Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL),

Abstract Abstract 3904 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50≤1 μM) against T and B lymphoid malignancies that overexpress Bcl-2. In preclinical models of B-cell lymphoma, navitoclax enhanced efficacy of rituximab (R) when used alone or in combination with chemotherapy. Based on phase 1 trial data, oral navitoclax monotherapy was well-tolerated and had anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). Thrombocytopenia was the dose-limiting toxicity (DLT). We examined whether navitoclax could be used safely in combination with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for treatment of pts with CLL. Methods: This ongoing, phase 1 dose-escalation study is evaluating the safety and pharmacokinetics (PK) of oral navitoclax used in combination with FCR (Arm A) or BR (Arm B) for treatment of pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥1000/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. Enrolled pts (6 pts/cohort) were assigned to Arm A or Arm B based on physician preference. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent 28-day cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Oral navitoclax was administered once daily (starting dose of 110 mg) pre-chemotherapy on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. Dose escalation decisions were made independently in each arm via a continuous reassessment method, and the objective was to identify a dose of navitoclax in combination with chemotherapy in which <33% of subjects experienced DLTs. Tumor responses were evaluated using NCI-WG 1996 criteria. Adverse events (AE) were graded by NCI CTCAE V3. Pts continued on navitoclax monotherapy up to the recommended phase 2 dose of 250 mg daily for 1 year or until progressive disease or intolerable toxicity. Results: As of July 2011, 28 pts (median age 59 yr [39–80]) have enrolled; 5 in Arm A (FCR+navitoclax; 110 mg) and 23 in Arm B (BR+navitoclax; 110–250 mg). The median number of prior therapies was 2 (range 1–13). In Arm A, 1 pt had a DLT of febrile neutropenia (110 mg). In Arm B, 5 pts had DLT; 1 had elevated ALT and AST (110 mg), 1 had grade 4 febrile neutropenia (200 mg), and 3 had grade 4 thrombocytopenia (250 mg). Overall, the most common (>20%) navitoclax-related AEs of any grade were nausea (73%), fatigue (50%), neutropenia (50%), cough (39%), vomiting (35%), chills (31%), diarrhea (31%), constipation (27%), headache (27%), anemia (23%), and thrombocytopenia (23%). The most common (>19%) grade 3/4 navitoclax-related AE was neutropenia (35%) and thrombocytopenia (19%); but only 2 of the latter pts had hemorrhagic events (Grade 1 epistaxis) unlikely related to navitoclax. Of the 28 pts evaluated for safety, 6 remain active and 22 discontinued (DC); 1 due to AE, 1 due to AE and progressive disease (PD), 3 due to PD, 6 withdrew consent, 3 due to physician discretion, 4 completed therapy, 2 proceeded to transplant, and 2 due to toxicity. Preliminary best anti-tumor responses were assessed in 20 pts. Of the 16 pts assessed in Arm B (BR), 6 achieved complete responses (CR), 7 partial responses (PR), 2 stable disease (SD) and 1 with PD. The ORR was 81% (13/16). In this arm, 3/5 pts with 17p deletion achieved PR. Of the 4 pts assessed in Arm A (FCR), 2 achieved PR, 1 SD and 1 with PD. Preliminary PK results suggest that there is no apparent PK interaction between navitoclax and bendamustine. Conclusions: The combination of navitoclax with BR appears well-tolerated and to have anti-tumor activity. The maximum tolerated dose of navitoclax has been reached at 250 mg for Arm B, but not for Arm A where escalation continues. To date, we have not observed unacceptable myelotoxicity when this bcl-2 antagonist was used in combination with standard cytotoxic chemo-immunotherapy regimens for treatment of pts with CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Off Label Use: R05429083 is a novel humanized antibody direct against the standard region of CD44. R05429083 is currently intensive pre-clinical studies and fist dosing of cancer patients has started in Europe in 2011. Swinnen:Abbott Laboratories: Research Funding. Yang:Abbott Laboratories: Employment. Cui:Abbott Laboratories: Employment, Stock Holder at Abbott Laboratories. Busman:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Enschede:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Humerickhouse:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock.

