scholarly journals Phase I Results of a Multicenter Clinical Trial Combining Guadecitabine, a DNA Methyltransferase Inhibitor, with Atezolizumab, an Immune Checkpoint Inhibitor, in Patients with Relapsed or Refractory Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1811-1811 ◽  
Author(s):  
Casey L. O'Connell ◽  
Patricia L. Kropf ◽  
Nathan Punwani ◽  
Dan Rogers ◽  
Richard Sposto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Chronic Myelomonocytic Leukemia ◽  
Multicenter Clinical Trial ◽  
Advisory Committees ◽  
Level 1 ◽  
Myelomonocytic Leukemia

Abstract Background: There are no FDA-approved therapies for patients with myelodysplastic syndrome (MDS) in whom hypomethylating agents (HMAs) fail, and mechanisms of resistance are not well-characterized. Preclinical and clinical data suggest that some myeloblasts express PDL-1 and that HMAs can induce expression of PD-1 on T cells, which may result in resistance through immune tolerance. We hypothesized that the addition of the PDL1-inhibitor atezolizumab to guadecitabine, a next generation HMA which has a longer in vivo exposure time, would induce or restore HMA sensitivity in patients with relapsed or refractory (R/R) MDS. Overlapping toxicities were not expected given atezolizumab is not myelosuppressive and guadecitabine does not appear to induce autoimmune or inflammatory conditions. Methods: We are conducting a phase I/II, multicenter clinical trial for adult patients with R/R, intermediate (3+) or high-risk MDS by the revised international scoring system, including chronic myelomonocytic leukemia (CMML). A 3x3 dose escalation design for guadecitabine was used for Phase I, beginning with 30 mg/m2 (Dose level -1) days 1-5 along with a fixed dose of atezolizumab 840mg IV days 8 and 22 of a 28-day cycle. The plan was to escalate to the recommended dose of guadecitabine, 60mg/m2 (Dose Level 1) if no dose limiting toxicities (DLTs) were identified during Dose Level -1. If ≥2/6 DLTs were observed during the Dose Level 1, de-escalation to 45mg/m2 (Dose Level -1.5) would occur. The primary endpoint of phase I was safety and tolerability of the combination. Overall survival (OS) from the on-study date and overall response rates (ORR), based on the 2006 Modified IWG Response Criteria for MDS, were secondary endpoints. Results: Nine patients (5M, 4F, median age 73) with intermediate or higher risk were treated during phase I. Three patients were treated at Dose Level -1 and sustained no DLTs. Similarly, no DLTs were observed among 6 patients treated at Dose Level 1. There were 17 grade 3 or 4 events considered possibly or probably related to the study treatments, the most common of which were: neutropenia (4), thrombocytopenia (4), and leukopenia (4). The median number of treatment cycles was 5 and the treatment duration for each patient is illustrated in Figure 1. Two patients achieved hematologic improvement (HI) and 1 patient achieved CR. Two patients died after coming off of the study (at 4.5 and 9 months respectively) and the median OS has not been reached. Discussion: The combination of guadecitabine at the recommended dose of 60mg/m2 D1-D5 along with atezolizumab 840mg IV d8, 22 was found to be safe with an acceptable toxicity profile in patients with R/R MDS. The ORR was 33% and a phase II study is ongoing. Disclosures Kropf: Celegene: Consultancy; Takeda: Consultancy. Grønbæk:Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Pharma: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Hypomethylating Agent Therapy for Chronic Myelomonocytic Leukemia Does Not Impact Acute Myeloid Leukemia Transformation or Survival

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Sandrine Niyongere ◽  
Yamini Kathari ◽  
Zeba Singh ◽  
Emily J. Vannorsdall ◽  
Ashkan Emadi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
Institutional Research ◽  
Research Support ◽  
Advisory Committees ◽  
Clinical Trial Research ◽  
Myelomonocytic Leukemia

