancer Center,, Columbus, OH
9Department of Hematology and Blood and Marrow Transplant, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
10Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston
11University of Montreal, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
12Bone and Marrow Transplant Program, University of Minnesota, Minneapolis, MN
13Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, ON, Canada
14Department of Medicine, The University of Sydney, Sydney, Australia
15Center for Allogeneic Stem Cell Transplantation, Würzburg University Medical Center, Würzburg, Germany
16Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
17Department of Oncology, Oslo University Hospital, Oslo, Norway
18Division of Hematology and Oncology, Weill Cornell Medicine /New York Presbyterian Hospital,
New York, NY
19Department of Hematology, Academic Medical Center, Amsterdam, Netherlands
20Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
21Department of Hematology, National Cancer Center Hospital, Tokyo, Japan
22University of Milan, Milan, Italy
23Novartis Pharma AG, Basel, Switzerland
24Novartis Pharmaceuticals Corporation, East Hanover
25Novartis Pharmaceuticals Corporation, East Hanover, NJ
26Department of Hematology, CHU Lyon-Sud Hospital, Hospices Civils de Lyon, Lyon, France
27Center for Hematologic Malignancies, Oregon Health & Science Knight Cancer Institute, Portland, OR

 

Background: CTL019 (tisagenlecleucel) is an investigational chimeric antigen receptor (CAR) T-cell therapy that identifies and eliminates CD19-expressing B cells. JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of CTL019 in adults with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with the best overall response (ORR) of 59% (complete response [CR], 43%; partial response [PR], 16%). Here, we report the results of the primary analysis of the JULIET study.

Methods: Eligible patients were 18 years or older with r/r DLBCL and had progressed after receiving ≥2 lines of chemotherapy, and were ineligible for or failed autologous stem cell transplant (auto-SCT). Centrally manufactured CAR T cells were provided to patients at 27 study centers in 10 countries on 4 continents using cryopreserved apheresis, central production facilities and a global supply chain. CTL019 was manufactured at 2 sites (United States and Germany). Autologous T cells were transduced with a lentiviral vector encoding an anti-CD19 scFv-CD3ζ-4-1BB CAR, expanded ex vivo, cryopreserved, shipped, and infused at study centers. The primary endpoint was best ORR (CR + PR) per independent review committee.

Results: As of data cutoff (8 March 2017), 147 patients were enrolled and 99 were infused with a single dose of CTL019 transduced cells (median, 3.1 × 108 [range, 0.1-6.0 × 108] cells). 90% of patients received bridging therapy. Prior to infusion, patients underwent restaging, and 93% received lymphodepleting chemotherapy (73% received fludarabine 25 mg/m2/cyclophosphamide 250 mg/m2/day × 3 days and 19% received bendamustine 90 mg/m2/day × 2 days). Median time from infusion to data cutoff was 5.6 months. The median age was 56 years (range, 22-76); 77% of patients had stage III or IV disease at study entry. The median number of prior lines of antineoplastic therapy was 3 (range, 1-6; 95% received ≥2 and 51% received ≥3 prior lines); 47% of patients had prior auto-SCT.

In this primary analysis of patients who received CTL019 from the US manufacturing site, among 81 infused patients with ≥3 months follow-up or earlier discontinuation the best ORR was 53.1% (95% CI, 42% to 64%; P<.0001) with 39.5% CR and 13.6% PR. At month 3, the CR rate was 32% and the PR rate 6%. Among patients evaluable at 6 months (n=46), the CR rate was 30% and PR rate was 7%. Response rates were consistent across prognostic subgroups (including those who received prior auto-SCT and those with double-hit lymphoma). Median duration of response was not reached; the 6-month probability of being relapse free was 73.5% (95% CI, 52.0% to 86.6%). Median overall survival was not reached; the 6-month probability of overall survival was 64.5% (95% CI, 51.5% to 74.8%). No patient who achieved a response (CR or PR) proceeded to allogenic- or auto-SCT. CTL019 was detected in peripheral blood by quantitative PCR for up to 367 days in responders. Overall, 86% of patients had grade 3 or 4 adverse events (AEs). Cytokine release syndrome (CRS) occurred in 58% of infused patients, with 15% grade 3 and 8% grade 4 using the Penn grading scale and managed by a protocol-specific algorithm. 15% of patients received anti-IL6 therapy, tocilizumab, for CRS management with good response and 11% of patients received corticosteroids. Other grade 3 or 4 AEs of special interest included neurologic AEs (12%, managed with supportive care), cytopenias lasting >28 days (27%), infections (20%), and febrile neutropenia (13%). Three patients died within 30 days of infusion, all due to disease progression. No deaths were attributed to CTL019. No CRS or neurologic event associated deaths occurred.