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Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v116.21.2455.2455 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2455-2455 ◽

Cited By ~ 4

Author(s):

Thomas J. Kipps ◽

William G. Wierda ◽

Jeffrey A. Jones ◽

Lode J. Swinnen ◽

Jianning Yang ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Cell Transplant ◽

Phase 2 ◽

Anti Tumor Activity

Abstract Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

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Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Blood ◽

10.1182/blood.v126.23.493.493 ◽

2015 ◽

Vol 126 (23) ◽

pp. 493-493 ◽

Cited By ~ 9

Author(s):

Stephan Stilgenbauer ◽

Osman Ilhan ◽

Darius Woszczyk ◽

Christoph Renner ◽

Eva Mikuskova ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Safety And Efficacy ◽

Grade 3

Abstract Background The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101; GAZYVA/GAZYVARO; G) combined with chlorambucil (Clb) has superior efficacy to Clb monotherapy and to rituximab plus Clb with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), as shown in the CLL11 study (Goede V, et al. NEJM 2014). GREEN is an ongoing, non-randomized, multi-cohort phase IIIb study (NCT01905943) investigating the safety (primary objective) and efficacy of G alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL and assessing various strategies (cohorts 1-3) for reducing the rate of infusion-related reactions (IRRs) during the first infusion of G (Bosch F, et al. Blood 2014). We report safety and efficacy data from a subgroup of previously untreated patients in cohort 1 who received G-bendamustine (G-B). Methods Subjects were aged ≥18 years withdocumented CLL (except one case of SLL), an ECOG performance status of 0-2, and adequate hematologic function. Non-fit patients were those with a CrCl of <70 mL/min, and/or a CIRS score of >6. Fit patients comprised all others. Treatment was six 28-day cycles of G-B, where G was administered IV on D1/D2 of C1 (split dose: 25mg D1/975mg D2), and 1000mg on D8 and D15 of C1 and D1 C2-6. B was administered ≥30 minutes after G on D1 and D2 of each cycle at 90mg/m2 IV, or at 70mg/m2 in non-fit patients at the investigator's discretion. Safety endpoints included incidence, type and severity of AEs. Efficacy endpoints included ORR (investigator-assessed) and minimal residual disease (MRD) measured 3 months post-treatment. ORR was strictly assessed per International Workshop Group criteria (iwCLL 2008). Patients with missing response assessment components had their responses downgraded mandatorily. MRD negativity was defined as <1x10-4 malignant B cells in peripheral blood or bone marrow aspirate, measured in a central laboratory by 4-color flow cytometry. The population comprised all patients from cohort 1 of GREEN who received at least a partial dose of both G and B, and was