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with features of both myeloproliferative neoplasm and myelodysplastic syndrome (MDS). CMML is characterized by persistent blood monocytosis >1 x 109/L, bone marrow dysplasia in one or more hematopoietic cell lines, and increased risk of transformation to acute myeloid leukemia (AML). Our review of SEER Medicare data (Haematologica 2013;98:584) demonstrated that, compared to MDS, CMML has shorter overall survival (OS) and more frequent progression to AML. Hypomethylating agents (HMAs) have become standard therapy for CMML, with reported response rates of 37-69%, but their impact on AML transformation and OS is unclear. Methods: We retrospectively reviewed CMML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between January 2000 and December 2019. Clinical characteristics, treatments, AML progression, time to AML progression (TTP), and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for time-to-event data. Statistical analyses were performed using GraphPad Prism 8®. Results: We identified 71 patients with CMML, 82% male and 73% white, with a median age of 69 (range 25 - 96) years; 51% had <10% bone marrow (BM) blasts and 45% had low-risk cytogenetic findings (normal karyotype or -Y). Most patients treated prior to 2005 received hydroxyurea and/or erythropoiesis-stimulating agents or were enrolled on clinical trials, while patients treated since 2005 received HMAs as primary therapy. Median follow-up was 41.1 months. The median OS of the entire cohort was 20 months, with 46% of patients progressing to AML with a median TTP of 11.5 months. By the MD Anderson Prognostic Scoring System at time of diagnosis, CMML was low-risk in 24 patients, intermediate-1 in 16, intermediate-2 in 14, and high-risk in 17. Forty-six patients received HMAs, with an overall response rate (ORR) of 54% (complete response or partial response), while 25 patients did not receive HMAs. Patient and disease characteristics were similar in HMA- and non-HMA-treated patients (Table 1). The estimated OS of HMA-treated patients was 20 months, compared to 14 months for non-HMA-treated patients (p =0.43) (Figure 1). AML transformation occurred in 52% of patients treated with HMAs, with TTP ranging from 3 to 65 months, and in 33% patients not treated with HMAs, with TTP ranging from 5 to 47 months. Most patients receiving HMAs (63%) received ≥ 6 cycles; 46% transformed to AML despite initial response, often in a sudden and unpredictable manner. HMAs were azacitidine in 13 patients, decitabine in 24, azacitidine followed by decitabine in 4, and decitabine followed by azacitidine in 5. Five CMML patients in our cohort underwent allogenic stem cell transplantation. Four of the five relapsed with transformation to AML post transplant, and only one patient remains in remission, 9 months post transplant. Conclusions: Despite a 54% ORR, HMA treatment did not have a significant impact on frequency of AML transformation, or OS in our cohort. Based on our data, favorable response rates previously reported with HMAs and also seen in our patients do not appear to translate into decreased frequency of AML transformation or prolonged OS. Though our study is a retrospective study with inherent selection bias, our results underscore the ongoing need for novel therapies and for clinical trials for CMML patients. Disclosures Niyongere: Kartos Therapeutics: Other: Received clinical trial research support with Kartos Therapeutics ; Forty Seven: Other: Received clinical trial research support with Forty Seven. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; NewLink Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding. Doung:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial research support; Incyte: Other: clinical trial research support; Astex: Other: clinical trial research support; MedPacto: Other: clinical trial research support. Baer:Takeda: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Kite: Other: Institutional research funding; Incyte: Other: Institutional research funding; Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding.

scholarly journals Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3268-3268
Author(s):  
Martha Q. Lacy ◽  
Kah-Whye Peng ◽  
Stephen J. Russell ◽  
Amylou C. Dueck ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Tumor Burden ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: 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; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Results of Phase I Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 188-188 ◽  
Author(s):  
Arielle L Langer ◽  
Susanna Miao ◽  
Markus Mapara ◽  
Jai Radhakrishnan ◽  
Mathew S. Maurer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Primary Objective ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Amyloid Deposits ◽  
Organ Response

