Weekly Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2612-2612 ◽  
Author(s):  
Daniel DeAngelo ◽  
Wendy Stock ◽  
Stephen Petersdorf ◽  
Shaw-Ling Wang ◽  
Angela Volkert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Research Funding ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Employment Equity ◽  
Inotuzumab Ozogamicin ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2612 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. CD22 is expressed on a majority of B-cell acute lymphoblastic leukemia (ALL). An initial study suggested INO efficacy and tolerability in ALL (Lancet Oncol 2012;13:403-11). Objectives: The current phase 1, multicenter, dose-escalation study was performed to optimize the INO dose and schedule (weekly dosing) based on safety, efficacy, and pharmacokinetic data in CD22+ relapsed or refractory ALL. The safety and efficacy of INO at the recommended dose and schedule will subsequently be further evaluated in a 12-patient (pt) expanded cohort. Methods: Eligible pts were aged ≥18 y with CD22+ ALL (defined as ≥20% blasts CD22+ by flow cytometry) refractory to initial induction or in relapse (≥first relapse), with no evidence of central nervous system disease. INO was administered in 28-d cycles (see Table), with a maximum of 6 cycles. The final dose was to be determined based on both toxicity (ie, rate of dose-limiting toxicities [DLT] at each dose level) and evidence of efficacy using the EffTox V2.10 software (Biometrics 2004;60:684–693). Adverse event (AE) severity was assessed per CTCAE V3 with DLTs defined as any of the following INO-related events during Cycle 1: grade ≥4 non-hematologic toxicity; prolonged myelosuppression (absolute neutrophil count [ANC] <500/μL or platelets <25,000/μL in bone marrow) with no evidence of leukemia persisting >45 d from last dose; grade 3 non-hematologic toxicity persisting >7 d from the last dose; grade ≥3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin persisting >7 d; or any toxicity resulting in permanent INO discontinuation. Weekly teleconferences with investigators were used to assess toxicity. Complete response (CR) was defined as <5% bone marrow blasts with absence of peripheral blasts, ANC ≥1,000/μL, platelets >100,000/μL, and no extramedullary disease; incomplete CR (CRi) was similar but permitted ANC <1,000/μL and/or platelets ≤100,000/μL. Results: We report preliminary data for 13 pts (see Table), with a median duration of follow-up of 147 d (range, 30–188 d). Median age was 56 y (range, 23–65 y), and 69% of pts were male. Five (39%) pts were in salvage 1, 2 (15%) were in salvage 2, and 4 (31%) were in salvage ≥3. Two pts had prior allogeneic stem cell transplant. Three (23%) pts were Ph+ and 7 (54%) pts had circulating blasts at baseline; median baseline WBC was 2.01×103/mm3 (range, 0.5–29.11×103/mm3). The single DLT observed to date was transient grade 4 elevated lipase occurring at INO dose level 3. The most frequent (≥10% of pts) treatment-related AEs were thrombocytopenia (31%, all grade 3/4), neutropenia (15%), and elevated ALT (15%). Treatment-related elevated AST and alkaline phosphatase were each reported for 8% of pts. Reported dose delays were due to thrombocytopenia (n = 3), neutropenia (n = 2), elevated LFT (n = 2), bacteremia, increased blood creatinine, periorbital cellulitis, and QTc prolongation (n = 1 each). Fourteen serious AEs were reported for 9 pts, including 2 cases each of febrile neutropenia and septic shock. Responses were observed across all INO doses explored to date (see Table). The preliminary response rate was 82% (9/11 evaluable pts), including 36% of pts with a CR and 45% with a CRi. Median time to response was 43 d (range, 28–56 d). Six of 9 (67%) pts who achieved CR/CRi also achieved minimal residual disease (<1 blast out of 104 mononuclear cells by flow cytometry). Seven pts discontinued treatment, including 1 each due to disease progression and an AE (acute renal failure, not treatment related), and 5 pts who proceeded to transplant. Four deaths were reported, including 1 due to disease progression and 3 due to sepsis occurring within 30 d after stem cell transplantation. Conclusions: INO had a safety profile consistent with prior reports, characterized by hematologic, gastrointestinal, and hepatic events and infection. The remarkable response rate of 82% for single-agent INO in this relapsed/refractory population warrants further exploration in CD22+ ALL. Updated results will be presented at the meeting. Disclosures: Stock: Tau for work done through the CALGB/ALLIANCE: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Volkert:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Advani:Pfizer Inc: Consultancy, Honoraria, Research Funding.

