Results From the Dose Escalation Phase of a Randomized Phase 1–2 First-in-Human (FIH) Study of SGI-110, a Novel Low Volume Stable Subcutaneous (SQ) Second Generation Hypomethylating Agent (HMA) in Patients with Relapsed/Refractory MDS and AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 414-414 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Gail J. Roboz ◽  
David A. Rizzieri ◽  
Wendy Stock ◽  
Casey L. O'Connell ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Clinical Activity ◽  
Daily Regimen ◽  
Injection Site Pain ◽  
Heavily Pretreated ◽  
Clinical Responses ◽  
Low Volume ◽  
Site Pain

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

DNA Demethylation Activity Over Time and Safety Of 3 Different Dose-Escalation Regimens Of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA), In The Treatment Of Relapsed/Refractory Patients With MDS and AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1548-1548
Author(s):  
Gail J. Roboz ◽  
Jean-Pierre Issa ◽  
David Rizzieri ◽  
Wendy Stock ◽  
Casey O'Connell ◽  
...  
Keyword(s):  
Injection Site ◽  
Dose Escalation ◽  
Research Funding ◽  
Injection Site Reaction ◽  
Dna Demethylation ◽  
Clinical Activity ◽  
Injection Site Pain ◽  
Clinical Responses ◽  
Previously Treated ◽  
Site Pain

Abstract Background SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine. The compound is delivered as a small volume, pharmaceutically stable subcutaneous (SQ) injection which allows longer half-life and more extended DAC exposure than DAC intravenous infusion. This pharmacokinetic profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012). Methods A randomized Phase 1-2 first-in-human PK/PD-guided, dose-escalation study was conducted in patients with relapsed or refractory intermediate or high-risk MDS or AML. Patients were initially randomized to one of two SQ regimens - Dailyx5 or Weeklyx3, for 28-day courses. Subsequently, a Twice Weeklyx3 regimen (Monday, Thursday) was added for evaluation based on emerging LINE-1 demethylation data from the Weeklyx3 regimen. Results 93 patients (74 AML, 19 MDS) were treated in the dose escalation phase: 44, 34, and 15 patients were treated in the Dailyx5, Weeklyx3, and the Twice Weeklyx3 regimens, respectively. Across the three regimens, median age was 70 years (range, 29–86), 68% male, and 87% had ECOG PS of 0-1. The median number of prior regimens was 3 (range, 1–9) and 68% of patients had prior HMA treatment (59% AML, and 100% MDS). Of the 74 AML patients treated, 31 (42%) had secondary AML including antecedent MDS. Patients received a median of 2 courses of SGI-110 (range, 1-20). LINE-1 demethylation data at the 2 highest dose levels which were well tolerated and evaluated for all 3 regimens (60 and 90 mg/m2) are shown in the figure below. The Dailyx5 regimen demonstrated the most potent average LINE-1 demethylation, while the Twice Weeklyx3 achieved the most prolonged LINE-1 demethylation. The least potent demethylation was seen with the Weeklyx3 regimen. There was no additional demethylation at the 90 mg/m2 dose compared to 60 mg/m2in all 3 regimens. Responses were reported according to the IWG Criteria 2006 (MDS)/2003 (AML). Complete remissions were observed in 5 AML patients (2CRs, 1CRp, and 2CRi). Clinical responses (2 mCR and 3 HI-E, 1 HI-N, 1 HI-P) were observed in 6 MDS patients, all of whom had been previously treated with HMA. All AML responses and both mCR in MDS patients achieved ≥10% LINE-1 demethylation. Safety is reported based on Adverse Events (AEs) as graded by the CTCAE v4 criteria. Across regimens, the Twice Weeklyx3 demonstrated an increased number of related AEs compared to the other regimens. The most commonly reported related AEs ≥ 10% in the Dailyx5 regimen (injection site pain, thrombocytopenia, neutropenia, anemia, fatigue), Weeklyx3 regimen (injection site pain and diarrhea), and Twice Weeklyx3 regimen (injection site pain, injection site reaction, fatigue, dizziness, febrile neutropenia, neutropenia, anemia, and thrombocytopenia). Conclusions SQ SGI-110 is a potent HMA using all 3 regimens evaluated. The most potent hypomethylation was achieved with Dailyx5 dosing and the most prolonged hypomethylation was achieved using the Twice Weeklyx3 regimen. All 3 regimens were well tolerated. Clinical responses were observed in heavily pretreated patients, including those with prior HMA exposure. These results support the ongoing Phase 2 expansion study investigating the Dailyx5 dosing schedule in patients with MDS and AML who are either HMA treatment naïve or previously treated with HMAs. Disclosures: Roboz: Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Ritchie:Astex Pharmaceuticals, Inc.: Research Funding. Rao:Astex Pharmaceuticals, Inc.: Research Funding. Larson:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Schimmer:Astex Pharmaceuticals, Inc.: Research Funding. Mesa:Astex Pharmaceuticals, Inc.: Research Funding. Blum:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals, Inc.: Research Funding.