based on a data cut-off of 26 March 2015. Results With a planned overall sample size of 950 patients in GREEN, the G-B subgroup in cohort 1 comprised 158 patients (157 CLL, 1 SLL; 74 fit, 84 non-fit). Median age was 67.6 years, 15.8% of patients had a CIRS score of >6, and 44.9% had a CrCl of <70 mL/min; 31.6% of patients had Binet stage A disease, 38% Binet B, and 30.4% Binet C. 7.0% of patients' disease displayed 17p deletion, 16.5% 11q deletion, and 58.2% unmutated IGHV. 91.1% of patients receiving B and 93.0% of those receiving G took ≥90% of the recommended total dose. The safety profile of G-B was as expected. 50% of patients developed grade 3-5 neutropenia and 12.7% developed a grade 3-5 infection. Other common grade 3-5 AEs included thrombocytopenia (12.7%) and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). There were nine deaths - one due to progression, and eight due to AEs (considered related to study drug by the investigator: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with TLS; considered unrelated: 2 infections and 2 secondary neoplasms). IRRs occurred in 55.7% of patients (15.2% grade 3-5, none fatal). Overall, 26 patients (16.5%) prematurely discontinued treatment due to ≥1 adverse event. The ORR was 78.5% (124/158). The rate of CR (including incomplete CR [CRi]) was 32.3% (51/158), PR 46.2% (73/158), SD 10.8% (17/158), and PD 0.6% (1/158); 10.1% (16/158) of patients had missing data. Response rates were similar in non-fit (34.5% CR/CRi, 41.7% PR, 10.7% SD, and 1.2% PD) and fit (29.7% CR/CRi, 51.4% PR, 10.8% SD, and 0% PD) patients. In an intent-to-treat analysis including all missing (not taken or evaluable) MRD results, MRD negativity was 58.9% (93/158, including 56 missing) in blood and 27.8% (44/158, including 95 missing) in bone marrow. With a median observation time of 11.2 months, PFS data were immature and the median was not reached. Conclusions Treatment with G-B in previously-untreated CLL patients is generally well tolerated and the observed toxicities are manageable and not unexpected. G-B achieves a promising rate of CRs and a high rate of MRD-negative remissions, and may offer a new treatment option for fit and non-fit patients with CLL. Disclosures Stilgenbauer: Gilead: Honoraria, Research Funding. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL. Renner:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Böttcher:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Research Funding; Beckton Dickinson: Honoraria. Tausch:Gilead: Other: Travel support. Moore:Roche: Employment. Tyson:Roche: Employment, Equity Ownership. Adamis:Roche: Employment. Leblonde:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Speakers Bureau. Bosch:Roche: Consultancy, Research Funding, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Biological and Clinical Features of Patients with Chronic Lymphocytic Leukemia Bearing Trisomy 12