scholarly journals Deep Sequencing Approach for Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1388-1388
Author(s):  
Malek Faham ◽  
Jianbiao Zheng ◽  
Martin Moorhead ◽  
Victoria Carlton ◽  
Patricia Lee Stow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Employment Equity ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Abstract 1388 Background: The clinical management of patients with acute lymphoblastic leukemia (ALL) relies on accurate prediction of relapse hazard to determine the intensity of therapy and avoid over- or under-treatment.1 The measurement of minimal residual disease (MRD) during therapy has now emerged as the most important predictor of outcome in ALL.2 We developed the LymphoSIGHT platform, a high-throughput sequencing method, which universally amplifies antigen-receptor gene segments and can identify all leukemia-specific sequences at diagnosis, allowing monitoring of disease progression and clonal evolution during therapy. In this study, we determined the sensitivity and specificity of this method, delineated the extent of clonal evolution present at diagnosis, and compared its capacity to measure MRD to that of flow cytometry and allele-specific oligonucleotide PCR (ASO-PCR) in follow-up samples from >100 patients with ALL. Methods: Using the sequencing assay, we analyzed diagnostic bone marrow samples from 100 ALL patients for clonal rearrangements of immunoglobulin (IgH@) and T cell receptor (TRB@, TRD@, TRG@) genes, as well as the extent of clonal evolution present at diagnosis. We assessed the capacity of the sequencing assay to detect MRD using diagnostic samples from 12 ALL patients carrying 13 leukemic IgH clonal rearrangements. Serial dilutions were prepared in normal peripheral blood mononucleated cells, at a range between <1 in 1 million to >1 in 1,000 cells. We also assessed MRD in follow-up samples from 106 ALL patients and analyzed concordance between MRD results obtained by the sequencing assay, flow cytometry and ASO-PCR. Results: In diagnostic bone marrow samples, we detected the presence of a high-frequency clonal rearrangement of at least one receptor (“calibrating receptor”) in all the 100 ALL samples; 94 samples had at least 2 calibrating receptors at diagnosis, with 51 having 3 or more. We also detected a variable degree of clonal evolution: the number of evolved clones in each sample ranged from 0 to 6933, with 39 (37%) samples having 1–50 evolved clones and 17 (16%) >50 (Figure 1). In experiments with mixtures of normal and leukemic cells, the sequencing assay unequivocally and accurately detected leukemic signatures in all dilutions up to a concentration of at least one leukemic cell in 1 million leukocytes. In direct comparisons with established MRD assays performed on follow-up samples from patients with B-ALL, sequencing detected MRD in all 28 samples positive by flow cytometry, and in 35 of the 36 positive by ASO-PCR; it also revealed MRD in 10 and 3 additional samples that were negative by flow cytometry and ASO-PCR, respectively (Figure 2). Conclusions: The sequencing assay is precise, quantitative, and can detect MRD at levels below 1 in 1 million leukocytes (0.0001%), i.e., represents sensitivity 1–2 orders of magnitude higher than standard flow cytometric and ASO-PCR methods. Our assay also allows monitoring of all leukemic rearrangements regardless of their prevalence at diagnosis, which abrogates the risk of false-negative MRD results due to clonal evolution. Finally, the sequencing assay utilizes a set of universal primers and does not require development of patient-specific reagents. These data, together with the results of our comparison with standard MRD assays in clinical samples, strongly support the use of the sequencing assay as a next-generation MRD test for ALL. Disclosures: Faham: Sequenta: Employment, Equity Ownership, Research Funding. Zheng:Sequenta: Employment, Equity Ownership, Research Funding. Moorhead:Sequenta: Employment, Equity Ownership, Research Funding. Carlton:Sequenta: Employment, Equity Ownership, Research Funding.