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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.

ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1860-1860 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey Zonder ◽  
Adam Cohen ◽  
Robert Z. Orlowski ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Febrile Neutropenia ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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.

scholarly journals 1045. Safety of the Synthetic Saponin Adjuvant TQL1055: Preliminary Results from a First-in-humans Trial

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S614-S614
Author(s):  
Sean R Bennett ◽  
Tyler Martin
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Dose Escalation ◽  
Large Scale ◽  
Phase 1 ◽  
Safety Data ◽  
Synthetic Analog ◽  
Injection Site Pain ◽  
The Mean ◽  
Site Pain

Abstract Background Saponin adjuvants reliably enhance immune response to a variety of antigens, but their use is hindered by dose-limiting toxicities and supply constraints. TQL1055 is a semi-synthetic analog of the natural saponin adjuvant QS-21, rationally modified to improve tolerability and enable large-scale manufacturing. We previously showed that the combination of acellular pertussis vaccine (aP) and TQL1055 was well-tolerated and increased anti-pertussis toxin (PT) antibody responses in mice and rabbits, with a no observed adverse effect level (NOAEL) > 2000 mcg/dose. Methods Here we report interim results from a Phase 1 first-in-humans dose-escalation study of TQL1055. Healthy adults 18 to 50 years of age were sequentially enrolled into 6 groups (n=12/group) and randomized 10:2 to receive one intramuscular dose of aP + TQL1055 or aP alone on Day 1. TQL1055 dose increased by group from 25 to 800 mcg (Figure 1). Local adverse events (AEs) (injection site pain, redness, swelling) and systemic AEs (fever, chills, headache, fatigue, myalgia, arthralgia, nausea, vomiting, diarrhea) were solicited through Day 8. Clinical laboratory panels (chemistry, hematology, coagulation) were performed on Days 1 (pre-dose), 8, and 29. Serious AEs were collected through Day 365. Antibodies to PT were assessed at all visits. Figure 1. Study Design Results Blinded safety data from the first four groups (n=48) through Day 8 were analyzed, including 2 subjects/group receiving aP alone. All solicited AEs were mild or moderate (Figure 2). Local AEs, mainly injection site pain, occurred in 75% of subjects (mild 65%, moderate 10%). The incidence of total local AEs increased with TQL1055 dose, from 50% at 25 mcg to 92% at 200 mcg. The mean duration of local AEs was 1.8 days and also increased with TQL1055 dose, from 1.3 days at 25 mcg to 2.1 days at 200 mcg. Systemic AEs, mostly fatigue, headache, and nausea, occurred in 63% of subjects (mild 40%, moderate 23%), with no fevers. The mean duration of systemic AEs was 1.4 days, with no association with TQL1055 dose. No severe or serious adverse events were reported. Figure 2. Solicited Adverse Events by Severity and TQL1055 Dose Conclusion In this early analysis, the safety profile of aP + TQL1055 appears similar to that of licensed aP vaccines, without severe or prolonged injection site pain. These data support further dose escalation and assessment of immunogenicity. Disclosures Sean R. Bennett, MD PhD, Adjuvance Technologies (Employee) Tyler Martin, MD, Adjuvance Technologies (Employee, Shareholder)

Safety Profile and Clinical Response To MEDI-551, a Humanized Monoclonal Anti-CD19, In a Phase 1/2 Study In Adults With Relapsed Or Refractory Advanced B-Cell Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1810-1810 ◽  
Author(s):  
Andres Forero-Torres ◽  
Mehdi Hamadani ◽  
Michelle A. Fanale ◽  
Celeste M. Bello ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Safety Profile ◽  
Stock Options ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Phase 2 ◽  
B Cell Malignancies