Conclusions: CTL019 produces high response rates with 95% of CRs at 3 months being sustained at 6 months in a cohort of highly pretreated adult patients with r/r DLBCL, results which confirm the findings of our earlier interim analysis. Centralized manufacturing was feasible in the first global study of CAR T cell therapy in DLBCL. CRS and other AEs could be effectively and reproducibly managed by appropriately trained investigators without treatment-related mortality.

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Result Type: Paper
Number: 578
Presenter: Sattva Neelapu
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Immune-Based Therapeutic Approaches

 

Ashley Paquin, BA1, Shaji K. Kumar, MD2, Francis K. Buadi, MD2*, Morie A. Gertz, MD2, Martha Q Lacy, MD2, Angela Dispenzieri, MD2, David Dingli, MD2, Lisa Hwa3*, Amie Fonder, PA-C2*, Miriam Hobbs, CNP2*, Suzanne R. Hayman, MD2, Steven Zeldenrust, MD2*, John A. Lust, MD, PhD2, Stephen J. Russell, MD, PhD2, Nelson Leung, MD2, Prashant Kapoor, MD2, Ronald S Go, MD2, Yi Lin, MD, PhD2, Wilson I Gonsalves, MD4, Taxiarchis Kourelis, MD2, Rahma Warsame, MD2, Robert A Kyle, M.D2 and S. Vincent Rajkumar, MD2

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Moffitt Cancer Center, Tampa, FL
3Washington University School of Medicine, Saint Louis, MO
4University of Miami Health System, Sylvester Comprehensive Care Center, Miami, FL
5Stanford University, Stanford, CA
6Dana-Farber Cancer Institute, Boston, MA
7Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
8Vanderbilt-Ingram Cancer Center, Nashville, TN
9City of Hope National Medical Center, Duarte, CA
10Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
11Mayo Clinic, Rochester, MN
12UCLA David Geffen School of Medicine, Los Angeles, CA
13University of Rochester School of Medicine, Rochester, NY
14Kite Pharma, Santa Monica, CA

 

Background: Patients with refractory NHL experience poor outcomes to currently available therapies. In the SCHOLAR-1 pooled analysis of patients with refractory aggressive NHL, the objective response rate (ORR) was 26% (complete response [CR] rate was 7%), and the median overall survival (OS) was 6.3 months (Crump et al. Blood. In press). The primary analysis of ZUMA-1 demonstrated positive results with an ORR of 82% and a CR rate of 54% after a single infusion of axi-cel. The safety profile was manageable: grade ≥ 3 cytokine release syndrome and neurologic events were generally reversible and reported for 13% and 28%, respectively (Locke et al. AACR 2017. #9986). With a median follow-up of 8.7 months, 44% of patients in ZUMA-1 were in ongoing response. We plan to present the 1-year follow-up of ZUMA-1 to confirm the stability of response following anti-CD19 CAR T cell therapy as previously suggested (Locke et al. Mol Ther. 2016; Kochenderfer et al. Mol Ther. 2017). Additionally, exploratory biomarker analyses were conducted to understand the mechanisms of resistance to anti-CD19 CAR T cell treatment.

MethodsPatients with refractory diffuse large B cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B cell lymphoma were enrolled and dosed per Locke et al. (AACR 2017. #9986). Refractory disease was defined as progressive disease or stable disease as best response to last line of therapy, or relapse ≤ 12 months after autologous stem cell transplant. Patients must have had a prior anti-CD20 antibody and an anthracycline-containing regimen. The primary endpoint was ORR per 2007 International Working Group criteria. Key secondary endpoints included duration of response (DOR), OS, and incidence of adverse events (AEs). A key exploratory endpoint was to investigate the mechanisms of resistance using post-treatment tumor biopsies obtained at time of relapse or progression.