An Open-Label, Phase 1 Study of R-CVP in Combination with Inotuzumab Ozogamicin in Patients with CD22-Positive B-Cell Non-Hodgkin's Lymphoma: Preliminary Safety and Efficacy Data

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1633-1633
Author(s):  
Michinori Ogura ◽  
Kiyohiko Hatake ◽  
Andrew Davies ◽  
Michael Crump ◽  
Kensei Tobinai ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Efficacy Data ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Common Grade ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of <33% in Cycle 1 and fewer than 1/3 of patients discontinuing prior to Cycle 3 due to an adverse event (AE). In Part 3 (n = 22), additional patients were enrolled to explore preliminary signs of activity of INO when given in combination with R-CVP. Results: In Parts 2 and 3, a total of 32 patients with follicular lymphoma (FL; n = 15), diffuse large B-cell lymphoma (DLBCL; n = 16), or mantle cell lymphoma (n = 1) were enrolled. CD22 expression was confirmed by immunohistochemistry or flow cytometry prior to enrollment. The median age was 65 years (range, 44–81 years); 34% of patients had 1 prior anti-lymphoma regimen, 34% had 2, 28% had ≥3, and 3% (n = 1) had no previous therapy (median, 2; range, 0–6). The median number of cycles received was 5 (range, 1–6). In Part 2, the MTD was confirmed as standard-dose R-CVP plus INO 0.8 mg/m2, with 2 of 10 patients presenting with a DLT (grade 3 increase in alanine/aspartate aminotransferases [ALT/AST] and grade 4 neutropenia requiring granulocyte-colony stimulating factor). Four patients discontinued due to AEs after 2 cycles (n = 1), 3 cycles (n = 2), and 5 cycles (n = 1), respectively. Across Parts 2 and 3, the most common treatment-related AEs (all grades) were thrombocytopenia (78%), neutropenia (66%), fatigue (53%), constipation (50%), leukopenia (50%), and nausea (41%); the most common grade 3/4 AEs included neutropenia (63%), thrombocytopenia (53%), leukopenia (38%), lymphopenia (31%), increased ALT (9%), increased AST (6%), and febrile neutropenia (6%). There was 1 case of treatment-related fatal pneumonia associated with grade 4 neutropenia. Ten patients discontinued study treatment due to AEs, with thrombocytopenia or delayed recovery from thrombocytopenia being the leading AE causing study drug discontinuation (n = 9 [grade 1/2, n = 6; grade 3/4, n = 3]). The best overall response (ORR; partial + complete response [CR]) from Part 2 and 3 (31 evaluable patients) was 77% (n = 24/31), including 29% (n = 9/31) with CR. Of patients with FL, the ORR was 100% (n = 15/15), including 53% (n = 8/15) with CR. Of patients with DLBCL, the ORR was 60% (n = 9/16), including 7% (n = 1/16) with CR. Conclusions: Results from this phase I study showed that R-CVP in combination with INO 0.8 mg/m2 may have acceptable toxicity and promising activity in patients with relapsed or refractory CD22+ B-cell NHL, based on the response rates in FL and DLBCL. The most common grade 3/4 AEs were hematological toxicities, notably thrombocytopenia and neutropenia. Follow-up for progression-free survival and overall survival is currently ongoing; however, the observed results warrant additional study in both indolent and aggressive B-cell NHL. Disclosures: Ogura: Pfizer Inc: Research Funding. Hatake:Pfizer Inc: Research Funding. Davies:Pfizer Inc: Research Funding. Crump:Pfizer, Celgene, Roche, Millennium, Seattle Genetic: Membership on an entity's Board of Directors or advisory committees. Tobinai:Merck, Zenyaku, Symbio, Biomedics, Pfizer, GSK, Chugai/Roche: Research Funding. Smith:Pfizer Inc: Research Funding. Offner:Pfizer Inc: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. MacDonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 968-968 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Daniel J. DeAngelo ◽  
Dan Douer ◽  
Hervé Dombret ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Mutation Status ◽  
Response Data ◽  
Notch Receptors ◽  
Equity Ownership ◽  
Grade 3 ◽  
Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

scholarly journals Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 897-897 ◽  
Author(s):  
William G. Wierda ◽  
Michael R. Bishop ◽  
Olalekan O. Oluwole ◽  
Aaron C. Logan ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Adult Patients ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Time To Onset

Abstract Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.

scholarly journals Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4471-4471 ◽  
Author(s):  
Michael Wang ◽  
Andre Goy ◽  
Peter Martin ◽  
Rod Ramchandren ◽  
Julia Alexeeva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Immune Microenvironment Analysis of Bone Marrow By Mass Cytometry and RNA Sequencing in Multiple Myeloma Patients Treated with Daratumumab and Durvalumab