Abstract Background: The murine (Mu) monoclonal antibody (mAb) 11-1F4 prepared against human light-chain-related fibrils recognizes an amyloid-associated conformational epitope when administered to mice bearing human AL amyloidomas and elicits a neutrophil/macrophage response that led to rapid and complete elimination of the amyloid tumors with no evidence of toxicity in the animals. PET/CT using I-124 labeled Mu mAb 11-1F4 revealed uptake by the organs known to contain amyloid in the majority of patients studied.1,2 These results led to production of GMP-grade amyloid fibril-reactive chimeric (Ch) IgG1 mAb 11-1F4 by the NCI's Biological Resource Branch for a Phase I clinical trial in patients with AL amyloidosis. Methods: This is an open-label, dose-escalation Phase I clinical trial of Ch IgG1 mAb 11-1F4 in patients with relapsed or refractory AL amyloidosis. The trial was conducted under the auspices of an Experimental Therapeutic Investigational New Drug (IND) with a primary objective of defining the maximum tolerated dose, and tolerability and safety of Ch IgG1 mAb 11-1F4 when given as a single intravenous infusion. Secondary objectives included pharmacokinetics, safety, and organ response. Patients were eligible if they had received prior systemic therapy for relapsed or refractory AL-Amyloidosis or had declined or were ineligible for standard systemic therapy and a life expectancy of at least 3 months. Patients were excluded if they had ventricular ejection fraction less than 40 percent, an interventricular septal thickness greater than 25mm, a history of sustained ventricular tachycardiac or cardiac arrest, 24 hour creatinine clearance of less than 30cc/min, alkaline phosphatase greater than three times the upper limit of normal, or total bilirubin greater than 3.0mg/dL. A dose-escalation "up and down" design was used with 7 sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2. Results: As of July 14, 2015, dose level 6 was completed including six patients who completed the study. Two patients had primarily cardiac, 2 patients primarily skin, and 2 primarily gastrointestinal (GI) involvement. All patients tolerated the dose received and no grade 3, 4 adverse events (AE) or deaths occurred. The AE included: dose level 5, one patient with grade 1 nausea and diarrhea and at dose level 4 one patient grade 2 rash for 11 days. Skin biopsy revealed previously undiagnosed cutaneous amyloid deposits and a neutrophilic infiltrate that may represent proof of antibody binding amyloid fibrils. Though the primary objective of the trial was to evaluate safety, 3 of 6 patient had evidence of organ response (2 cardiac and 1 GI) after only one infusion of Ch IgG1 mAb 11-1F4. Conclusions: To date, Ch IgG1 mAb 11-1F4 was well tolerated by all study subjects without any adverse reactions and promising organ response after completion of 6 dose levels. Development of an AL-fibril-specific mAb treatment would be an invaluable adjunct in the treatment of patients with AL amyloidosis and lead to improved medical management of this incurable and ultimately fatal disease. Clinical Trial Information: NCT02245867 References Wall, J., Kennel, S.J., Stuckey, A.C., Long, M.J, Townsend, D.W., Smith, G.T., Wells, K.J., Fu, Y., Stabin, M.G., Weiss, D.T., and Solomon, A. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis, Blood. 116: 2241-2244, 2010.Solomon, Alan. Personal Communication. Apr 2014. Disclosures Lentzsch: Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Axiom: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Monoclonal antibody 11-1F4 is the drug under investigation in this trial as a therapy for amyloidosis. It currently has no FDA approved indication..

scholarly journals Biological and Clinical Impact of JAK2/mTOR Blockade in Gvhd Prevention: Preclinical and Phase I Trial Results

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Joseph Pidala ◽  
Kelly Walton ◽  
Hany Elmariah ◽  
Jongphil Kim ◽  
Asmita Mishra ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Acute Gvhd ◽  
Advisory Committees ◽  
Mtor Inhibition ◽  
Level 1 ◽  
Level 2