Results: A long-term follow-up analysis will be performed with a data cut-off of August 11, 2017. To date, no patients have been lost to follow-up, and all patients who are alive remain in disease and survival follow-up. Updated DOR and OS will be presented with a minimum follow-up of 1 year and a median follow-up of 15 months. Updated subgroups and associative analyses of efficacy outcomes will be presented. Baseline and post-progression biopsies were evaluable by central review from 12 patients. CD19 and PD-L1 immunohistochemistry results are tabulated. Three of 11 (27%) patients with CD19-positive status at baseline developed CD19-negative disease at time of disease progression. Eight of 10 (80%) patients evaluable for PD-L1 at time of disease progression had PD-L1–positive disease. Of the 8 patients with CD19-positive samples at progression, 5 (63%) demonstrated PD-L1–positive tumor cells. Of the 3 patients with CD19-negative samples at progression, 2 had PD-L1–positive tumor cells.

In addition, post-progression biopsies from 6 separate patients were evaluable by local review, of which 3 (50%) had ≤ 1% CD19 staining. Cumulatively, 17 patients were evaluable for CD19 expression at time of progression by either central or local review, and 6 (35%) had ≤ 1% CD19 expression. Updated results will be presented.

Conclusions: In the ZUMA-1 study, axi-cel demonstrated significant clinical benefit with manageable AEs in patients with no curative treatment options. Additional long-term efficacy, safety, subgroup, and biomarker associative analyses with a median of 15 months of follow-up will be presented. Loss of CD19 and gain of PD-L1 expression in tumors are identified as possible mechanisms of resistance following axi-cel treatment. These results provide insights into development of novel therapeutic strategies to overcome CD19 CAR T resistance and further improve outcomes in these patients.

Drs. Neelapu and Locke contributed equally to this work.

A Comparison of One Year Outcomes in ZUMA-1 (axicabtagene ciloleucel) and SCHOLAR-1 in Patients with Refractory, Aggressive Non-Hodgkinlymphoma (NHL)

Result Type: Paper
Number: 579
Presenter: Sattva Neelapu
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Immune-Based Therapeutic Approaches

Sattva S. Neelapu, MD1, Frederick L. Locke, MD2, Nancy L. Bartlett, MD3, Lazaros J. Lekakis, MD4*, Patrick M. Reagan, MD5, David B. Miklos, MD, PhD6, Caron A. Jacobson, MD7, Ira Braunschweig, MD8, Olalekan O. Oluwole, MBBS, MPH9*, Tanya Siddiqi, MD10,11, Yi Lin, MD, PhD12, Michael Crump, MD13, John Kuruvilla, MD13, Eric W. Van Den Neste, MD, PhD14, Umar Farooq, MD15, Lynn Navale, MS16*, William Y. Go, MD, PhD16, Jeffrey S. Wiezorek, MD, MS16*and Christian Gisselbrecht14

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Moffitt Cancer Center, Tampa, FL
3Washington University School of Medicine, Saint Louis, MO
4University of Miami Health System, Sylvester Comprehensive Care Center, Miami, FL
5University of Rochester School of Medicine, Rochester, NY
6Stanford University School of Medicine, Stanford, CA
7Dana-Farber Cancer Institute, Boston, MA
8Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
9Vanderbilt University Medical Center, Nashville, TN
10City of Hope National Medical Center, Duarte, CA
11Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
12Mayo Clinic, Rochester, MN
13Canadian Cancer Trials Group at Queen’s University, Kingston, ON, Canada
14Cliniques Universitaires UCL Saint-Luc, Brussels, Belgium
15University of Iowa, Iowa City, IA
16Kite Pharma, Santa Monica, CA

 

