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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1540-1540 ◽  
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.

A Phase 1 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2600-2600 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Rami S. Komrokji ◽  
Daohai Yu ◽  
Anjali S. Advani ◽  
Tammy Searles ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Survival Data ◽  
Research Funding ◽  
Drug Exposure ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 1 Study ◽  
Simultaneous Exposure

Abstract Abstract 2600 Background: Lenalidomide (Len) is an immunodulatory agent with proven efficacy in lower-risk myelodysplastic syndromes (MDS) and with strong signals of single-agent activity in higher-risk MDS and AML patients (pts). Our preclinical data showed that Len antagonized cytarabine cytotoxicity with simultaneous exposure, while augmenting the effects of anthracyclines and cytarabine with sequential drug exposure. We initiated a phase 1 combination study in patients with AML investigating sequential standard induction chemotherapy followed by Len. Objectives: 1) to determine the safety and maximum tolerated dose (MTD) of Len following idarubicin/cytarabine induction. 2) to assess preliminary signs of efficacy of this regimen in adults with previously untreated AML. Methods: This was a multicenter, open-label, dose escalation phase 1 study with a 3+3 dosing design of idarubicin (12 mg/m2, day 1–3), cytarabine (100 mg/m2, CI day 1–7) + Len (starting dose 5 mg, day 8–21). Len dose was escalated in 5 mg increments up to a maximum of 25 mg/day. Eligibility included pts with AML age ≥60 years or age <60 with associated del 5/5q; or MDS/RAEB-2 with prior hypomethylating agent failure. Other inclusion criteria included: ECOG PS 0–2 and adequate end-organ function (including normal LVEF of ≥ 50%). Pts who achieved CR/CRi after 1 or 2 cycles of induction were eligible to receive post-remission idarubicin/cytarabine/Len (at the same dose level) for up to 2 cycles, followed by Len maintenance 10 mg/day for up to 12 months. The MTD cohort was expanded to 10 patients. Results: Of 23 enrolled and treated pts, 21 have completed at least 1 treatment cycle. Median age was 68 years (range 44–79); males: 18 (78%). Eleven pts had del 5/5q associated karyotype (10 of whom had complex karyotype), and 15 had secondary AML (including 8 who received prior hypomethylating agents). Len dose escalation reached 25mg/day, with MTD determined to be 20 mg/day. Dose-limiting toxicities occurred in 2 of 3 patients treated at Len 25 mg/day (grade 3 rash; grade 4 neutropenia and thrombocytopenia persisting beyond day 56) and in 1 of 8 patients treated at Len 20 mg/day (grade 4 cardiac ischemia). Only 1 of 21 (5%) patients died within 30 days of treatment initiation. The most common therapy-related non-hematologic toxicities (occurring in ≥ 20% of patients, the vast majority of which were grade 1–2) included: diarrhea (76%), infection/febrile neutropenia (71%), rash (62%), nausea (43%), pain (43%), hemorrhage (33%), fatigue (29%), and non-neutropenic fever (24%). Of the 20 patients evaluable for response, 7 achieved CR and 1 CRi, for an overall response rate (ORR) of 40%. Of 11 evaluable patients treated at the MTD (Len 20 mg/day) and higher, the ORR was 55%. CR occurred in 3 out of 10 (30%) patients with associated del 5/5q. Conclusion: Sequential idarubicin/cytarabine + Len was generally well-tolerated in a primarily older population of patients with previously untreated AML, with MTD of 20 mg/day for Len. Clinical activity in this poor-risk population appears promising at the MTD and higher. Further exploration of this regimen in older AML patients is warranted, with plans for a phase 2 expansion underway. Updated toxicity, response, and survival data will be presented. Disclosures: Lancet: Celgene: Research Funding. Off Label Use: Lenalidomide is approved for use in MDS. Its investigational role in AML will be discussed. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Sekeres:Celgene: Advisory Board. List:Celgene: Consultancy.

scholarly journals First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1826-1826 ◽  
Author(s):  
Martine Bagot ◽  
Pierluigi Porcu ◽  
Caroline Ram-Wolff ◽  
Michael Khodadoust ◽  
Maxime Battistella ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Research Funding ◽  
Ex Vivo ◽  
Phase 1 ◽  
Clinical Activity ◽  
Autologous Tumor ◽  
Employment Equity ◽  
T Cell Lymphomas ◽  
Equity Ownership