Background: Distinct from broadly acting graft-versus-host disease (GVHD) prophylaxis, JAK2 inhibition suppresses alloreactive T cells, while sparing regulatory T cells (Tregs) and graft-versus-leukemia (GVL). Early IL-6 activity via JAK2 and phosphorylated STAT3 in CD4+ T cells is associated with acute GVHD onset. In mice, we show combined JAK2/mTOR blockade synergistically prevents xenogeneic GVHD. In this first-in-human phase I/II GVHD prevention trial we combine pacritinib, a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL-6 activity. With phase I complete, we demonstrate that dual JAK2/mTOR inhibition is safe, suppresses pathogenic Th1 and Th17 cells, spares Tregs and key GVL effector cells, and exhibits preliminary activity in preventing GVHD. The primary aim of phase I was to identify the lowest biologically active dose of pacritinib (defined as < 35% of CD4+ pSTAT3+ T cells at day +21) that is safe when combined with sirolimus-based immune suppression. The preliminary activity of JAK2/mTOR inhibition in GVHD prevention was also investigated. Materials and Methods: This single-arm phase I/II trial (NCT02891603) tested the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation (alloHCT). A 3+3 dose escalation design was followed, including dose level 1 (PAC 100mg daily), level 2 (PAC 100mg twice daily), and level 3 (PAC 200mg twice daily). Clinical safety, pharmacodynamic assessments, and pharmacokinetic (PK) studies were followed during the study. Acute GVHD was scored through day +100. Patient characteristics are described in Table 1 (n=12). Allowed donor types were HLA-A, -B, -C, and -DRB1 matched-related or unrelated donors. Adequate vital organ function and Karnofsky performance status (KPS ≥ 80%) were required. Results: Dose level 2, PAC 100mg twice a day, was the lowest biologically active and safe dose, and thus the recommended phase II dose. Blood samples acquired at day +21 showed that PAC 100mg twice a day reduced the mean frequency and geometric MFI of CD4+ pSTAT3+ T cells (Figure 1A, B). Consistent with suppressed pSTAT3, PAC 100mg twice a day decreased pathogenic Th1 and Th17 cells (Figure 1C, D). pSTAT5 is critical for Tregs and effectors of GVL. PAC 100mg twice a day favored STAT5 phosphorylation in CD4+ T cells, preserved Tregs and increased the ratio of Tregs to pathogenic T helper cells, and supported CD3+ T cell and NK cell effectors (Figure 1E-J). Patients treated on dose level 2 of PAC exhibited a robust increase in Th2 cells at day +21 (29.5% v 4.87% level 1 or 4.5% baseline, P<0.001 ANOVA). Additionally, neutrophil and platelet engraftment occurred without delay (Figure 1K, L). A single dose limiting toxicity was observed in dose level I only, and consisted of angioedema possibly related to PAC. CMV reactivation or disease were not observed among patients treated at dose level 2, with only a single case of CMV reactivation among dose level 1 (8 of 12 recipients were CMV seropositive). A single patient treated on dose level 2 developed grade 4 acute GVHD and died, after prematurely discontinuing TAC for acute kidney injury and electively stopping PAC. A patient died of relapsed disease in dose level 1. To test the efficacy of dual JAK2/mTOR inhibition in vivo, NSG mice were transplanted with human peripheral blood mononuclear cells (PBMCs) and treated with either vehicle, PAC, STAT3 inhibitor S3I-201, SIR, PAC/SIR, or S3I/SIR. The combination of JAK2 or downstream STAT3 inhibition plus SIR significantly reduced xenogeneic GVHD in mice (Figure 1M) and maintained donor anti-tumor activity by CD8+ T cells (data not shown). Further, dual JAK2 or STAT3 inhibition with mTOR blockade significantly increased the induction of Tregs in mice transplanted with Treg-depleted human PBMCs (62.3% PAC/SIR or 74% S3I/SIR v 29.9-38% with vehicle or inhibitors alone, P<0.01 ANOVA). Conclusions: We demonstrate that PAC/SIR/TAC (RP2D: PAC 100mg twice a day) is safe and effectively reduces IL-6 signal transduction, pathogenic Th1 and Th17 cells, and preserves Tregs and effectors necessary for GVL and antiviral immunity. Preliminarily, adding pacritinib limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial. Disclosures Pidala: Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Sebti:Patent Pending: Patents & Royalties: Dr. Sebti has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. OffLabel Disclosure: Pacritinib and its use in GVHD prevention as part of a phase I trial