BackgroundPatients with refractory, aggressive non-Hodgkin lymphoma (NHL), including diffuse large B cell lymphoma, primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL), have a very poor prognosis. SCHOLAR-1 is a retrospective evaluation and the largest reported analysis of outcomes in patients with refractory, aggressive NHL (Crump et al. Blood. In Press). SCHOLAR-1 described an objective response rate (ORR) of 26% and complete response (CR) rate of 7% with currently available salvage therapies. These results provided a benchmark for evaluation of new approaches. ZUMA-1 (NCT02348216) is a prospective, interventional and first multicenter, pivotal trial of an autologous anti-CD19 CAR T cell therapy, axicabtagene ciloleucel (axi-cel, formerly KTE-C19), in patients with refractory, aggressive NHL. Axi-cel treatment resulted in an ORR of 82% and a CR rate of 54% (Locke et al. AACR 2017. #9986). Presented here are comparative analyses of outcomes from ZUMA-1 and SCHOLAR-1 studies after adjusting for imbalances in key prognostic covariates.

Methods: Patients in both studies had refractory, aggressive NHL (stable disease ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant [SCT]). While patients in both studies fulfilled similar inclusion criteria for refractory disease, potential imbalances in other prognostic characteristics may still occur. To address these potential imbalances, standardized analyses were performed which equally weighted the proportions of patients with select prognostic covariates important for both response and survival between the 2 studies. The prespecified covariates selected for weighting were refractory subgroup and occurrence of SCT after refractory status. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity.

ResultsOne hundred and one patients received axi-cel in ZUMA-1, and data from 508 patients were analyzed in SCHOLAR-1. In SCHOLAR-1, 64% of patients were male and 15% were ≥ 65 years. ECOG, disease stage, and International Prognostic Index (IPI) score were assessed in approximately 50% of patients. Among the assessed patients, 80% had ECOG 0-1, 67% had stage III/IV disease, and 35% had IPI ≥ 3. Four percent of patients had TFL or PBMCL. Twenty percent of patients were primary refractory, 62% were refractory to second- or later-line therapy, 18% relapsed within 1 year of SCT, and 27% had received ≥ 3 lines of therapy. Median follow-up for ZUMA-1 was 8.7 months at the primary analysis and will be updated. While, studies were generally balanced across sex and disease subtype, ZUMA-1 had a greater proportion of patients aged ≥ 65 years (24%), with stage III/IV disease (85%), and with IPI score ≥ 3 (48%). ZUMA-1 patients were generally more heavily pretreated, with more patients refractory to second- or later-line therapy (77%) and more patients who received ≥ 3 lines of therapy (70%). All patients in ZUMA-1 had an ECOG 0-1. In an analysis standardized to ZUMA-1, the ORR and CR rate in SCHOLAR were 20% and 6%, respectively. Odds ratios for ORR and CR rate were 8-fold and 10-fold higher, respectively, in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 6-month survival rate for SCHOLAR-1, standardized to ZUMA-1, was 35%. This corresponded to a 77% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.23; P < .0001). An updated analysis comparing SCHOLAR-1 outcomes to ZUMA-1 with a minimum follow-up of 12 months and a median follow-up of 15 months, as well as propensity score analyses to compare the studies will be presented. Conclusions: This standardized comparison between the ZUMA-1 and SCHOLAR-1 studies suggests patients treated with axi-cel experience nearly 10-fold higher odds of CR and a 77% decrease in the risk of death. Despite limitations of this retrospective analysis, these results indicate that axi-cel represents an improved treatment option for patients with refractory, aggressive NHL.

Encouraging Early Results from the First in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory B-Cell Lineage Non-Hodgkin Lymphoma

Result Type: Paper
Number: 187
Presenter: Brad Kahl
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Novel Agents and Upfront Approaches

Brad S. Kahl, MD1, Mehdi Hamadani, MD2, Paolo Caimi, MD3, Carmelo Carlo-Stella, MD4, Erin Reid, MD5*, Jay Feingold, MD, PhD6*, Kirit M Ardeshna, MD7*, John Radford, MD8*, Melhem M Solh, MD9, Ki-Young Chung, MD10*, Leonard Heffner, MD11, Shui He, PhD12*, Joseph Boni, PhD12* and Owen Anthony O’Connor, MD13*

