scholarly journals Venetoclax in Combination with FLAG-IDA Chemotherapy (FLAG-V-I) for Fit, Relapsed/Refractory AML Patients: Interim Results of a Phase 1b/2 Dose Escalation and Expansion Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4048-4048 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Maher Albitar ◽  
Tapan M. Kadia ◽  
Kiran Naqvi ◽  
Kenneth Vaughan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Single Agent ◽  
Response Assessment ◽  
Early Mortality ◽  
Genetics Research ◽  
Best Response ◽  
Significant Difference ◽  
Phase 1B ◽  
Refractory Aml

Abstract Background: Venetoclax (VEN) is a potent and selective small molecule BCL2 inhibitor, with activity both as a single agent in relapsed/refractory AML, and in frontline combinations with hypomethylating agents and low-dose cytarabine. The ability of VEN to reduce the apoptotic threshold indicates it may be effective in combination with genotoxic agents which induce apoptosis, such as the FLAG-IDA regimen. Objectives: A Phase 1b/2 clinical trial was designed to assess the safety and efficacy of VEN in combination with FLAG-IDA induction/consolidation. The primary safety endpoint was the overall incidence and severity of adverse events by CTCAE criteria. The primary efficacy endpoint was ORR by modified IWG AML criteria, and defined as CR, CRi, and PR. Secondary analyses include duration of response (DOR) and overall survival (OS), and exploratory analyses include gene expression signatures by RNA sequencing. Methods: Eligibility for the Phase 1b portion includes medically fit, relapsed/refractory (R/R) AML patients of any age with adequate organ function and ECOG PS ≤ 2. Patients receive FLAG-IDA induction/consolidation, in combination with VEN orally daily. FLAG-IDA induction for R/R AML consists of fludarabine 30 mg/m2 IV days 2-6, cytarabine 2 g/m2 IV days 2-6, idarubicin 6 mg/m2 IV days 4-6, and filgrastim 5 mcg/kg daily days 1-7 (or peg-filgrastim 6 mg after day 5 to replace remaining injections). The first cohort (dose -1) received FLAG-IDA with VEN 200 mg on days 1-21 of induction, incorporating a 2-day VEN dose ramp up. After the observation of gram-negative bacteremia and/or sepsis in 5 of the first 6 patients during cycle 1 nadir, an amended dose level -1 induction was designed with VEN 200 mg on days 1-14 and cytarabine 1.5 g/m². After completion of induction/consolidation, single-agent VEN at 400 mg orally continuously is provided as maintenance for patients not proceeding to SCT. The data cutoff for this analysis was 7.26.2018. Results: Twelve patients with a median age of 49 years (range 32 - 72) have been enrolled. All patients had relapsed/refractory AML with a median of 2 (range 1 - 4) prior treatments, and four (33%) patients had received ≥1 prior allogeneic SCT. Six patients (50%) had complex cytogenetics, 3 (25%) were intermediate risk, and 3 (25%) were favorable risk. Additional demographics including molecular annotation at study enrollment are provided in Table 1. The median number of FLAG-IDA + VEN cycles received is 2 (0.5 - 3). Severe adverse events regardless of causality were neutropenic fever/bacteremia (n=5), pneumonia/lung infection (n=4), sepsis (n=4), typhlitis (n=1), and hypotension (n=2). All cases of sepsis occurred in the original dose -1 cohort. No early mortality was observed on study (30-d and 60-d mortality 0%). Of 12 patients, one remains too early for response assessment. Of 11 patients, 8 patients (73%) achieved a best response of CR/CRi (7 CR, 1 CRi). Seven patients attained a best response within the first induction cycle, and one attained blast reduction after cycle 1 followed by CR after re-induction. Median time to ANC recovery > 500/ul in responding patients was 28 days (range 23 to 33 days). Of the 8 responding patients, three patients proceeded to allogeneic SCT, 2 remain on study, 2 patients relapsed, and 1 patient died in CR. Figure 1 depicts OS and DOR. With a median follow-up time of 4 months to date, median DOR has not been reached and the 6-month OS is 67%. NGS evaluation of RNA at pre-treatment and end of cycle 1 (EOC1) timepoints demonstrated no significant difference in BCL2 expression, either before/after therapy per patient, or based on clinical response. In patients who failed to achieve CR/CRi, significantly lower EOC1 expression (p=0.05) of BAX, BCLXL, BCL10, BCL2A1, BCL3, BCL9, TRS1, and TP53 was identified. Additionally, increased MCL1 expression at EOC1 was significantly (p=0.04) associated with relapse. Conclusion: FLAG-IDA chemotherapy with venetoclax demonstrates notable activity in a heavily pre-treated and R/R yet medically fit patient population. Neither prolonged cytopenias nor early mortality was observed. The ongoing Phase 1b portion aims to establish the best VEN dose in combination with intensive chemotherapy, to be followed with a Phase 2 portion with treatment arms for both newly diagnosed and R/R AML patients. Disclosures DiNardo: Medimmune: Honoraria; Bayer: Honoraria; Karyopharm: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy. Albitar:Neogenomics Laboratories: Employment. Kadia:Abbvie: Consultancy; Jazz: Consultancy, Research Funding; BMS: Research Funding; BMS: Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding. Ravandi:Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Konopleva:Stemline Therapeutics: Research Funding.

Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 639-639 ◽  
Author(s):  
Jeffrey A. Jones ◽  
Jennifer Woyach ◽  
Farrukh T. Awan ◽  
Kami J. Maddocks ◽  
Thomas Whitlow ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Objective Response ◽  
Response Assessment ◽  
Phase 2 ◽  
Advisory Committees ◽  
Once Daily ◽  
Phase 1B

Abstract BACKGROUND Venetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination. METHODS Patients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14. RESULTS Twelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200). CONCLUSIONS G, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. Table. Table. Disclosures Jones: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3024-3024 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
David Samuel diCapua Siegel ◽  
Seema B. Singhal ◽  
Jeffrey R. Infante ◽  
Edward A. Sausville ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Response Assessment ◽  
Phase 2 ◽  
Peripheral Blood Mononuclear ◽  
Phase 1B

Abstract Abstract 3024 Background: Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods: This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results: To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table. Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions: In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial. Disclosures: Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

scholarly journals Results of a Phase 1, Dose-Escalation Study of FF-10501-01 in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) or Hypomethylating Agent (HMA)-Resistant Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1438-1438 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Michael R. Kurman ◽  
Courtney D. DiNardo ◽  
Naveen Pemmaraju ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Adverse Events ◽  
Oral Mucositis ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Blood Concentrations ◽  
Genetics Research ◽  
Refractory Aml

Abstract Introduction FF-10501-01 is an orally bioavailable potent inhibitor of inosine-5-monophosphate dehydrogenase (IMPDH). In vitro, FF-10501-01 reduced the proliferation of multiple human-derived myeloid leukemia parent and hypomethylating agent (HMA)-resistant cell lines in a concentration dependent manner. Incubation of cells with FF-01501-01 also reduced intracellular pools of GMP, GDP and GTP, and this effect was reversed by addition of guanosine, demonstrating that the effect was due to inhibition of IMPDH. FF-10501-01 was evaluated in a Phase 1 clinical trial in patients with relapsed/refractory AML and HMA-resistant MDS and results are presented below. Methods This was an open-label, single-institution, Phase 1, dose escalation study in patients with refractory AML and MDS, or in patients with AML > 60 years of age not eligible for other treatment. The study was conducted as a "3+3" design. The objectives of the study were to describe the adverse event profile, pharmacokinetics, pharmacodynamics, recommended Phase 2 dose (RP2D) and preliminary efficacy of FF-10501-01. Oral FF-10501-01 was administered in escalating doses ranging from 50 - 500 mg/m2 twice daily (BID) for periods of 14, 21 or 28 days in a 28-day treatment cycle and dose escalation to the next dose cohort was governed by the decision of a safety review committee. The pharmacokinetics of FF-10501-01 and its primary active metabolite were determined by measuring blood levels at various times after administration; pharmacodynamics were based on measurements of xanthine monophosphate (XMP) at various time points. The institutional review board of the participating institution approved the protocol and all protocol amendments, and all patients provided written informed consent. Results Thirty-seven patients were treated with FF-10501-01. Most (78%) of patients had AML; the median age of all patients was 78 (range: 58 - 88). All patients had received prior therapy (median number 3, range: 1 - 6) and 3 patients had undergone stem-cell transplantation. FF-10501-01 was well tolerated; the most frequently observed treatment-emergent related adverse events were fatigue (22%), diarrhea (11%), nausea (11%) and oral mucositis (8%). Of all adverse events reported, only 3 were Grade 3 in severity (one episode each of neutropenia, thrombocytopenia and oral mucositis); all others were Grade 1 or 2. The RP2D was determine to be 400 mg/m2 given for 21 days every 28 days. In the MDS cohort, 1 of 8 evaluable patients demonstrated a complete bone marrow response that persisted for 19 months and 3 of 24 evaluable patients with AML demonstrated partial responses; in 1 of these patients, the response persisted for 31 months. One additional patient with AML continued treatment with FF-10501-01 for 14 months without evidence of progression. FF-10501-01 displayed dose proportional pharmacokinetics with no evidence of drug accumulation; mean steady-state observed half-lives ranged from 3 - 9 hours. Blood concentrations of XMP were variable between subjects as a function of dose and time. Following a single administration of FF-10501-01, on average, there appeared to be a reduction in XMP from baseline and maximum inhibition of pre-dose blood concentrations of XMP were consistently near or above 50% following the first administration of FF-10501-01. Conclusion FF-10501-01, was well tolerated and demonstrated evidence of efficacy in a heavily pre-treated population of patients with AML and MDS. FF-10501-01 had predictable pharmacokinetics and pharmacodynamic testing verified its mechanism of action as an IMPDH inhibitor. FF-10501-01 in combination with other agents, is currently undergoing additional clinical testing. Disclosures Kurman: Fujifilm Pharmaceuticals USA, Inc.: Consultancy. DiNardo:Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria. Madden:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Maier:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Iwamura:Fujifilm Corporation: Employment.

