Results of a Phase 1/2 Study for KW-0761, a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4), In CTCL Patients

Abstract Abstract 962 Introduction: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is over expressed in PTCL and CTCL, and is a potential target for anti-neoplastic therapy in these disorders. Study Design: This multicenter, open-label, dose escalation phase 1/2 study is in patients with previously treated PTCL and CTCL (including MF and SS). The study is composed of a dose escalation phase (Phase 1) and preliminary assessment of safety and efficacy (Phase 2). The phase 1 portion is a standard 3+3 design at doses of 0.1, 0.3, and 1 mg/kg. In the first treatment course, KW-0761 is administered i.v. once a week for four weeks, followed by a 2-week observation period. Subjects demonstrating a response or maintaining stable disease may receive additional infusions of KW-0761 every other week until progression or withdrawal from study. For CTCL patients, the overall global response score is a composite of response in all compartments (skin, lymph nodes, viscera). For subjects with Sezary Syndrome (SS), response in blood is also considered for overall response. For PTCL patients, the response is based on criteria defined by the International Working Group (IWG). Results: Forty-two patients who had received at least one prior systemic therapy (median 5; range 1–17) are enrolled. The median age is 67 (range: 35–85) years with more males (57%) than females (43%). A total of 40 patients received at least four doses of KW-0761 at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3) and 1 mg/kg (n=34). There are no dose limiting toxicities (DLT) or drug-related serious adverse events (SAEs) reported in the dose escalation portion of the study. Most observed adverse events (AEs) are mild to moderate in severity. There does not appear to be any dose relationship with the incidence or severity of the AEs. The most frequent AEs are chills, headache, nausea, pyrexia, infusion related reactions and back pain. There does not seem to be an increase in the rate of infections associated with the use of this drug. Six of 42 patients who received at least one dose of KW-0761 developed a new skin eruption not consistent with the patients' underlying disease, including one grade 3 hypersensitivity rash with eosinophils. No significant hematologic AEs have been observed except for lymphopenia which is due to the pharmacologic effect of the drug. A total of 38 patients (23 with MF; 15 with SS) are evaluable for efficacy (only one subject with PTCL was enrolled and is not included in this analysis). A summary of all patients evaluable for efficacy to date is presented in the table belowa: Conclusions: KW-0761 is well tolerated at doses of 0.1–1.0 mg/kg. The MTD has not been reached in this study. The overall response rate is 39% for all patients in the phase 1/2 trial with a higher rate in SS patients (47%) versus MF patients (35%). Additionally, 12 of 15 SS patients had a response in the blood, including 7 CRs. These promising results warrant further clinical studies using KW-0761 in refractory or relapsed CTCL patients. Disclosures: Duvic: Kyowa-kirin-pharma.com: Consultancy, Research Funding. Pinter-Brown:Kyowa-Kirin: Consultancy, Research Funding. Foss:Kyowa-Kirin: Consultancy, Research Funding. Sokol:Kyowa-Kirin: Research Funding. Jorgensen:Kyowa Hakko Kirin Co, Ltd.: Research Funding. Spitalny:Kyowa-Kirin: Employment. Kim:Kyowa-Kirin: Consultancy, Research Funding.

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Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211873 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2065-2070 ◽

Cited By ~ 33

Author(s):

Lisa K Stamp ◽

Peter T Chapman ◽

Murray Barclay ◽

Anne Horne ◽

Christopher Frampton ◽

...

Keyword(s):

Adverse Events ◽

Dose Escalation ◽

Controlled Trial ◽

Serum Urate ◽

Extension Study ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Randomised Controlled ◽

Kidney Impairment

ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932

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Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2580 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2580-2580

Author(s):

Jermaine Coward ◽

Afaf Abed ◽

Adnan Nagrial ◽

Ben Markman

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Advanced Solid Tumors ◽

Open Label ◽

Dose Escalation Study ◽

Label Dose ◽

Febrile Episodes ◽

Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

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A Phase 1 Study of Sea-CD70 in Myeloid Malignancies

Blood ◽

10.1182/blood-2020-136203 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ahmed Aribi ◽

Anjali S Advani ◽

William Donnellan ◽

Amir T. Fathi ◽

Marcello Rotta ◽

...

Keyword(s):

Board Of Directors ◽

Immune Evasion ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Steering Committee ◽

Advisory Board ◽

Open Label ◽

Advisory Committees ◽

Myeloid Malignancies

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽

10.1182/blood.v108.11.1149.1149 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1149-1149

Author(s):

Bruce A. Wallin ◽

Denise Ramjit ◽

Michael Seiberling ◽

David Zopf

Keyword(s):

Adverse Events ◽

Animal Studies ◽

Phase 1 ◽

Stopping Rules ◽

Open Label ◽

Serious Adverse Events ◽

Maximal Increase ◽

The Mean ◽

Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

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Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v126.23.1540.1540 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1540-1540 ◽

Cited By ~ 4

Author(s):

Sheeba K. Thomas ◽

Wael A. Harb ◽

Joseph Thaddeus Beck ◽

Gabrail Nashat ◽

M. Lia Palomba ◽

...

Keyword(s):

Clinical Trial ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Preliminary Evidence ◽

Clinical Activity ◽

Open Label ◽

Label Dose ◽

Myd88 L265p Mutation ◽

Myd88 L265p

Abstract Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.

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Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01565-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2879-2886 ◽

Cited By ~ 52

Author(s):

Leonard E. Weisman ◽

Helen M. Thackray ◽

Joseph A. Garcia-Prats ◽

Mirjana Nesin ◽

Joseph H. Schneider ◽

...

Keyword(s):

Monoclonal Antibody ◽

Birth Weight ◽

High Risk ◽

Adverse Events ◽

Dose Escalation ◽

Very Low Birth Weight ◽

Phase 1 ◽

Double Blind ◽

Double Blind Placebo ◽

Vlbw Infants

ABSTRACT Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ± 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

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704 A Phase 1 Open-Label, Single-Dose, Dose-Escalation Study of Mdx-1100, a High-Affinity, Neutralizing, Fully Human Igg1κ Anti-CXCL10 (Ip10) Monoclonal Antibody, in Ulcerative Colitis

Gastroenterology ◽

10.1016/s0016-5085(08)60466-7 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-99-A-100 ◽

Cited By ~ 7

Author(s):

Robert Hardi ◽

Lloyd Mayer ◽

Stephan R. Targan ◽

Michael Yellin ◽

Pina M. Cardarelli ◽

...

Keyword(s):

Ulcerative Colitis ◽

Monoclonal Antibody ◽

Single Dose ◽

Dose Escalation ◽

Phase 1 ◽

Open Label ◽

Dose Escalation Study ◽

High Affinity

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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 ◽

10.1182/blood-2018-99-116613 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1438-1438 ◽

Cited By ~ 1

Author(s):

Guillermo Garcia-Manero ◽

Michael R. Kurman ◽

Courtney D. DiNardo ◽

Naveen Pemmaraju ◽

Yesid Alvarado ◽

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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.

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