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3296-3296 ◽  
Author(s):  
Frances Seymour ◽  
Mary H Young ◽  
Mark Tometsko ◽  
Jamie Cavenagh ◽  
Ethan G. Thompson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Nk Cells ◽  
Research Funding ◽  
Cell Populations ◽  
Mass Cytometry ◽  
Immune Microenvironment ◽  
Employment Equity ◽  
Equity Ownership

Abstract Introduction Relapsed and refractory multiple myeloma (RRMM) remains a challenging disease to treat due to its heterogeneity and complexity. There is an urgent need for novel combination strategies, including immunotherapy. The study of the tumour and immune microenvironment before and after treatment with combination therapy is a crucial part of understanding the underpinning of disease response. Methods Longitudinal samples of bone marrow aspirates and whole blood were collected from a phase II clinical trial, MEDI4736-MM-003 (NCT02807454) where daratumumab and durvalumab naïve patients were exposed simultaneously to both these drugs. A combination of mass cytometry (CyTOF), RNAseq and flow cytometry were performed on a subset of samples from these subjects. Specifically, paired bone marrow mononuclear cells (BMMC) samples from nine patients taken at screening and six weeks post-treatment were analysed by mass cytometry (CyTOF) using a 37-marker pan-immune panel that included both lineage and functional intracellular/extracellular markers. In addition, whole blood sample specimens were collected at screening and on treatment (8, 15, 30, and 45 days after treatment) and analysed by flow cytometry. Flow cytometry panels were designed to allow interrogation of the abundance and activation status of immune cell subsets. Finally, RNA from bone marrow aspirates at screening and C2D15 were analysed by RNA sequencing. Expression profiles from the aspirates were used to estimate cell proportions by computational deconvolution. Individual cell types in these microenvironments were estimated using the DCQ algorithm and a gene expression signature matrix based on the published LM22 leukocyte matrix (Newman et al., 2015) augmented with 5 bone marrow- and myeloma-specific cell types. Results In a heavily pre-treated population with RRMM, treatment with durvalumab and daratumumab leads to shifts in a number of key immunological populations when compared to pre-treatment. In the bone marrow, CD8 and CD4 populations rise (by CyTOF and RNAseq), while NK, DC and B cell populations fall (by CyTOF). In the bone marrow within CD8+ T lymphocyte populations, we observed a post-treatment rise in markers of degranulation (granzyme p=0.0195, perforin p=0.0078, Wilcoxon signed-rank test). This is also accompanied by a fall in PD1 expression (p=0.0078) and rise in the co-stimulatory receptor DNAM1 (p=0.0273). These changes are most marked on cells with an effector memory CD45RA+ CD8+ T cell phenotype. In the blood, similar to the bone marrow, CD8+ T cells proliferate over the course of treatment (flow cytometry). A fall in both naïve and active NK cell populations is seen following treatment in bone marrow. NK cells express high levels of CD38 and are therefore depleted by daratumumab. Those NK cells which remain have an active phenotype with increased expression of TNFa (p=0.0039) and IFNg (p=0.0195) following treatment. Across the time points sampled in peripheral blood, NK cells were also decreased and those that remained were proliferating. Dendritic cells with a tolerogenic phenotype can be identified prior to treatment and are seen to fall in abundance following treatment with durvalumab and daratumumab. Conclusions The combination of durvalumab and daratumumab leads to several immune microenvironment changes that biologically portend clinical effect. We see increases in the abundance of cell populations with functional anti-tumour activity, including granzyme B+ CD8 T cells and a reduction in PD1high T cells. Despite the treatment expectedly reducing NK cell numbers, many functionally competent NK cells remain, as evidenced by the presence of anti-tumour cytokines. This combination strategy also reduces immunosuppressive tolerogenic DCs, which suppress CD4 and CD8 T cell activity. Taken together, this suggests that this chemotherapy free, doublet treatment has the potential to up-regulate anti-tumour immunological responses, which may restore immunosurveillance mechanisms critically needed in these highly refractory patients. Disclosures Seymour: Celgene: Research Funding. Young:Celgene Corporation: Employment, Equity Ownership. Tometsko:Celgene Corporation: Employment, Equity Ownership. Cavenagh:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thompson:Celgene Corporation: Employment, Equity Ownership. Whalen:Celgene Corporation: Employment, Equity Ownership. Danziger:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene Corporation: Employment, Equity Ownership. Foy:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Gribben:Acerta Pharma: Honoraria, Research Funding; Cancer Research UK: Research Funding; TG Therapeutics: Honoraria; Roche: Honoraria; NIH: Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Pharmacyclics: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership.

Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Eytan M. Stein ◽  
Anthony Stein ◽  
Roland B. Walter ◽  
Amir T. Fathi ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Intensive Therapy ◽  
Employment Equity ◽  
Rapid Clearance ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background CD33 is expressed on the surface of myeloblasts in 85 to 90% of patients with AML and represents a promising target regardless of age, risk factors, or underlying mutational heterogeneity. SGN-CD33A is an anti-CD33 engineered cysteine antibody conjugated to an average of 2 molecules of a pyrrolobenzodiazepine (PBD) dimer, a highly potent DNA crosslinking agent. Upon binding to the cell surface, SGN-CD33A is internalized and transported to the lysosomes where PBD dimer is released within the cell through proteolytic cleavage of the linker, crosslinking DNA and leading to cell death. Methods This phase 1, open-label, 3+3 dose-escalation study (NCT01902329) is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-leukemic activity of SGN-CD33A. Eligible patients (ECOG 0-1) must have CD33-positive AML, and have either relapsed disease following initial remission (CR) of > 3 months, or have declined conventional induction/consolidation. SGN-CD33A is administered outpatient IV every 3 weeks for up to 4 cycles (Part A), followed by optional maintenance treatment for patients achieving a CR/CRi (Part B). Investigator assessment of response is per IWG criteria (Cheson 2003). Results To date, 40 patients (48% female) with a median age of 75 years (range, 27-86) have been treated. Twenty patients had relapsed AML after 1st CR with intensive therapy (3 of these had intensive frontline therapy plus 1 additional line of low intensity therapy); 20 had declined conventional intensive therapy (13 of these patients had received 1-2 prior low intensity therapies, primarily hypomethylating agents). Of the patients enrolled, 45% had underlying myelodysplasia and most had disease with intermediate (70%) or adverse (18%) cytogenetic risk, 8% with mutated NPM1 (without FLT3 mutation) and 13% with mutated FLT3. Dose levels tested were 5 mcg/kg (n=3), 10 mcg/kg (n=3), 20 mcg/kg (n=13), 40 mcg/kg (n=18), and 60 mcg/kg (n=3). To date, a maximum of 4 cycles was received in Part A and 10 cycles in Part B (total median of 2 cycles on treatment; range, 1-13 cycles). Thirteen patients remain on treatment and enrollment is ongoing. Two dose-limiting toxicities have been reported, a Grade 3 pulmonary embolism (20 mcg/kg) and a Grade 4 hypocellular marrow (>28 days; 40 mcg/kg). The only Grade 3 or higher adverse event (AE) reported in >10% of patients was febrile neutropenia (55%). Other treatment-emergent AEs regardless of relationship to study treatment reported in ˃10% of patients were fatigue (48%), diarrhea (20%), constipation (18%), cough (18%), dyspnea (18%), epistaxis (18%), peripheral edema (18%), malaise (15%), hypokalemia (13%), and pleural effusion (13%). The 30-day mortality was 2.5%, with no treatment-related deaths occurring during that time; 1 elderly patient died from a traumatic fall unrelated to SGN-CD33A. Blast clearance in marrow was obtained in 16 of 38 efficacy evaluable patients (42%) across all dose levels. A dose-response relationship is evolving with rapid and marked decreases in bone marrow blasts at 40 and 60 mcg/kg in 19 of 21 patients (Figure 1). Of 17 efficacy evaluable patients treated at 40 mcg/kg, 8 experienced clearance of marrow blasts; these patients achieved a best clinical response of CR (2), CRi (3), and morphologic leukemia-free state (mLFS; 3) thus far. In addition, complete remissions were observed at 5 mcg/kg (1 CR), 10 mcg/kg (1 CRi), and 20 mcg/kg (2 CRis). Preliminary PK data demonstrated rapid clearance of ADC, suggesting target-mediated disposition. Plasma ADC exposure generally increased with increasing dose levels. Conclusions A MTD for SGN-CD33A is not yet identified and enrollment continues. AEs observed were generally manageable, often associated with underlying myelosuppression. To date, SGN-CD33A has demonstrated antileukemic activity with 47% achieving blast clearance at the 40 mcg/kg dose level. The observed low 30-day mortality (2.5%) and rapid clearance of marrow blasts in patients with poor risk factors (median age 75, predominantly intermediate and adverse cytogenetic risk, and 45% underlying myelodysplasia) with outpatient administration are encouraging. Enrollment is ongoing to further define optimal dose and schedule. In addition, combinations of SGN-CD33A with standard AML and MDS agents will be evaluated. Figure 1: Bone Marrow Blasts Over Time Figure 1:. Bone Marrow Blasts Over Time Disclosures Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy. Off Label Use: SGN-CD33A is an investigational agent being studied in patients with AML. SGN-CD33A is not approved for use. Stein:Seattle Genetics, Inc.: Research Funding. Walter:Seattle Genetics, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding. Fathi:Exelixis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Lancet:Seattle Genetics, Inc.: Consultancy, Research Funding. Kovacsovics:Seattle Genetics, Inc.: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Erba:Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Research Funding.