Blood ◽

10.1182/blood.v120.21.3907.3907 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3907-3907

Author(s):

Paolo Strati ◽

Lynne V. Abruzzo ◽

William Wierda ◽

Susan Lerner ◽

Susan M. O'Brien ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Progressive Disease ◽

Clinical Course ◽

Lymphocytic Leukemia ◽

Interphase Nuclei ◽

Advisory Committees ◽

Trisomy 12

Abstract Abstract 3907 Cytogenetic abnormalities are among the most important predictors of clinical course and response to therapy in patients (pts) with chronic lymphocytic leukemia (CLL). Conventional chromosome banding (CBA) and fluorescence in situ hybridization (FISH) analyses detect abnormalities in 40–50% and 80% of pts, respectively. Trisomy 12 (+12), observed in ∼20% of CLL pts by FISH, is associated with atypical morphology and immunophenotype, and a more aggressive clinical course. We, therefore, review the clinical characteristics and outcome of 312 CLL pts with +12 evaluated at our center between 1988 and 2011. FISH analysis for common abnormalities associated with CLL was performed on interphase nuclei obtained from cultured bone marrow cells using a multi-color probe panel designed to detect deletions of 11q22.3 (ATM), 13q14.3 (D13S319), 13q34 (LAMP1), 17p13.1 (TP53) and trisomy 12 (12p11.1-q11) (Abbott Molecular, Abbott Park, IL). Survival curves were calculated using Kaplan-Meier estimates and compared using the log-rank test. Differences were considered significant for p < 0.05. Patient characteristics at diagnosis are presented in Table 1. Of 215 pts assessed by both CBA and FISH, 105 were positive for +12 by both analyses and 110 were positive only by FISH. By CBA (112 pts, including 7 assessed only by CBA), +12 was the sole abnormality in 52 pts (47%); +12 was associated with +19 in 17 pts (16%), with del(14q) in 9 pts (8%), with +18 in 8 pts (7%), with +8 in 3 pts (3%), with del(13q) in 3 pts (3%), with t(14;19)(q32;q13) in 3 pts (3%) and with other abnormalities in 17 pts (13%). By FISH (287 pts), +12 was the sole abnormality in 225 pts (78%) and was associated with del(13q) in 62 pts (22%). The median number of interphase nuclei positive for +12 by FISH was 47% (range, 5–93%). One-hundred-eighty-seven pts (60%) needed treatment, with a median Time-To-Treatment (TTT) of 46 months (range, 35–56). The TTT was significantly shorter in pts with Rai stage III-IV disease, splenomegaly, lymphadenopathy, B2m > 4 mg/L, CD38+, ZAP70+, +12 detected by both CBA and FISH, and +12 associated with del(14q) or t(14;19). All 187 pts with progressive disease received treatment: 105 with an FCR-based regimen, 28 with rituximab(R)-based therapy (R+ GM-CSF or R+ methylprednisolone), and 28 with investigational drugs (Lenalidomide, R+ lenalidomide, GS101, or Ibrutinib). Overall response rate was 98%, 89% and 96%, respectively, whereas complete remission rate was 87%, 11% and 36%, respectively. Fifty-five pts failed first-line treatment; their median Failure-Free Survival (FFS) was 27 months (range, 0–87). The FFS was significantly longer in pts who received FCR-based regimens (p<0.001)(Fig 1). The median overall survival (OS) has not been reached, and only 33 pts have died. The OS was significantly shorter in pts older than 65 years, with ALC > 30,000, and with a median +12 positivity in >30% of interphase nuclei by FISH. A trend toward longer OS was observed for pts with +12 associated with +19 (p=0.07). Richter's Syndrome (RS) and second malignancies (SM) were the leading causes of death (5 and 13 of 33 deaths, respectively). RS was reported in 12 pts (4%), after a median time of 36 months from diagnosis. SM was reported in 31 pts (10%), after a median time of 30 months from diagnosis. At the time of diagnosis of SM, 13 patients had received a therapy for CLL and 18 were untreated. In conclusion, pts with CLL and +12 have unique laboratory and clinical features. A high proportion develops progressive disease and requires treatment. Among available therapies, FCR-based regimens are associated with a longer FFS. A high rate of SM is observed in pts with +12, including in pts who have not received prior treatment Disclosures: Wierda: Abbott Laboratories: Research Funding. O'Brien:Avila: Research Funding; Bayer: Consultancy; Bristol-Myers Squibb: Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Cephalon: Consultancy; CII Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Research Funding; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Seattle Genetics, Inc.: Consultancy; Sigma Tau Pharmaceuticals: Consultancy; Talon: Research Funding; The Medal Group: Speakers Bureau.

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Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v126.23.376.376 ◽

2015 ◽

Vol 126 (23) ◽

pp. 376-376 ◽

Cited By ~ 2

Author(s):

Jatin J. Shah ◽

Lei Feng ◽

Sheeba K. Thomas ◽

Donna Weber ◽

Michael Wang ◽

...

Keyword(s):

Febrile Neutropenia ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Lung Infection ◽