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 197-197 ◽  
Author(s):  
Koen van Besien ◽  
Justin Kline ◽  
Lucy A Godley ◽  
Richard A. Larson ◽  
Vu H. Nguyen ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Renal Toxicity ◽  
Phase Ii Study ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Grade 3 ◽  
One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

Phase Ib Study of Oral Panobinostat In Combination with 5-Azacitidine (5-aza) In Patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4957-4957 ◽  
Author(s):  
Pierre Fenaux ◽  
Daniel J DeAngelo ◽  
Guillermo Garcia-Manero ◽  
Michael Lübbert ◽  
Anand P. Jillella ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Adverse Events ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
Advisory Committees ◽  
Dose Cohort ◽  
Phase Ib ◽  
Myelomonocytic Leukemia

Abstract Abstract 4957 Background: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that causes increased acetylation of target proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preliminary evidence from phase I trials has demonstrated anti-tumor activity in patients with hematologic malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The advent of hypomethylating agents, such as 5-aza, represent a significant advancement in the treatment of MDS, chronic myelomonocytic leukemia (CMML), and AML. Although an improvement in clinical outcomes has been observed, including increased overall survival in patients with MDS, a substantial number of patients do not benefit from the therapies currently available. Preclinical studies suggest that the combination of a demethylating agent and a pan-DACi represents a rational strategy to reverse silencing of tumor suppressor genes, which contributes to the malignant phenotype, and improve outcomes in patients with MDS and AML. In this study, the combination of the pan-DACi, panobinostat, and the hypomethylating agent, 5-aza, was evaluated in patients with MDS, CMML and AML. Methods: This phase Ib, open-label, multicenter, dose-finding study is comprised of 2 stages: a dose-escalation stage to determine the maximum tolerated dose (MTD) of panobinostat in combination with standard dose 5-aza, and a subsequent expansion stage to evaluate safety, tolerability, and preliminary activity at the MTD dose level. The primary endpoint is incidence of dose-limiting toxicity (DLT) and secondary endpoints include type, duration, frequency, and relationship of adverse events (AEs) to the combination. Exploratory endpoints include clinical response and hematologic improvement according to IWG response criteria, and biomarker analysis of methylation status and expression of disease-associated genes in peripheral blood cells prior to and during therapy. Adult patients with IPSS INT-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and ≤ 30% marrow blasts who are candidates for therapy with 5-aza and have not received a prior hypomethylating agent or pan-DACi are eligible for enrollment on the trial. Oral panobinostat was administered on Days (D) 3, 5, 8, 10, 12, and 15, starting at 20 mg, in combination with 5-aza (75 mg/m2 sc D 1–7) during a 28-D cycle. Patients received treatment for ≤ 6 cycles or until progression of disease, incidence of unacceptable toxicity, or withdrawal of consent. Results: To date, 11 patients have been enrolled including 9 patients with MDS, 1 patient with AML and 1 patient with CMML. The median age of patients enrolled on the trial was 69.0 (60-80). Patients have been evaluated at 2 panobinostat dose cohorts; 6 (20 mg) and 5 (30 mg). The AE analysis is based on 9 patients (6 from 20 mg cohort and 3 from 30 mg cohort) and the nature and incidence of AEs observed in the two cohorts were similar. Adverse events regardless of study drug relationship included nausea (4 [44%]), vomiting, fatigue (5 [55%] each) and asthenia (3 [33%]). Grade 3/4 AEs suspected to be treatment related included thrombocytopenia (2 [22%], febrile neutropenia and arthritis (1 [11%] each). Serious adverse events observed included febrile neutropenia, asthenia (2 [22%] each), atrial fibrillation and septic shock (1 [11%] each). One DLT has been observed (grade 4 febrile neutropenia) in the 20 mg panobinostat dose cohort. Conclusions: Panobinostat has been well tolerated up to a dose of 30 mg in combination with 5-aza (75 mg/m2) with dose escalation ongoing. Patients are currently being enrolled at the 40mg dose cohort. The most common AEs observed included febrile neutropenia, thrombocytopenia with one DLT observed (grade 4 febrile neutropenia) in the 20mg panobinostat dose cohort. The current data show that the addition of panobinostat to 5-aza is safe with no unexpected toxicities. Updated data, including safety and preliminary efficacy data will be presented at the meeting. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Winiger: Novartis Pharma AG: Employment. Squier: Novartis: Employment. Li: Novartis: Employment. Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Carfilzomib, Lenalidomide, and Dexamethasone In Newly Diagnosed Multiple Myeloma: Initial Results of Phase I/II MMRC Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 862-862 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
Dominik Dytfeld ◽  
Sundar Jagannath ◽  
David H. Vesole ◽  
Tara B. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Level 3 ◽  
Equity Ownership ◽  
Level 1 ◽  
Level 2