The Bruton Tyrosine Kinase (Btk) Inhibitor ACP-196: Marked Activity in Relapsed/Refractory CLL with a Favorable Safety Profile

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 831-831
Author(s):  
John C. Byrd ◽  
William Wierda ◽  
Jeffrey Jones ◽  
Susan O'Brien ◽  
Jennifer R. Brown ◽  
...  
Keyword(s):  
High Risk ◽  
Safety Profile ◽  
Research Funding ◽  
Response Rate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Grade 3 ◽  
Favorable Safety

Abstract Introduction Btk is a kinase involved in B-cell receptor (BCR) signal transduction and a critical target in chronic lymphocytic leukemia (CLL). ACP-196-a potent, second generation Btk inhibitor that is more selective than the first-in-class Btk inhibitor, ibrutinib (Covey AACR2015)-has demonstrated antitumor activity in preclinical CLL models (Niemann AACR2014). Here, we present preliminary data from patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL) enrolled in an ongoing Phase 1/2 study of single-agent ACP-196 (ClinicalTrials.gov NCT02029443). Methods and Patients This first-in-human study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and efficacy of orally administered ACP-196 in patients with R/R CLL/SLL. Patients were continuously treated with ACP-196 at dosages ranging from 100 to 400 mg once daily (QD) as part of the dose-escalation portion of the study (4 cohorts of 6-8 patients per cohort), and 100 mg twice daily (BID) and 200 mg QD as part of the expansion portion of the study (2 cohorts). Of note, CLL patients with any degree of pancytopenia and prior exposure to PI3K inhibitors were allowed. CLL responses were investigator assessed per IWCLL criteria (modified Hallek 2008). SLL responses were investigator assessed per IWG criteria (Cheson 2007). Patients had a median age of 62 years (range 44-84), bulky lymph nodes ≥ 5 cm (47%) and median of 3 prior therapies (1-13). High-risk prognostic factors included del(17)(p13.1) 31% (18/58), del(11)(q22.3) 29% (17/58) and unmutated IGVH genes 75% (38/51). Results Results are presented through 01 June 2015 for the first 61 R/R patients, including 60 evaluable for response. The median time on study (N=61) was 10.3 (0.5-15.9) months. ACP-196 has been well tolerated with 93% (57/61) of patients continuing on study drug. Of the 4 patients who discontinued, 1 patient each discontinued due to withdrawal of consent, physician decision, unrelated AE (pre-existing, active autoimmune hemolytic anemia) and related AE (Grade 3 dyspnea). To date, no dose-related effect has been observed in frequency or severity of AEs or serious adverse events. No dose-limiting toxicities have occurred, and most AEs were Grade ≤ 2. The most common Grade 1/2 AEs (≥ 15%) were headache (39%), diarrhea (33%) and URI (16%). Grade 3/4 AEs that occurred in ≥ 3 patients were anemia (7%), pneumonia (7%) and hypertension (5%). No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome or pneumonitis have occurred suggesting an improved safety profile compared with other BCR and BCL-2-targeted therapies. Clinical activity has been observed in patients with R/R CLL/SLL at all doses evaluated. All patients experienced rapid reductions in lymphadenopathy. Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients. In general, lymphocytosis peaked at a median of 3 weeks and resolved by a median of 19 weeks (range 1 to 58 weeks). The rapid decrease in lymphadenopathy and treatment-related lymphocytosis along with concurrent improvement in baseline cytopenias has led to a high proportion of partial responses (PRs) early in treatment (Figure 1). Best overall response rate including PR and PR with lymphocytosis (PR+L) was 93% (PR=70%, PR+L=23%, SD=7%, PD=0%). For patients with del(17)(p13.1), the response rate was 100% (PR=72%, PR+L=28%). In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%). To date, no disease progression or Richter's transformation has occurred (Figure 2). Pharmacokinetic results showed exposure of ACP-196 was dose proportional with no drug accumulation. At dosages as low as 100 mg QD, pharmacodynamic results showed low intra-patient variability, high Btk occupancy (> 90% over 24 hr) and high phospho-Btk inhibition (> 90% over 24 hr). Conclusion ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile. Responses occur early in treatment with no disease progression to date either in heavily pretreated patients or those with high-risk prognosis factors. ACP-196 is currently in Phase 3 trials for TN (ClinicalTrials.gov NCT0247568) and R/R high-risk CLL (ClinicalTrials.gov NCT02477696). Disclosures Byrd: Acerta Pharma BV: Research Funding. Jones:Acerta Pharma BV: Research Funding. O'Brien:Acerta Pharma BV: Research Funding. Schuh:Acerta Pharma BV: Research Funding. Hillmen:Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Acerta Pharma BV: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stephens:Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Ghia:Pharmacyclics: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Acerta Pharma BV: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Acerta Pharma BV: Research Funding. Chaves:Acerta Pharma BV: Research Funding. Barrientos:Acerta Pharma BV: Research Funding. Wang:Acerta Pharma BV: Employment, Equity Ownership. Huang:Acerta Pharma BV: Employment, Equity Ownership. Covey:Acerta Pharma BV: Employment, Equity Ownership, Patents & Royalties. Navarro:Acerta Pharma BV: Employment, Equity Ownership. Rothbaum:Acerta Pharma BV: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties. Hamdy:Acerta Pharma BV: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Updated Study Results of CX-01, an Inhibitor of CXCL12/CXCR4, and Azacitidine for the Treatment of Hypomethylating Agent Refractory AML and MDS