A Phase 1b/2 Study of Prolonged Infusion Carfilzomib in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma: Updated Efficacy and Tolerability From the Completed 20/56mg/m2 Expansion Cohort of PX-171-007

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2930-2930 ◽  
Author(s):  
Kyriakos P Papadopoulos ◽  
Peter Lee ◽  
Seema Singhal ◽  
Joseph R. Holahan ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Safety Data ◽  
Advisory Committees ◽  
Best Response ◽  
Phase 1B ◽  
Expansion Cohort

Abstract Abstract 2930 Background: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In patients with multiple myeloma (MM), single-agent carfilzomib shows activity with an acceptable safety and tolerability profile when administered IV over a period of 2–10 minutes at doses up to 27 mg/m2. Based on preclinical safety data that a slower infusion was better tolerated than a 2- to 10- minute infusion, the Phase 1b/2 PX-171-007 was designed to evaluate a 30-minute infusion of carfilzomib using a modified stepped-up dosing regimen. Preliminary data of encouraging activity and an acceptable safety profile have been previously reported from the dose-escalation phase, where a maximum tolerated dose (MTD) of 56 mg/m2 was initially established. Here we report the updated results from this study, including interim efficacy and safety data of the complete 56 mg/m2 dose-expansion cohort. Methods: Carfilzomib was given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). C1 D1–2 doses were 20 mg/m2, followed by escalation to a higher dose of either 36, 45, 56, or 70 mg/m2. Dexamethasone as premedication to mitigate infusion-related reactions (4 mg for ≤45 mg/m2, 8 mg for >45 mg/m2) was given prior to infusion. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Pharmacokinetic and pharmacodynamic analyses were performed on samples obtained at C1D1 and C2D1. Safety assessments included incidence, severity, and duration of adverse events (AEs). Subjects were evaluated for dose-limiting toxicity (DLT) according to the Common Terminology Criteria for Adverse Events v 3.0. Results: A total of 33 patients were enrolled (4 at 36 mg/m2; 3 at 45 mg/m2; 24 at 56 mg/m2; 2 at 70 mg/m2). Patients had received a median of 5 (range 1–9) prior treatment regimens. The median duration of carfilzomib treatment is 4 cycles (range 1–17); 5 patients went on to receive ≥10 cycles, reinforcing carfilzomib tolerability at higher doses. DLTs occurred in 2 patients treated at 70 mg/m2, with both patients able to continue carfilzomib at reduced doses (1 patient reduced to 56 mg/m2 achieved a PR, ongoing into cycle 12). Best response to carfilzomib is detailed in the table. The 56 mg/m2 cohort had an ORR of 60%, with 1 patient achieving sCR, 4 patients achieving VGPR, and 7 patients attaining PR, as assessed by the investigator. Three patients remain active at this dose, with best response of 1 VGPR, 1 PR, and 1 SD. The majority of the AEs in the 20/56 mg/m2 cohort were G1-2 in severity with the exception of anemia and thrombocytopenia. The most common AEs, irrespective of relationship to carfilzomib, in this cohort were dyspnea (54%), fatigue (54%), nausea (54%), pyrexia (54%), anemia (38%), chills (38%), hypertension (38%), and thrombocytopenia (38%). There was 1 report of G1 peripheral neuropathy (4%) in this cohort. Additionally, the most common ≥G3 AEs in this group were thrombocytopenia (38%), anemia (21%), and hypertension (13%). Five patients (21%) treated at 20/56 mg/m2 required dose reductions. Pharmacodynamic analysis demonstrated inhibition of proteasome chymotrypsin-like activity in peripheral blood mononuclear cells of >80% at 20 mg/m2 and ≥95% at ≥56 mg/m2. Carfilzomib at 56 mg/m2 inhibited all 3 subunits of the immunoproteasome, resulting in ∼78% inhibition in total activity. Conclusions: The 20/56 mg/m2 dose for carfilzomib administered as a 30-minute IV infusion was associated with 60% ORR, noteworthy for a late-line, heavily pretreated patient population. The dose group additionally reported an acceptable safety profile (with 1 patient reporting G1 neuropathy), supporting the pre-clinical finding that longer infusion time enables higher dose and achieves greater levels of proteasome inhibition. Disclosures: Papadopoulos: Proteolix: Consultancy, Research Funding; Onyx Pharmaceuticals: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Holahan:Onyx Pharmaceuticals: Consultancy, Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Hannah:Onyx Pharmaceuticals: Consultancy. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 1b Study Investigating the Combination of the Tetravalent Bispecific NK Cell Engager AFM13 and Pembrolizumab in Patients with Relapsed/Refractory Hodgkin Lymphoma after Brentuximab Vedotin Failure: Updated Safety and Efficacy Data