Abstract Abstract 862 Background: Carfilzomib (Cfz) is a novel, irreversible proteasome inhibitor that has demonstrated promising single-agent activity and favorable toxicity profile, including very low rates of peripheral neuropathy and neutropenia in relapsed/refractory multiple myeloma (MM). Combining Cfz with Lenalidomide (Revlimid®, Len), and Dexamethasone (Dex) into CRd shows an additive anti-MM effect in preclinical studies and lack of overlapping toxicity allowing for the use of these agents at full doses and for extended duration of time in relapsed/refractory MM (Niesvizky et al, ASH, 2009). This Phase I/II study was designed to determine the maximum tolerated dose (MTD) of CRd and to assess safety and evaluate efficacy of this combination in newly diagnosed MM. Methods: In Phase I, dose escalation follows the TITE-CRM algorithm, with Cfz as the only escalating agent starting at 20 mg/m2 (level 1), maximal planned dose 27 mg/m2 (level 2), and 15 mg/m2, if needed (level -1), given IV on days 1, 2, 8, 9, 15, 16 in 28-day cycles. Len is used at 25 mg PO (days 1–21), and Dex at 40/20 mg PO weekly (cycles 1–4/5-8) for all dose levels. Based on toxicity assessment, the study was amended to add dose level 3 with Cfz at 36 mg/m2 and the number of pts in the Phase I was increased to 35. A total of 36 pts are planned to be treated at the MTD in Phase I/II. Pts who achieve ≥ PR can proceed to stem cell collection (SCC) and autologous stem cell transplant (ASCT) after ≥ 4 cycles, although per protocol design, ASCT candidates are offered to continue CRd treatment after SCC. After completion of 8 cycles, pts receive 28-day maintenance cycles with Cfz (days 1, 2 15, 16), Len days 1–21, and Dex weekly at the doses tolerated at the end of 8 cycles. Responses are assessed by IMWG criteria with the addition of nCR. Results: The study has enrolled 24 pts to date, 4 pts at level 1 (Cfz 20), 14 at level 2 (Cfz 27) and at 6 at level 3 (Cfz 36). Toxicity data are available for 21 pts, of which 19 have completed at least the first cycle required for DLT assessment; 2 pts were removed during the first cycle for events unrelated to study therapy (1 at level 1 and 1 at level 2), and 3 are currently within their first cycle of treatment. There was a single DLT event at dose level 2 (non-febrile neutropenia requiring dose reduction of Len per protocol) and the MTD has not been reached. Hematologic toxicities were reversible and included Grade (G) 3/4 neutropenia in 3 pts, G3/4 thrombocytopenia in 3, and G3 anemia in 2. There have been additional G3 non-hematologic AEs including 1 case of DVT while on ASA prophylaxis, 1 fatigue, 1 mood alteration, and 5 glucose elevations; the last 2 AEs were related to Dex. There was no emergence of peripheral neuropathy (PN), even after prolonged treatment, except in 2 pts who developed G1 sensory PN. Twenty-three pts continue on treatment, most (20 pts) without need for any dose modifications. After a median of 4 (range 1–8) months of treatment, preliminary response rates by IMWG in 19 evaluable pts who completed at least 1 cycle are: 100% ≥ PR, 63% ≥ VGPR, 37% CR/nCR, including 3 pts with sCR. Responses were rapid with 17 of 19 pts achieving PR after 1 cycle and improving responses with continuing therapy in all pts. To date, 7 pts proceeded to SCC using growth factors only, with a median 6.3 × 106 CD34+ cells/kg collected (range 4.1–8.2), after a median of 4 cycles of CRd (range 4–8); all resumed CRd treatment after SCC. After a median of 4 months of follow-up, none of evaluable pts progressed and all are alive. Conclusion: CRd is well tolerated and highly active in newly diagnosed MM with ≥ PR of 100%, including 63% ≥VGPR and 37% CR/nCR. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. The results of this study represent the first report of treatment of frontline myeloma with Cfz to date, and provide additional support to recently initiated Phase 3 trial of CRd vs. Rd in relapsed MM. Disclosures: Jakubowiak: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for newly diagnosed multiple myeloma. Jagannath:Millennium: Honoraria; OrthoBiotech (Canada): Honoraria; Celgene: Honoraria; Merck: Honoraria; Onyx Pharmaceuticals: Honoraria; Proteolix, Inc: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millennium: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Barrickman:Celgene: Employment, Equity Ownership. Kauffman:Onyx Pharmaceuticals: Employment, Equity Ownership. Vij:Proteolix: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Transition of Chronic Myeloid Leukemia to Chronic Myelomonocytic Leukemia As a Tool to Observe Development of Chronic Myelomonocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5223-5223
Author(s):  
Jamshid S Khorashad ◽  
Srinivas K Tantravahi ◽  
Dongqing Yan ◽  
Anna M. Eiring ◽  
Hannah M. Redwine ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Clonal Evolution ◽  
Chronic Myelomonocytic Leukemia ◽  
Imatinib Treatment ◽  
Advisory Committees ◽  
Clonal Architecture ◽  
Myelomonocytic Leukemia