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3915-3915 ◽  
Author(s):  
Eric Huselton ◽  
Amanda F Cashen ◽  
John F. DiPersio ◽  
Meagan Jacoby ◽  
Iskra Pusic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pilot Study ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Study Results ◽  
Equity Ownership ◽  
Grade 3 ◽  
Refractory Aml

Hypomethylating agents (HMAs) are standard first line therapy for patients with high risk MDS and older patients with AML. Outcomes for patients who do not respond or progress on HMAs are poor, and there are no standard treatment options for these patients. The interaction between leukemic blasts and the bone marrow microenvironment is thought to play an important role in disease pathogenesis and possibly chemotherapy resistance, so we hypothesized that blocking the CXCL12/CXCR4 axis with CX-01 may improve response rates to azacitidine in patients who have failed HMA therapy. CX-01 is a low molecular weight heparin derivative with minimal anticoagulant activity that binds CXCL12 as well as neutralizes PF4, a negative regulator of megakaryopoiesis. We report updated study results of a single institution a pilot study (NCT02995655) that enrolled patients with HMA-refractory (received 4 or more cycles of HMA without response or disease progression on HMA therapy) AML or MDS (INT-1 or greater). Patients received 7 day continuous infusion of CX-01 (0.25 mg/kg/hr) and azacitidine 75 mg/m2 daily days 1-7, in 28 day cycles. The primary objective of this trial was to assess the overall response rate (ORR). 20 patients were enrolled between May 2017 and February 2018. The median age was 74 years (range 62-88 years) and 35% were female. Nine patients had MDS and 11 had AML, with 7 patients having antecedent MDS and 2 having therapy-related AML. Half of the patients had high risk cytogenetic abnormalities and 3 had TP53 mutations. Patients had a median of 2 prior lines of therapy (range 1-3) with median of 6 prior cycles of HMA therapy (range 4-20). Only 4 patients had a confirmed response to prior HMA therapy. Of the 20 patients that were enrolled, 15 were considered evaluable for response with a bone marrow biopsy after cycle 2. Of the 5 unevaluable patients, 3 were removed from the trial before completing C1 due to transaminitis, discovery of a second primary malignancy, and an elevated PTT on day 2. One patient had grade 5 sepsis during C1, and another withdrew for unrelated reasons. As expected with azacitidine therapy in this patient population, hematologic toxicity was common with 16 instances of grade 3/4 neutropenia/leukopenia, 5 instances of grade 3/4 anemia, and 10 instances of grade 3/4 thrombocytopenia. Other common grade 3/4 adverse events were various infections (20), febrile neutropenia (13), hypertension (10), electrolyte disturbance (9), and transaminitis (3). Mild prolongations in PTT (22) and INR (7) were common, and there was one instance of grade 3 PTT prolongation, two instances of grade 3 epistaxis, and one instance of grade 3 hematuria. The incidences of bleeding were not thought related to CX-01 infusion. The 15 evaluable patients received a median of 3 cycles of CX-01 and azacitidine (range 2-9). Of 15 evaluable patients, there was 1 CR and 3 bone marrow CRs (mCR, with incomplete blood count recovery), 9 stable disease, and 2 progressive disease for an ORR of 27%. Of the 3 patients with a mCR after cycle 2, two had hematologic improvement of their neutrophil and platelet counts, respectively, by the end of cycle 4. A patient with stable disease also had hematologic improvement in platelets. The median OS of evaluable patients was 221 days (95% CI 179 days-not reached) and median overall survival was not significantly different between AML patients at 221 days and MDS patients at 248 days (p = 0.8). In this pilot study we demonstrated the feasibility of treating HMA-refractory AML and MDS with CX-01 and azacitidine. While this study is limited by its small sample size, we observed higher than expected response rate and favorable OS compared to historical controls. Figure Disclosures Cashen: Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. DiPersio:Incyte: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy.