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1620-1620 ◽  
Author(s):  
Nancy L. Bartlett ◽  
Robert W. Chen ◽  
Eva Domingo-Domenech ◽  
Andres Forero-Torres ◽  
Ramon Garcia-Sanz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Nk Cells ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Nk Cell ◽  
Single Agent ◽  
Brentuximab Vedotin ◽  
Advisory Committees ◽  
Phase 1B

Abstract Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.

scholarly journals A Phase 1b Study of Vadastuximab Talirine As Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 340-340 ◽  
Author(s):  
Jay Yang ◽  
Farhad Ravandi ◽  
Anjali Advani ◽  
Sumithira Vasu ◽  
Roland B. Walter ◽  
...  
Keyword(s):  
Research Funding ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Genetics Research ◽  
Laboratory Services ◽  
Leukemic Relapse ◽  
Phase 1B ◽  
Equity Ownership ◽  
To Receive

Abstract Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3]), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Dinaciclib (SCH 727965) and Ofatumumab for the Treatment of Relapsed and Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Results of a Phase 1b/2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 329-329 ◽  
Author(s):  
Jeffrey Alan Jones ◽  
Susan Geyer ◽  
Leslie A. Andritsos ◽  
Farrukh Awan ◽  
Joseph M Flynn ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Research Funding ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Response Rates ◽  
Abnormal Karyotype ◽  
High Risk Disease ◽  
Phase 1B ◽  
Grade 3