Advisory Committees ◽

Kinesin Spindle Protein

Abstract Background: Filanesib (ARRY-520), a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib/carfilzomib/lenalidomide and pomalidomide-refractory MM. Carfilzomib (car), an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM at 27 mg/m2 as well as at 56 mg/m2 in combination with dexamethasone. Part A of the phase 1 trial previously presented demonstrated Car 20/27mg/m2 can be safely combined with filanesib 1.5 mg/m2. We subsequently enrolled and now present additional pts in Part A dose expansion with a cohort of Car naïve and Car refractory pts; we also continued in Part B of the trial with subsequent dose escalation of Car to 56 mg/m2. Methods: The primary objective was to determine the MTD and the safety/tolerability of Car and filanesib in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib and have had prior lenalidomide exposure. Filanesib was administered intravenously (iv) on days 1, 2, 15 and 16; car was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: 51 pts were enrolled in the study (20 patients in Part A dose escalation; 15 carfilzomib-naïve pts in Part A dose expansion; 7 carfilzomib-refractory pts in Part A dose expansion; 9 pts in Part B dose escalation). The median age was 63 (range 41-84); 18 females; 32 males. Of the 15 car-naïve pts dosed in the Part A dose expansion: 1 patient was non-compliant/lost to followup after 2 cycles and inevaluable for response. The ORR (≥ PR) was 36% (5/14; 4 pts with PR and 1 with VGPR). With the addition of 19/20 carfilzomib naïve patients from the Part A dose escalation phase, a total of 33 evaluable pts were dosed who were Car-naïve; 27/33 pts were lenalidomide refractory/intolerant and all pts were bortezomib refractory/intolerant. The ORR (≥PR) was 42% (14/33) and clinical benefit rate (≥MR) was 52% (17/33). 8 pts remain on therapy. In the dose expansion with 7 patients with car refractory disease in Part A, the best response observed was SD in 2 pts dosed for 5 and 6 cycles. In Part B, car was escalated in 3 cohorts to 36 mg/m2, 45 mg/m2 and 56 mg/m2; the filanesib dose remained at 1.5 mg/m2. 9 pts were dosed in the dose escalation. 7/9 pt were lenalidomide refractory; 9/9 pts were refractory to bortezomib; 8/9 pts were refractory to lower doses of carfilzomib. No DLTs were observed in 3 pts dosed in each of the 3 cohorts. The final planned cohort with car 56 mg/m2 and filanesib at 1.5 mg/m2 is ongoing with additional 3 pts, for a total of 6 patients, to confirm the recommended phase 2 dose. Hematologic adverse events included: Grade 3/4 (G3/4) anemia in 14/51 pts; G3/4 thrombocytopenia in 20/51 pts; and G3/4 neutropenia in 21/51 pts. G3/4 non hematologic adverse events were limited and included 1 pt respectively with elevated alanine aminotransferase, aspartate aminotransferase, bacteremia, diarrhea, dizziness, febrile neutropenia, fluid overload, fever, mucositis, peripheral neuropathy, sepsis; 2 pt with dyspnea, sinusitis; 3 pt with elevated creatinine, myalgia and elevated serum lipase; 5 pts with fatigue ; 8 pts with lung infection. Treatment emergent SAEs among all 51 pts included 11 pts with lung infection; 4 pts with renal dysfunction (G2, G3, G3, and G5 each); 3 pts with febrile neutropenia G3 (n=2) and G5 FN (n=1); 2 pts with heart failure; and 1 patient each with G3 bacteremia, G2 lethargy, G2 sinusitis, G3 diarrhea. Conclusions: Full dose filanesib, 1.5 mg/m2,can be safely combined with Carfilzomib 27 mg/m2, in a steroid sparing regimen, with an ORR of 42% and CBR of 52% in bortezomib-refractory patients. The preliminary data from ongoing part B dose escalation supports full dose filanesib can also be combined with carfilzomib 56 mg/m2 and is well tolerated with limited hematologic and the final data set to be presented at ASH. Disclosures Shah: Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Thomas:Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Wang:Pharmacyclics, Janssen, Celgene, Oncopep, Kite, Juno: Research Funding; Janssen: Honoraria. Orlowski:Array BioPharma: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy.

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Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

Blood ◽

10.1182/blood.v120.21.3643.3643 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3643-3643 ◽

Cited By ~ 2

Author(s):