1Washington University School of Medicine, Saint Louis, MO
2Division of Hematology and Oncology, CIBMTR (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI
3University Hospitals of Cleveland, Cleveland, OH
4Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas University, Milan, Italy
5Department of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, CA
6ADC Therapeutics America Inc, Murray Hill, NJ
7Department of Haematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
8University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Centre, Manchester, United Kingdom
9Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA
10Department of Hematology and Oncology, Greenville Health System, Greenville, SC
11Department of Hematology and Medicial Oncology, Winship Cancer Institute, Emory university, Atlanta, GA
12ADC Therapeutics America, Inc., Murray Hill, NJ
13Center for Lymphoid Malignancies, Columbia University Medical Center New York Presbyterian Hospital, New York, NY

 

Introduction: CD19 is expressed on the cell surface of many types of non-Hodgkin lymphoma (NHL), including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) comprising a humanized antibody (Ab) directed against human CD19 conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. Loncastuximab tesirine (Lonca-T) has demonstrated potent anti-tumor activity against CD19-expressing B-cell malignancies in preclinical models. Interim results of the first-in-human clinical study of Lonca-T in the difficult-to-treat relapsed/refractory (R/R) NHL setting are reported here.

Methods: Patients (pts; ≥18 years of age) with R/R B-cell lineage NHL who have failed or are intolerant to established therapies, or have no other treatment options available, are being enrolled in this Phase 1, multicenter, open-label, two-part study. The primary objectives for Part 1 (dose escalation) are to evaluate the safety and tolerability of Lonca-T, and to determine the maximum tolerated dose (MTD) and the recommended dose(s) to use in Part 2 (dose expansion). The primary objective for Part 2 is to evaluate the safety and tolerability of the dose(s) determined in Part 1. Efficacy (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival), pharmacokinetics, pharmacodynamics, and other exploratory endpoints are also being assessed in both parts of the study. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle) according to a 3+3 dose-escalation study design. No intra-patient dose escalation is allowed.

Results: As of July 5, 2017, 80 pts (55 male, 25 female; median age: 65.5 years [range 24–85]; median number of previous therapies: 3 [range 1–10]) have been recruited. Diagnoses were DLBCL (n=56), mantle cell lymphoma (MCL; n=9), FL (n=6), marginal zone B-cell lymphoma (n=3), chronic lymphocytic leukemia (n=2) and other (n=4). Pts have received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1–16]). Treatment-emergent adverse events (TEAEs) were reported in 76 (95.0%) pts, and grade ≥3 TEAEs in 46 (57.5%) pts. The most common non-hematological all-grade TEAEs were fatigue (35 [43.8%] pts), peripheral edema (21 [26.3%] pts) and nausea (20 [25.0%] pts), and grade ≥3 TEAEs were increased gamma-glutamyltransferase (7 [8.8%] pts) dyspnea (4 [5.0%] pts) and fatigue (4 [5.0%] pts). Hematological abnormalities included decreased hemoglobin (74/77 [96.1%] and 9/77 [11.7%] pts with all-grade and grade ≥3 TEAEs, respectively), decreased neutrophil count (42/69 [60.9%] and 29/69 [42.0%] pts, respectively) and decreased platelet count (55/77 [71.4%] and 21/77 [27.3%] pts, respectively). TEAEs in 8 (10.0%) pts led to treatment withdrawal (increased gamma-glutamyltransferase [n=4]; increased blood alkaline phosphatase [n=1]; periorbital edema [n=1]; fatigue [n=1]; abdominal pain [n=1]; thrombocytopenia [n=1]). A dose-limiting toxicity (DLT) was reported in 1 pt (worsening of thrombocytopenia at 200 µg/kg) and the MTD has not yet been reached. Table 1 shows the best overall response by dose. At doses ≥120 µg/kg, 16/47 (34.0%) and 12/47 (25.5%) evaluable pts achieved a complete response (CR) or partial response (PR), respectively (ORR: 28/47 [59.6%]). ORR for pts with DLBCL was 20/35 (57.1%), with a CR rate of 34.3% (12/35). Figure 1 depicts the waterfall plot. Pharmacokinetic measures for total- and PBD-conjugated Ab exposures were comparable, were proportional to dose, and were associated with modest accumulation by Cycle 2. Measures for unconjugated PBD were predominantly below quantification levels for all doses and time points. Associations of exposure to safety and efficacy are reported in a companion abstract (O O’Connor et al.).

Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in pts with R/R B-cell lineage NHL. One DLT has been reported and the MTD has not yet been reached. Evaluation in specific NHL subtypes is now warranted, and a dose expansion in pts with DLBCL is planned initially. Updated safety, tolerability, and efficacy results will be presented at the meeting.

Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017

A Phase I, Open-Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma

Result Type: Paper
Number: 192
Presenter: Peter Martin
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Novel Agents and Upfront Approaches

Peter Martin, FRCPC, MD, MS1, Nancy L. Bartlett, MD2, Ildefonso Ismael Rodriguez Rivera, MD1, Maria Revuelta, PhD3*, Julio C. Chavez, MD4, John L. Reagan, MD5, Sonali M. Smith, MD6, Ann S. LaCasce, MD7, Lei Zhang, MD8*, Merry Zhai, BS8*, Chengqing Wu, PhD8*, John P. Leonard, MD3 and Leandro Cerchietti, MD9

1Weill Cornell Medicine, New York, NY
2Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO
3Department of Medicine, Weill Cornell Medicine, New York, NY
4H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
5Division of Hematology/Oncology, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI
6University of Chicago, Chicago, IL
7Dana-Farber Cancer Institute, Boston, MA
8Celgene Corporation, Summit, NJ
9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY

 

Introduction: Approximately 40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) do not achieve complete response (CR) or relapse after receiving R-CHOP. A proposed mechanism of chemoresistance is aberrant DNA methylation. Preclinical data show low doses of DNA methyltransferase inhibitors, such as azacitidine, suppress DLBCL tumor growth, while causing minimal DNA damage and enhancing chemosensitivity. In an earlier phase I clinical trial, subcutaneous (SC) azacitidine + R-CHOP showed 10/11 CRs in DLBCL pts with international prognostic index (IPI) score >2 (Clozel et al. Cancer Discovery 2013), providing a rationale for this study of oral azacytidine (CC-486) which is easier to administer and may achieve more continuous hypomethylation effects.

Methods: The CC-486-DLBCL-001 phase I trial examined 4 escalating doses (100, 150, 200, and 300 mg) of CC-486 combined with standard R-CHOP21 in pts with previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed FL; IPI score ≥2; ECOG PS ≤2; and Ann Arbor stage II-IV disease (NCT02343536). Pts were enrolled sequentially starting at 100 mg CC-486 in a time-to-event continual reassessment method (TiTE-CRM) design. Priming with CC-486 was given for 7 days prior to R-CHOP initiation on day 1 of cycle 1. Thereafter, CC-486 was given for 14 days (days 8-21) before the next R-CHOP cycle. Patients standardly received G-CSF. Treatment was given for six, 21-day cycles. Primary endpoints were to determine safety, dose-limiting toxicity (DLT), and maximal administered dose (MAD) of CC-486 combined with R-CHOP (per NCI CTCAE v4.03). Secondary endpoints included PK and preliminary efficacy, including overall response rate (ORR) and CR per 2014 IWG criteria. Correlative analyses were performed at day -6 (pre-CC-486) versus day 1 of cycle 1 (post-CC-486) in matched tumor and circulating cell-free DNA (cf-DNA) samples for DNA bisulfite sequencing and gene expression, and in plasma for cytokine levels. The study design consisted of “dose escalation” assessing 4 dose levels, followed by a “dose expansion” at the recommended phase II dose (RP2D). The data reported here are from the completed dose escalation phase.