Abstract Introduction. Development of abnormal Philadelphia (Ph) negative clones following treatment of chronic myeloid leukemia (CML) patients with imatinib has been observed in 3 to 9% of patients. Here we report on a 77 year old male diagnosed with CML that responded to imatinib treatment and subsequently developed chronic myelomonocytic leukemia (CMML). He achieved major cytogenetic response within 3 months but this response coincided with the emergence of monocytosis diagnosed as CMML. Five months after starting imatinib treatment the patient succumbed to CMML. We analyzed five sequential samples to determine whether a chronological order of mutations defined the emergence of CMML and to characterize the clonal evolution of the CMML population. Materials and Method. Five samples (diagnostic and four follow up samples) were available for analysis. CMML mutations were identified by whole exome sequencing (WES) in CD14+ cells following the onset of CMML, using CD3+ cells as constitutional control. Mutations were validated by Sequenom MassARRAY and Sanger sequencing and quantified by pyrosequencing. Deep WES was performed on the diagnostic sample to determine whether the mutations were present at CML diagnosis. To determine the clonal architecture of the emerging CMML, colony formation assays were performed on the diagnostic and the next two follow-up samples (Samples 1-3). More than 100 colonies per sample were plucked for DNA and RNA isolation. The DNA from these colonies were tested for the presence of the confirmed CMML mutations and the RNA was used for detection of BCR-ABL1 transcript using a Taqman real time assay. Results. Four mutations were identified by Sequenom and WES throughout the patient's time course [KRASG12R, MSLNP462H, NTRK3V443I and EZH2I669M ]. Sequenom did not identify these at diagnosis while deep WES did. Clones derived from colony formation assay revealed three distinct clones present in all samples analysed. Clone 1 had only KRASG12R, clone 2 had KRASG12R, MSLNP462H, and NTRK3V443I, and clone 3 had all four mutations. All clones containing any of these four mutations were BCR/ABL1 negative. Analysis of clonal architecture indicated that KRASG12R was acquired first and EZH2I669M last, while MSLNP462H and NTRK3V443I were acquired in between. These CMML clones increased proportionately as clinical CML metamorphosed into clinical CMML after initiation of imatinib therapy. Consistent with the colony data, pyrosequencing revealed that the ratio between the mutants remained largely stable throughout the follow up period. Conclusion. This case illustrates how targeted therapy impacts clonal competition in a heterogeneous MPN. While the CML clone was dominant in the absence of imatinib, it was quickly outcompeted by the CMML clones upon initiation of imatinib therapy. The clonal architecture analysis, in combination with in vivo kinetics data, suggest that the KRASG12R mutation alone was able to produce a CMML phenotype as clones with just KRASG12R remained at a relatively stable ratio during follow up. Unexpectedly, acquisition of additional mutations, including EZH2I669M as the last mutational event identified in this patient, did not increase clonal competitiveness, at least in the peripheral blood. These data show that clonal evolution may not invariably increase clonal fitness, suggesting that factors other than Darwinian pressures contribute to clonal diversity in myeloproliferative neoplasms. Disclosures Deininger: Gilead: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