Abstract Background MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa monoclonal antibody directed against CD19 and induces malignant clone destruction by antibody-dependent cellular cytotoxicity. This study evaluates the safety profile and clinical activity of MEDI-551 in patients with relapsed/refractory B-cell malignancies. These include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Objectives Determine the safety profile and maximum tolerated dose (MTD) of MEDI-551 in patients with relapsed/refractory B-cell malignancies. Secondary objectives include clinical activity of MEDI-551. Methods In this phase 1/2 open-label multicenter, global dose-escalation and expansion study, patients with relapsed or refractory CLL, DLBCL, FL, or MM received MEDI-551 (at 0.5, 1, 2, 4, 8, or 12 mg/kg) by intravenous infusion administered over 28-day cycles using standard 3+3 dose escalation. Dose escalation continued to the maximum dose ≤12 mg/kg or until MTD was reached. Therapy continued for 2 cycles beyond complete response (CR), or until unacceptable toxicity or disease progression. Dose-limiting toxicity was defined as a MEDI-551-related adverse event (AE) that prevented completion of a full first cycle of MEDI-551, or as a ≥grade 3 toxicity (excluding hematologic toxicity) that could not be ascribed to another cause. Results Of 91 patients who received ≥1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010–Aug 2011). No MTD was achieved. The phase 2 expansion phase included 66 patients (CLL [23], DLBCL [20], FL [22], MM [1]) as of 14Jul2013. Three patients were re-treated with MEDI-551 upon relapse. Median age of patients treated was 66 years; median lines of prior therapy was 6. The median number of treatment cycles was 5 with a maximum of 28 cycles. There were 14 deaths due to AEs (none were drug-related) and 15 subjects discontinued treatment. One subject each discontinued due to drug-related neutropenia and infusion reaction. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Of 91 patients, 5 (5.5%) patients had grade 4 TEAEs (2 with drug-related neutropenia) and 9 (9.9%) had grade 5 events, none were drug related. Of 19 patients with 38 serious AEs (SAE), 2 patients had 3 events that were considered drug-related; pneumonia and sepsis in 1 patient and infusion related reaction in the other. Of 83 patients in the efficacy evaluable population (includes all patients who received any treatment of MEDI-551 and completed at least 1 post-baseline disease assessment), 9 had CR, 12 had partial responses (PR) and 42 had stable disease (SD; Figure 1). ORR to single-agent MEDI-551 was 24%, 24%, or 31% respectively in heavily pre-treated patients with CLL, DLBCL, or FL. Median progression-free survival was ≈9 months (Figure 2). Conclusions MEDI-551 has an acceptable safety profile warranting further study. Anti-tumor activity was achieved in a heavily pre-treated population of DLBCL, CLL, and FL patients respectively in this single-agent study. Phase 2 studies of MEDI-551 in combination with chemotherapy in DLBCL and CLL are ongoing. Funding Source This study was sponsored by MedImmune. Disclosures: Forero-Torres: MedImmune: Research Funding. Hamadani:MedImmune: Research Funding. Fanale:MedImmune: Research Funding. Bello:MedImmune: Research Funding. Kipps:MedImmune: Research Funding. Offner:MedImmune: Research Funding. Verhoef:MedImmune: Research Funding. Federico:MedImmune: Research Funding. Gregory:MedImmune: Research Funding. Sonet:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Pérez de Oteyza:MedImmune: Research Funding. Tomas:MedImmune: Research Funding. Cuneo:MedImmune: Research Funding. Elgeioushi:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Goswami:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Ibrahim:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Herbst:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Cheson:MedImmune: Research Funding.

scholarly journals Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1587-1587
Author(s):  
Ian W. Flinn ◽  
Jason R. Westin ◽  
Jonathon B. Cohen ◽  
Luke P. Akard ◽  
Samantha Jaglowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Board ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Clinical Responses

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse <1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in >2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

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 Phase 1 Dose Escalation and Expansion Study to Determine Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the BET Inhibitor FT-1101 As a Single Agent in Patients with Relapsed or Refractory Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3907-3907 ◽  
Author(s):  
Manish R. Patel ◽  
Guillermo Garcia-Manero ◽  
Ronald Paquette ◽  
Shira Dinner ◽  
William B. Donnellan ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Disease Progression ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Bet Inhibitor