Abstract BACKGROUND: Despite recent advances in the treatment of relapsed/refractory (R/R) CLL/SLL, patients (pts) with genetically high-risk disease, particularly complex abnormal karyotype and deletion(17p), continue to demonstrate inferior survival. Dinaciclib, a selective inhibitor of cyclin-dependent kinases (CDKs), has demonstrated activity in high-risk CLL/SLL. In an effort to improve response rates and reduce the risk for hyperacute tumor lysis syndrome (TLS), we conducted a NCI-sponsored phase 1b/2 study (NCI 9268) to characterize the safety and efficacy of dinaciclib when given in combination with the anti-CD20 monoclonal antibody ofatumumab. METHODS: Pts with CLL/SLL R/R after ≥1 prior therapy, age ≥ 18 years, ECOG ≤ 2, and retained end-organ function received ofatumumab according to the approved dose and schedule (weekly x 8, monthly x 4) starting on Cycle 1 Day 1. Dinaciclib was administered as a 2-hour infusion on days 1, 8, and 15 of a 28-day cycle beginning on Cycle 2 Day 1 and continued for up to 6 cycles. Pts could then continue single-agent dinaciclib indefinitely at MD discretion. During the phase 1b portion of the study, 3 pts were treated with 7 mg/m2 on Day 1 escalated to 10 mg/m2 on Day 8 (DL1); 3 additional phase 1b pts and all pts enrolled to the phase 2 were escalated to 14 mg/m2on Day 15 (DL2). All pts received aggressive hydration and pre-medication prior to dinaciclib to prevent TLS, peg-filgrastim on Day 16 of Cycles 2-7, and required antimicrobial prophylaxis (val-/acyclovir, ciprofloxacin, and TMP/SMX). Response was assessed with CT imaging according to IWCLL 2008 criteria at the end of cycle 1, after odd-numbered cycles, and every 3 months during follow-up. RESULTS: As of 30 July 2014, 36 pts (DL1 n = 4; DL2 n=32) have been treated: median age 62.5 years (range 35-80), 13 (36%) female, ECOG ≤1 in 32 (89%), and median number prior therapies was 2 (range 1-5). Del (17p) was present in 25 pts (69%), del (11q) in 16 (44%), and complex abnormal karyotype in 15 (42%). No dose limiting toxicities were observed in the phase 1b portion of the study. The most common grade ≥ 3 adverse events (without regard to attribution) included hyperglycemia in 5 pts (16%), hypocalcemia in 4 (13%), hypophosphatemia in 13 (41%), leukopenia in 12 (37%), anemia in 11 (34%), and thrombocytopenia in 9 (28%). Neutropenia was common (18% grade 3, 47% grade 4), but grade ≥ 3 infections were rare (1 pleural, 5 lung, 2 sepsis). Only 1 pt with highly proliferative disease refractory to both ibrutinib and IPI-145 developed TLS, which was further complicated by grade 5 sepsis. Pts have received a median 4 cycles (range 1-12), and 4 pts (11%) remain on treatment. Reasons for discontinuation are listed in the table. Best protocol response of partial response was recorded for 12 pts (33%), and an additional 20 (56%) patients achieved stable disease. Responses were observed in all genetic subgroups and deepened with continued dinaciclib treatment (see table). Estimated median PFS was 10.4 months (95%CI 8.2-12.2 months) and median overall survival (OS) had not been reached (95%CI 13.2-NR). CONCLUSIONS: Dinaciclib can be safely administered with ofatumumab to pts with R/R CLL/SLL. Serious non-hematologic adverse events are infrequent, and supportive measures help limit infectious complications. Initiating treatment with ofatumumab, stepwise dose escalation of dinaciclib, and rigorous prophylaxis abrogate the risk for TLS. These results confirm the activity of dinaciclib in a population enriched for genetically high-risk CLL/SLL. Responses improved with continued therapy, and discontinuation prior to best response likely impacted observed response rates. Further study of dinaciclib in combination with novel monoclonal antibodies and/or other kinase inhibitors is warranted, particularly in genetically high-risk disease. Table Reason for Discontinuation n=36 (%) Completed planned therapy 13 (41) Adverse event/complication 6 (19) Disease progression 6 (19) Alternative therapy 3 (9) Death on study 2 (6) Other 2 (6) Best Protocol Response to Date n=36 (%) PR 12 (33) SD 20 (56) PD 2 (6) IE 1 (3) Cycle 2 Response n=34 (%)* PR 0 SD 32 (94%) PD 2 (6) Cycle 4 Response n=23 (%) PR 5 (22) SD 18 (78) PD 0 Cycle 6 Response n=15 (%) PR 11 (73) SD 4 (27) PD 0 *1 pt with probable PD discontinued during Cycle 1 Disclosures Off Label Use: Dinaciclib is an investigational agent made available through NCI/CTEP. Awan:Boehringer Ingelheim: Consultancy; Lymphoma Research Foundation: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Byrd:Pharmacyclics: Research Funding.

scholarly journals Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1357-1357 ◽  
Author(s):  
Hannah Asghari ◽  
Dasom Lee ◽  
Yehuda E. Deutsch ◽  
Onyee Chan ◽  
Najla Al Ali ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
Initial Therapy ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Significant Difference ◽  
Frontline Therapy ◽  
Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

scholarly journals Baseline Hypoalbuminemia Does Not Appear to be an Adverse Prognostic Factor in Patients with Relapse/Refractory B-Cell Lymphomas Treated with Axicabtagene Ciloleucel (axi-cel)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5343-5343
Author(s):  
Megan Melody ◽  
Sangeetha Gandhi ◽  
Zaid Abdel Rahman ◽  
Paula A Lengerke Diaz ◽  
Nicole Gannon ◽  
...  
Keyword(s):  
Serum Albumin ◽  
B Cell ◽  
Mayo Clinic ◽  
Research Funding ◽  
Response Rate ◽  
Normal Serum ◽  
Advisory Board ◽  
Genetics Research ◽  
Significant Difference