scholarly journals Preliminary Results from a Phase II Study of the Combination of Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 464-464 ◽  
Author(s):  
Kelly S. Chien ◽  
Jorge E. Cortes ◽  
Gautam Borthakur ◽  
Courtney D. DiNardo ◽  
Naval G. Daver ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Myelodysplastic Syndrome ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
International Prognostic Scoring System ◽  
Advisory Committees ◽  
Genetics Research ◽  
Ongoing Phase

Abstract Background: The survival of patients with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure is poor at about 4 to 6 months. The exposure of CD34 positive cells from patients with MDS to HMA has been shown to result in increased expression of PD-1 and PD-L1, with a sequential increase in the expression of PD-1 and PD-L1 particularly in patients that have failed HMA (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2, that has been FDA-approved for certain solid tumors. Consequently, we designed an ongoing phase II clinical trial to evaluate the safety and clinical activity of the combination of azacitidine and pembrolizumab in patients with higher-risk MDS. Methods: Adult patients with intermediate-1 or higher disease by the International Prognostic Scoring System (IPSS) were eligible for the study. Patients were divided into two cohorts: those who had not received prior therapy and those who had not responded to, progressed on, or relapsed after HMA therapy, with a goal enrollment of 20 patients per cohort. Patients received azacitidine 75 mg/m2 IV or SQ daily for 7 days on a 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 3 weeks thereafter independent of azacitidine dosing schedule. The endpoints were overall response rate and safety. Patients were discontinued from the clinical trial if there was disease progression, unacceptable adverse experiences, intercurrent illness preventing further administration of study treatment, confirmed positive serum pregnancy test, noncompliance, loss to follow-up, completion of 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of the study medication (whichever occurred later), lack of efficacy, or any other reason leading to the investigator's decision for withdrawal. Clinical trial information: NCT03094637. Results: At data cut-off (July 2018), 18 patients have been treated with azacitidine and pembrolizumab with a median follow-up time of 16 weeks and 9 patients continuing on treatment in cycles 1-6. Twelve patients were enrolled in the HMA failure cohort and 6 patients in the previously untreated MDS cohort. Of the 12 patients evaluable for response, 7 were in the HMA failure cohort and 5 in the previously untreated MDS cohort. In the HMA failure cohort, 1 patient achieved CR, 1 patient demonstrated hematological improvement with mCR or CRi, and 5 patients progressed. In the previously untreated MDS cohort, 1 patient attained CR, 2 patients exhibited hematological improvement, 1 patient showed progression, and 1 patient died due to treatment-unrelated causes. The most frequently observed mutations in the 5 responding patients were TET2 in 3 patients and ASXL1, DNMT3A, and RUNX1 in 2 patients each. Three of the responders had diploid cytogenetics, 1 had del(10), and 1 had complex karyotype. Treatment was overall well-tolerated. Most common treatment-related adverse events (all grades) were neutropenia (22%); elevated ALT, elevated AST, anemia, and injection site reactions (17%); and constipation, joint pain, anorexia, pneumonitis, and pneumonia (11%). Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and may have antitumor activity in patients who failed HMA. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Bayer: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Daver:Sunesis: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Alexion: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Pfizer: Research Funding. Jain:Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Sign in / Sign up

Export Citation Format

Share Document