Franck Morschhauser ◽

Louis Terriou ◽

Bertrand Coiffier ◽

Gilles Salles ◽

Ioana Kloos ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Abstract Abstract 3643 Background. Abexinostat is a new hydroxymate-based pan-HDAC inhibitor of class I and II that induces apoptosis and cell cycle arrest in various human tumor cell lines and inhibits tumor growth in several lymphoma xenograft models. Aim. The primary objective of the Phase I was to assess the safety profile and to determine the recommended Phase 2 dose (RP2D) as well as the optimal administration schedule of abexinostat in patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia. The secondary objectives included assessment of pharmacokinetic and pharmacodynamic profiles and preliminary antitumor activity. Methods. Eligibility criteria included ECOG ≤ 1 and adequate hematological, renal and hepatic functions. This study used a 3+3 cohort expansion design to reach the RP2D. Three different 3-week schedules of abexinostat were tested: schedule 1 (S1) with 14 days of treatment (day 1 – day 14); schedule 2 (S2) with 10 days of treatment (day 1 – day 5 and day 8 – day 12); schedule 3 (S3) with 12 days of treatment (day 1 – day 4, day 8 – day 11 and day 15 – day 18). The schedules were evaluated at different dose levels of abexinostat b.i.d. (4 h apart): S1 at 30 mg/m2, and all 3 schedules at both 45 mg/m2 and 60 mg/m2. The following were considered DLTs if they occurred in cycle 1: ≥ grade 3 non-hematologic toxicity, prolongation of QTc interval and febrile neutropenia; grade 4 neutropenia or thrombocytopenia; and next cycle postponed by > 1 week. Results. A total of 35 patients were included. The median age was 61 (21–83). The sex ratio M/F was 22/13. The median number of prior therapies was 5 (2–11). Lymphoma subtypes were Hodgkin's lymphoma (HL) (n=11), follicular lymphoma (FL) (n=7), diffuse large B-cell lymphoma (DLBCL) (n=6), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (n=4), marginal zone B-cell lymphoma (MZL) (n=3), mantle cell lymphoma (MCL) (n=3) and peripheral T-cell lymphoma (n=1). One DLT (thrombocytopenia) was observed in S2 at 45 mg/m2. At 60 mg/m2, 2 DLTs were observed in each schedule: thrombocytopenia in S1 and S2 (2 each), thrombocytopenia and febrile neutropenia (1 each) in S3. Grade 3 and 4 toxicities were exclusively hematologic: thrombocytopenia (G3: 31.4% patients, G4: 25.7% patients), neutropenia (G3: 11.4% patients, G4: 5.7% patients), febrile neutropenia (G3: 2.9% patients, G4: 2.9% patients), anemia (G3: 2.9% patients, G4: 2.9% patients) and leukopenia (G3: 2.9% patients). The other frequent drug-related adverse events were grade 1 and 2: asthenia (34.3% patients), gastro-intestinal disorders (60% patients) and dry skin (17.1% patients). No prolonged QTc intervals were observed in any schedule. A dose reduction occurred in 28.6% patients in S1, 33.3% in S2 and 37.5% in S3. S1 was selected for Phase 2 since it allowed a full week for platelets recovery, a longer drug exposure than S2 and a safety profile similar to the 2 other schedules. Cmax was reached after each administration with median tmax between 0.5 h and 1 h for each schedule and at each dose level. The median apparent terminal elimination half-life was around 4 h. These results are consistent with the limited accumulation of abexinostat with these dose regimens. There is no evidence of time dependent pharmacokinetics. No correlations have been demonstrated so far between histones H3 acetylation in peripheral blood mononuclear cells and PK parameters or clinical activity. Eight out of 29 (27.5%) evaluable patients achieved objective response: 2 complete responses (2 FL) and 6 partial responses (1 FL, 1 CLL, 1 MZL and 3 HL). At the time of data cut off, all but 1 (HL) responses were ongoing between cycle 6 and cycle 22 (median 13.5 cycles). One stable disease (1 MZL) was observed and was still ongoing after cycle 9. Nineteen patients withdrew for progressive disease, including 9 patients who withdrew after at least 2 cycles (4 HL, 2 DLBCL, 1 MCL, 1 MZL and 1 FL). Conclusion. Abexinostat is well tolerated and demonstrates promising durable responses (including CRs) in indolent lymphomas and Hodgkin's lymphoma patients. Enrollment in the Phase II part of the study is ongoing following S1 (3-week cycles – 14 days of treatment) at the RP2D (45 mg/m2b.i.d.). Disclosures: Terriou: Servier: Honoraria; Pfizer: Consultancy; Amgen: Honoraria; GSK: Honoraria. Coiffier:Servier: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kloos:Institut de recherches internationales Servier: Employment. Tavernier:Institut de recherches internationales Servier: Employment. Depil:Institut de recherches Internationales Servier: Employment. Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding.