Results: A total of 33 pts were enrolled in dose escalation as of May 31, 2017. The median age was 65 years (range, 25-80), 67% were >60 years, and 55% were male. 32 (97%) pts had DLBCL (including 5 transformed from FL), and 1 patient had grade 3B FL. Thirty (91%) pts had stage III-IV disease, and 19 (58%) had IPI score ≥3. 91% of pts completed 6 full cycles of planned study treatment. CC-486 dose reduction occurred in 9 (27%) pts due to adverse events (AEs). Treatment with CC-486 (150 mg) was discontinued in 1 patient due to febrile neutropenia. The most common any-grade AEs included neutropenia (70%), nausea (64%), constipation (58%), fatigue (55%), vomiting (48%), and diarrhea (48%). Grade 3/4 treatment-related AEs occurred in 21 (64%) pts; most common (≥10%) were neutropenia (58%) and febrile neutropenia (21%). Serious AEs (SAEs) occurred in 13 (39%) pts; febrile neutropenia was the only SAE occurring in >1 pt (24%). There were no deaths related to the study. DLTs were seen in 2 pts, including 1 grade 4 febrile neutropenia (200 mg cohort) and 1 grade 4 neutropenia (300 mg cohort). The MAD was 300 mg, which was identified as the RP2D for dose expansion. 32 of 33 efficacy-evaluable pts responded for 97% ORR, with 28 (85%) pts achieving a PET-negative CR. In 19 pts with IPI score ≥3, ORR was 100%, and CR was 84%. Correlative analyses for cytokine levels and DNA methylation pre- versus post-CC-486 showed significantly decreased IFN-α2a and increased IFN-β and IFN-λ in blood (n=24), and significant tumor and cf-DNA hypomethylation. There was a significant change in gene expression for IFN-related immune response and lymphoma microenvironment pathways (n=3). PK was similar to the known PK profile in AML and MDS patients and was unaffected by co-administration of R-CHOP.

Conclusions: CC-486 combined with R-CHOP showed promising preliminary efficacy in pts with high-risk, previously untreated DLBCL or grade 3B FL. Results from this study identified a RP2D of 300 mg for future studies of CC-486 plus R-CHOP in DLBCL pts. Adverse events were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP. Correlative analyses showed pharmacodynamic activity, the majority related to anti-lymphoma immune regulation.

Addition of Polatuzumab Vedotin to Bendamustine and Rituximab (BR) Improves Outcomes in Transplant-Ineligible Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Versus BR Alone: Results from a Randomized Phase 2 Study

Result Type: Paper
Number: 2821
Presenter: Laurie Sehn
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster II

Laurie H. Sehn, MD, MPH1, Alex F. Herrera, MD2, Matthew J. Matasar, MD3, Manali Kamdar4, Andrew K. McMillan, FRCP5, Tae Min Kim6*, Won Seog Kim, M.D., Ph. D.7*, Mark Hertzberg, MBBS, PhD8*, Muhit Ozcan, MD9, Elicia Penuel10*, Ji Cheng11*, Jamie M. Hirata10*, Grace Ku10* and Christopher Flowers, MD, MS12

1British Columbia Cancer Agency and the University of British Columbia, Vancouver, BC, Canada
2City of Hope, Duarte, CA
3Memorial Sloan Kettering Cancer Center, New York, NY
4University of Colorado, Denver, CO
5Department of Clinical Haematology, Nottingham City Hospital, Nottingham, United Kingdom
6Seoul National University Hospital, Seoul, Korea, Republic of (South)
7Samsung Medical Center, Seoul, Korea, Republic of (South)
8Prince of Wales Hospital, Sydney, Australia
9Ankara University, Ankara, Turkey
10Genentech, Inc., South San Francisco, CA
11F. Hoffmann-La Roche Ltd, Mississauga, Canada
12Winship Cancer Institute Bone Marrow & Stem Cell Transplantation, Atlanta, GA

 

Introduction: Transplant ineligible patients (pts) with R/R DLBCL have poor outcomes. Polatuzumab vedotin (pola) is an antibody drug conjugate that delivers the microtubule inhibitor MMAE to CD79b-expressing cells, including DLBCL (Dornan et al. Blood 2009). A P1b/2 study evaluating pola plus bendamustine (B) together with rituximab (R) or obinutuzumab (G) in R/R follicular lymphoma and R/R DLBCL is ongoing (ClinicalTrials.gov NCT02257567). Previously we reported results from the P1b (pola + BR, pola + BG) and P2 expansion of pola + BG and showed that these regimens were tolerable (Matasar et al. EHA 2017). We now report results of the randomized DLBCL cohorts that compared pola + BR to BR.

Aims: The P2 primary aim was to assess the efficacy of pola + BR vs BR at PRA (primary response assessment: 6-8 weeks after last study treatment) by an independent review committee (IRC) using modified Lugano Classification (CR required PET negativity and bone marrow biopsy confirmation of clearance if positive at screening). Secondary aims included safety evaluation and investigator-assessed responses by PET/CT and CT alone. Exploratory aims included duration of response (DOR), PFS, OS, and biomarker analysis.