scholarly journals Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3986-3986 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Vincent Ribrag ◽  
Craig H. Moskowitz ◽  
Jean-Marie Michot ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Employment Equity ◽  
Advisory Committees ◽  
Humanized Monoclonal Antibody ◽  
Heavily Pretreated ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Like classical Hodgkin lymphoma (cHL), PMBCL frequently harbors genetic alterations of the 9p24.1 locus, leading to overexpression of the PD-1 ligands, PD-L1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in cHL. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b trial testing the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Based on its genetics, PMBCL was included as an independent cohort in this trial. Here we report the preliminary results in this patient population. Methods: The PMBCL cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) disease who have relapsed after or are ineligible for autologous stem cell transplant (ASCT). Pembrolizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or unacceptable toxicity. The primary end points are safety and antitumor activity. Response is being evaluated using computed tomography (CT) and positron emission tomography (PET) at week 12 and every 8 weeks thereafter, using IHP 2007 criteria. Other end points include complete remission (CR) rate, duration of response (DOR), and exploratory biomarker analyses. Results: As of July 23, 2015, 10 patients with R/R PMBCL with a median age of 28 (23-62) years have been enrolled in this cohort. Patients were heavily pretreated: 40% had ≥4 prior lines of therapy, and 60% had prior radiation. Six patients (60%) experienced at least 1 adverse event (AE) of any grade related to study treatment. These treatment-related AEs, all grade 1/2, were: hypothyroidism and decreased appetite (2 patients each), and diarrhea, nausea, vomiting, fatigue, edema, weight loss, and arthralgia (1 patient each). There were no grade 3-5 treatment-related AEs. Two patients experienced a serious AE (grade 3 infectious pneumonia) unrelated to study drug. No patient discontinued for toxicity. Nine patients were evaluable for response (1 discontinued treatment based on clinical progression before week 12). The objective response rate (ORR) was 44% (4/9), with 1 patient achieving a CR and 3 patients achieving a partial response. The intent-to-treat ORR was 40%. With a median follow-up of 144 days, the median DOR has not been reached (1+ to 291+) days, with all 4 responses ongoing at the time of data cutoff. Six of 10 patients have discontinued study treatment because of disease progression, and 4 patients remain on study. Conclusion: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. Those patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population. Disclosures Zinzani: Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Ribrag:Pharmamar: Honoraria, 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; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Karyopharm: Honoraria. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Snyder:Merck: Employment, Equity Ownership. Marinello:Merck: Employment, Equity Ownership. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Armand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; BMS: Research Funding.

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