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Use of Medium Potency Statins Is Associated with Improved Outcomes after Frontline RCHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-45
Author(s):  
Sushanth Gouni ◽  
Paolo Strati ◽  
Jason Westin ◽  
Loretta J. Nastoupil ◽  
Raphael E Steiner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Research Funding ◽  
Response Assessment ◽  
Cholesterol Content ◽  
In Vivo Studies ◽  
High Cholesterol ◽  
Improved Outcomes ◽  
Significant Difference

Background: Pre-clinical studies show that statins may improve the efficacy of chemoimmunotherapy in patients with DLBCL, through interference with cell membrane-initiated signaling pathways. Clinical retrospective studies, however, yield conflicting data, due to heterogeneous properties of statins, including potency and hydrophilicity. Methods: This is a retrospective analysis of patients with previously untreated, advanced stage DLBCL, non-double hit, treated with frontline R-CHOP between 01/01/2000 and 09/01/2019 (data cut-off 04/15/2020) at MD Anderson Cancer Center, and for whom data regarding statin use at time of initiation of treatment were available. Lugano 2014 response criteria were applied retrospectively for response assessment. Cellular cholesterol levels were analyzed in 6 DLBCL cell lines using an Amplex red fluorometric assay. A doxorubicin (DXR)-resistant cell line was generated exposing SUDHL4 cells to escalating doses of DXR; a DXR-resistant DLBCL patient-derived xenograft (PDX) model was established through serial transplantation and exposure to DXR. Results: 271 patients were included in the analysis, 182 (67%) were older than 60 years, 134 (49%) were male, 212 (72%) had stage IV disease, and 217 (80%) had an IPI score &gt; 3; upon pathological review, 38 (36%) cases were non-GCB type, and 18 (28%) were double-expressors; 214 (79%) were able to complete all planned 6 cycles of RCHOP. Seventy-nine (29%) patients received statins at time of initiation of chemoimmunotherapy: 15 patients received low potency statin, 51 medium and 13 high; 18 patients received hydrophilic statins and 61 lipophilic. Patients receiving statins were significantly older as compared to patients who did not (p&lt;0.001); no other significant difference in baseline characteristics was observed when comparing the 2 groups. Overall, 265 out of 271 patients were evaluable for response, as 6 stopped treatment because of toxicity before first response assessment. Among these, ORR was 95% (252/265) and CR rate was 62% (165/265). ORR rate was identical in patients who were treated with statin and those who did not (95% both, p=1). After a median follow-up of 77 months (95% CI, 70-84 months), 119 patients progressed/died, median PFS was not reached and 6-year PFS was 57%. 6-year PFS rate according to statin intensity was: 48% (low), 72% (medium), 57% (high). PFS. 6-year PFS rate was 64% for hydrophilic and 72% for lipophilic statins. Patients treated with statins had a trend for longer PFS (p=0.06), significantly longer for patients receiving medium potency statins (p=0.04). No significant difference in PFS was observed when comparing patients treated with lipophilic statins to all others (not reached vs 84 months, p=0.22). To confirm these clinical data, in-vitro and in-vivo studies were performed. Six cell lines were tested: 4 with high cholesterol content (SUDHL4, HBL1, HT, and U2932; 5.0-8.0 µg/mg protein), and 2 with low cholesterol content (DOHH2 and OCI-LY19; 1.5-2.0 µg/mg protein); the latter showed the highest sensitivity to DXR-mediated killing. The combination of lovastatin and DXR (10nM) was tested in all 4 cell lines with high cholesterol content, resulting in more cell death than either treatment alone. Lovastatin (at the nanomolar range) resensitized DXR-resistant SUDHL4 cells to DXR. Finally, in a DXR-resistant PDX model, the combination of lovastatin and DXR resulted in delayed tumor growth as compared to chemotherapy alone. Conclusions: Use of medium potency statins is associated with improved outcomes after frontline RCHOP in patients with DLBCL. This was further confirmed in functional in-vitro and in-vivo studies. Future interventional studies, aimed at improving outcomes in these patients using this novel combination, are warranted. Disclosures Westin: Amgen: Consultancy; 47: Research Funding; Kite: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding. Nastoupil:Gamida Cell: Honoraria; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria. Neelapu:Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Karus Therapeutics: Research Funding; N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Calibr: Other; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding. Landgraf:NCI/NIH: Research Funding. Vega:NCI: Research Funding.

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