Methods: After informed consent, 80 R/R DLBCL pts were randomized to pola 1.8 mg/kg plus R (375 mg/m2) and B (90 mg/m2) or BR every 21 days for 6 cycles. Transplant eligible pts were excluded but pts could have had prior autologous but not allogeneic transplant. Pts were stratified by DOR to last prior treatment ≤12 months (mo) vs >12 mo.

Results: Of 40 pts randomized to each arm, 39 pts in each arm received ≥1 treatment dose. Baseline characteristics of safety evaluable pts were comparable between the two arms (Table 1). As of 3 May 2017, median follow up for surviving pts was 10.9 mo for pola + BR and 7.6 mo for BR. Pola + BR pts completed more treatment cycles vs BR pts, with median of 5 vs 3 completed cycles, and 6 cycles completed by 46% vs 18% pts, respectively. Early treatment discontinuation due to PD occurred in 15% of pola + BR pts vs 54% of BR pts. AEs led to early treatment discontinuation in 33% pola + BR pts vs 10% BR pts. Safety: Non-heme AEs (all grades) occurring in >20% of pola + BR vs BR pts included diarrhea 41% vs 21%, infections 39% vs 41%, fatigue 36% vs 28%, pyrexia 33% vs 23%, nausea 26% vs 28%, decreased appetite 26% vs 15%, constipation 21% vs 18%, rash 10% vs 21%, and infusion related reactions 31% vs 21%. Heme AEs (all grades) in pola + BR vs BR were neutropenia 54% vs 39%, thrombocytopenia 49% vs 23%, and anemia 44% vs 15%, respectively. Peripheral neuropathy occurred in 39% pola + BR pts [21% Grade (Gr) 1, 18% Gr 2] vs 3% BR pts (3% Gr 2) and led to pola discontinuation in 1 pt and dose reduction in 2 pts. Gr 3-4 AEs occurring in >10 % of pts were infections (13% pola + BR vs 18% BR) and cytopenias. Gr 3-4 cytopenias were higher in pola + BR vs BR: neutropenia (46% vs 36%), thrombocytopenia (33% vs 21%), anemia (26% vs 13%) but were manageable with similar transfusion rates between the two arms. SAEs occurring in ≥ 10% of pts were infections (21% pola + BR vs 26% BR), febrile neutropenia (10% pola + BR vs 5% BR), and pyrexia (10% pola + BR vs 3% BR). Seven (18%) Grade 5 AEs occurred in each arm, including 3 (8%) in the setting of PD in each arm. Infection was the most common Gr 5 AE (3 per arm). Efficacy: Investigator-assessed best ORR and CR rates by PET/CT were higher in pola + BR vs BR with ORR 70% vs 33%, CR 58% vs 20% and at PRA with ORR 48% vs 18% and CR 43% vs 15%, respectively (Table 2). Median DOR for pola + BR vs BR was 8.8 mo vs 3.7 mo, respectively. Although the study was not powered for survival analyses, a significant benefit was seen in PFS and OS for pola + BR compared to BR (Figure 1). Median PFS for pola + BR vs BR was 6.7 mo (95% CI 4.9, 11.1) vs 2.0 mo (95% CI 1.5, 3.7) with stratified HR 0.31 (95% CI 0.18, 0.55) and p-value <0.0001 (calculated by Cox regression and log rank, respectively). Median OS for pola + BR vs BR was 11.8 mo (95% CI 9.5, NR) vs 4.7 mo (95% CI 3.7, 8.3) with stratified HR 0.35 (95% CI 0.19, 0.67) and p-value 0.0008. The OS benefit was proven to be consistent by subgroup and multivariate analyses. OS at 1 year for pola + BR was 48% vs 24% for BR. IRC, subgroup/multivariate analysis, and biomarker data will be updated at presentation. Conclusion: Pola + BR increased response rates, prolonged PFS and OS and provided significant clinical benefit with manageable toxicity in this population with high unmet need. Further evaluation of this promising therapy is warranted.