Background: BET inhibitors have demonstrated therapeutic potential in hematologic malignancies; however low therapeutic margins have limited clinical development. FT-1101 (also known as CC-95775) is a BET bromodomain inhibitor of all 4 BET family members BRD4, BRD2, BRD3, and BRDT (Kd ≤20 nM) and shows additional activity towards several non-BET bromodomain proteins (including CECR2 and BRD9). In vitro, FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia cell lines. In xenograft and syngeneic models, FT-1101 achieved superior tumor growth inhibition (including regressions) relative to JQ1, another BET inhibitor (Millan 2015). Methods: A Phase 1 study evaluated the safety, PK/PD, and clinical activity of FT-1101 in patients (pts) with relapsed/refractory (R/R) AML/MDS, or non-Hodgkin lymphoma (NHL) (NCT02543879). Oral FT-1101 (10 mg - 600 mg) was dosed once a week (QW), every other week (QOW), or monthly (QM) during dose escalation. Safety was assessed via treatment-emergent AEs (TEAEs) for all pts; efficacy (response) was assessed in evaluable pts by investigators. Pharmacodynamic biomarkers (CCR1 and HEXIM1 mRNA expression) were assessed in whole blood. Results: Between 17-Nov-2015 and 05-Mar-2019, a total of 84 AML/MDS pts and 10 NHL pts received FT-1101 in dose escalation with a median of 2 (range 1-13) treatment cycles and median exposure of 43 (1-401) days for AML/MDS and 51.5 (1-183) days for NHL pts. Most AML/MDS pts (n=80) received FT-1101 monotherapy; a small cohort (n=4) received FT-1101 200 mg QOW in combination with azacitidine. FT-1101 appeared to demonstrate dose-proportional PK (10-600 mg/dose) with a median Tmax of 4 (1-24) hrs and a mean T1/2 of 52 (18-123) hrs. Pharmacodynamic responses correlated with FT-1101 concentrations; preliminary analysis indicated that PD biomarker modulation (↓ CCR1 and ↑ HEXIM1) was seen with FT-1101 doses as low as 80 mg, with more robust modulation observed at FT-1101 doses >180 mg. The most common (>20%) TEAEs (all grades) were diarrhea (32%), fatigue (30%), dyspnea (29%), nausea (27%), anemia (24%), and platelet count decreased (21%) among AML/MDS pts and diarrhea (60%), nausea or pleural effusion (40% each), and cough, decreased appetite or dyspnea (30% each) among NHL pts. The most common (>10%) severe (≥ grade 3) TEAEs were anemia (21%), decreased platelets (19%), pneumonia (16%), sepsis (13%), febrile neutropenia (12%), and disease progression (11%) among AML/MDS pts and pleural effusion or disease progression (20% each) among NHL pts. AEs led to treatment discontinuation in 22 AML/MDS pts (26%) and 2 NHL pts (20%). Twenty AML/MDS pts (24%) and 2 NHL pts (20%) died due to AEs, all assessed as unrelated to study treatment. Disease progression was the most common fatal TEAE in AML/MDS and NHL pts (10% and 20%, respectively). The maximum tolerated dose (MTD) on the QOW schedule was 400 mg FT-1101; MTDs were not determined for other schedules. Among evaluable AML/MDS pts who received >180 mg FT-1101 monotherapy (n=30), one pt (3%) on the 400 mg QOW schedule achieved complete remission with incomplete hematologic recovery (CRi) and 19 pts (63%) achieved stable disease, including 2 pts receiving >7 cycles of treatment. Among evaluable NHL patients who received >180 mg FT-1101 monotherapy (n=3), one pt (33%) achieved stable disease. Conclusions: FT-1101, as monotherapy, shows acceptable safety, PK, and modest clinical activity in R/R AML/MDS and NHL pts. Intermittent (QOW) dosing within a tolerable range elicits PD activity (CCR1 suppression and HEXIM1 upregulation) consistent with preclinical observations indicating antitumor activity, and provides a rationale for testing FT-1101 in combination with standard therapies in AML/MDS and NHL. Disclosures Patel: Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Grunwald:Forma Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Medtronic: Equity Ownership; Cardinal Health: Consultancy; Merck: Consultancy; Genentech/Roche: Research Funding; Trovagene: Consultancy; Janssen: Research Funding. Ribadeneira:FORMA Therapeutics: Employment. Schroeder:FORMA Therapeutics: Employment. Brevard:FORMA Therapeutics: Employment. Wilson:FORMA Therapeutics: Employment. Sweeney:FORMA Therapeutics: Employment. Kelly:FORMA Therapeutics: Employment. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

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