Abstract KIR3DL2 is expressed in all subtypes of cutaneous T-cell lymphomas (CTCL), irrespective of clinical stage, with the highest prevalence of expression in Sézary syndrome (SS) and transformed mycosis fungoides (MF), two subgroups of patients with a high unmet need for clinically impactful therapies. KIR3DL2 belongs to the killer immunoglobulin-like receptor (KIRs) family and is expressed on minor subpopulations of normal NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-KIR3DL2 monoclonal antibody (mAb). It selectively depletes KIR3DL2-expressing cells by recruiting immune effectors. Its main modes of action include antibody-dependent cell-cytotoxicity (ADCC) and -phagocytosis (ADCP). IPH4102 has shown potent efficacy in preclinical models, in particular ex vivo autologous assays using primary CTCL cells. IPH4102 is currently being investigated in a first-in-human dose-finding phase 1 study (NCT02593045) evaluating repeated administrations of single-agent IPH4102 in relapsed/refractory CTCL patients. The primary objective is to assess the safety and tolerability of increasing doses of IPH4102. Secondary objectives include PK, immunogenicity and signals of anti-tumor clinical activity. Exploratory biomarkers aim to characterize KIR3DL2-expressing and non-expressing cells in involved tissue/disease compartments and to monitor changes during IPH4102 treatment. Minimal residual disease (MRD) is measured in the skin, blood and/or lymph nodes. Assessment of ex vivo NK cell-mediated ADCC against autologous tumor cells is also performed pre-dose on SS patient samples. The study has two sequential portions, a dose-escalation followed by a cohort expansion. The dose-escalation portion has a 3+3 design with accelerated titration and aims to determine the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D). In the cohort expansion portion, two CTCL subtype-specific cohorts will be studied, each to include 10 additional patients to further explore MTD or RP2D. Eligible CTCL patients must have received at least 2 lines of anti-neoplastic systemic therapy. Centrally assessed KIR3DL2 expression on malignant cells in skin or blood is required for inclusion. Patients receive IPH4102 administrations until progression or unacceptable toxicity. Intra-patient dose-escalation is allowed, only past the first complete clinical assessment at week 5 and provided the upper next dose-level is declared safe by the safety committee. Enrollment into study IPH4102-101 started in November 2015 and is currently ongoing. At time of abstract submission, dose-levels #1 to #6 have been completed. A total of 13 patients have been treated at these 6 dose-levels and are evaluable for safety and clinical activity. These patients comprise 10 SS (including 1 with evidence of large-cell transformation), 2 MF and 1 "not-otherwise-specified" CD4+ CTCL. Median age is 71 years (range 50 - 90). For these 13 patients, only grade 1 or 2 related adverse events (AEs) have been reported with IPH4102 treatment. No patient experienced a DLT or a related AE of grade ≥3. No IPH4102-related skin rashes or infections have been observed so far. Results of immuno-phenotyping of patients' blood lymphocytes show consistency of local and central assessments. In addition, ex vivo functional assay results confirm that SS patients' NK cells are functional and able to kill autologous tumor cells through ADCC with IPH4102. Our preliminary data from the phase 1 study of a novel targeted immune therapy show excellent tolerability in advanced CTCL patients. Updated results including exploratory biomarker assessment results will be presented and discussed at the meeting. Disclosures Bagot: Millenium: Other: Investigator in a clinical trial; Kiowa Hakko Kirin: Other: Investigator in a clinical trial; Innate Pharma: Equity Ownership, Other: Investigator in a clinical trial, Patents & Royalties, Research Funding. Porcu:celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Ram-Wolff:Innate Pharma: Other: Investigator in a clinical trial. Battistella:Innate Pharma: Consultancy, Research Funding. Marie-Cardine:Innate Pharma: Research Funding. Mathieu:Innate Pharma: Other: Investigator in a clinical trial. Vermeer:Innate Pharma: Other: Investigator in a clinical trial. Whittaker:Seattle Genetics: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; Takeda: Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding. Duvic:Kiowa Hakko Kirin: Other: investigator in a clinical trial, Research Funding; Rhizen Pharmaceuticals: Other: Investigator in a clinical trial; Innate Pharma: Consultancy, Other: Investigator in a clinical trial; Millenium: Other: Investigator in a clinical trial; Angimmune LLC: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial. Bensussan:Innate Pharma: Patents & Royalties, Research Funding. Paturel:Innate Pharma: Employment, Equity Ownership. Bonnafous:Innate Pharma: Employment, Equity Ownership. Widemann:Innate Pharma: Employment. Bonin:Innate Pharma: Employment. Sicard:Innate Pharma: Employment, Equity Ownership. Paiva:Innate Pharma: Employment. Pilz:Innate Pharma: Consultancy. Kim:Kyowa Hakko Kirin: Consultancy, Honoraria, Other, Research Funding; Innate Pharma: Other: Investigator in a clinical trial; Millenium: Consultancy, Other: Investigator in a clinical trial; Seattle Genetics: Consultancy, Other: Investigator in a clinical trial; Merck: Other: Investigator in a clinical trial; Genentech: Other: Investigator in a clinical trial; MiRagen: Consultancy; Neumedicine: Consultancy; Soligenix: Consultancy; Eisai: Consultancy, Other: Investigator in a clinical trial; Actelion: Consultancy, Other: Investigator in a clinical trial; Celgene: Consultancy; Galderma: Consultancy; Horizon: Consultancy.

scholarly journals A phase 1/2, open‐label, dose‐escalation study of midostaurin in children with relapsed or refractory acute leukaemia

2018 ◽  
Vol 185 (3) ◽  
pp. 623-627 ◽  
Author(s):  
C. Michel Zwaan ◽  
Stefan Söderhäll ◽  
Benoit Brethon ◽  
Matteo Luciani ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Acute Leukaemia ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2831-2831 ◽  
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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