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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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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IKZF3 Overexpression Phenocopies Gain-of-Function Mutation in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-137085 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-9

Author(s):

Shanye Yin ◽

Gregory Lazarian ◽

Elisa Ten Hacken ◽

Tomasz Sewastianik ◽

Satyen Gohil ◽

...

Keyword(s):

Gene Expression ◽

Chronic Lymphocytic Leukemia ◽

Dna Binding ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Bcr Signaling ◽

Experimental Group

A hotspot mutation within the DNA-binding domain of IKZF3 (IKZF3-L162R) has been identified as a putative driver in chronic lymphocytic leukemia (CLL); however, its functional effects are unknown. We recently confirmed its role as a CLL driver in a B cell-restricted conditional knock-in model. IKZF3 mutation altered mature B cell development and signaling capacity, and induced CLL-like disease in elderly mice (~40% penetrance). Moreover, we found IKZF3-L162R acts as a gain-of-function mutation, altering DNA binding specificity and target selection of IKZF3, and resulting in overexpression of multiple B-cell receptor (BCR) genes. Consistent with the murine data, RNA-sequencing analysis showed that human CLL cells with mut-IKZF3 [n=4] have an enhanced signature of BCR-signaling gene expression compared to WT-IKZF3 [n=6, all IGHV unmutated] (p<0.001), and also exhibited general upregulation of key BCR-signaling regulators. These results confirm the role of IKZF3 as a master regulator of BCR-signaling gene expression, with the mutation contributing to overexpression of these genes. While mutation in IKZF3 has a clear functional impact on a cardinal CLL-associated pathway, such as BCR signaling, we note that this driver occurs only at low frequency in patients (~3%). Because somatic mutation represents but one mechanism by which a driver can alter a cellular pathway, we examined whether aberrant expression of IKZF3 could also yield differences in BCR-signaling gene expression. We have observed expression of the IKZF3 gene to be variably dysregulated amongst CLL patients through re-analysis of transcriptomic data from two independent cohorts of human CLL (DFCI, Landau et al., 2014; ICGC, Ferreira et al., 2014). We thus examined IKZF3 expression and BCR-signaling gene expression, or the 'BCR score' (calculated as the mean expression of 75 BCR signaling-associate genes) in those cohorts (DFCI cohort, n=107; ICGC cohort, n=274). Strikingly, CLL cells with higher IKZF3 expression (defined as greater than median expression) had higher BCR scores than those with lower IKZF3 expression (<median) (p=0.0015 and p<0.0001, respectively). These findings were consistent with the notion that IKZF3 may act as a broad regulator of BCR signaling genes, and that IKZF3 overexpression, like IKZF3 mutation, may provide fitness advantage. In support of this notion, our re-analysis of a gene expression dataset of 107 CLL samples (Herold Leukemia 2011) revealed that higher IKZF3 expression associated with poorer prognosis and worse overall survival (P=0.035). We previously reported that CLL cells with IKZF3 mutation appeared to increase in cancer cell fraction (CCF) with resistance to fludarabine-based chemotherapy (Landau Nature 2015). Instances of increase in mut-IKZF3 CCF upon treatment with the BCR-signaling inhibitor ibrutinib have been reported (Ahn ASH 2019). These studies together suggest an association of IKZF3 mutation with increased cellular survival following either chemotherapy or targeted treatment. To examine whether higher expression of IKZF3 was associated with altered sensitivity to ibrutinib, we performed scRNA-seq analysis (10x Genomics) of two previously treatment-naïve patients undergoing ibrutinib therapy (paired samples, baseline vs. Day 220). We analyzed an average of 11,080 cells per patient (2000 genes/cell). Of note, following ibrutinib treatment, remaining CLL cells expressed higher levels of IKZF3 transcript compared to pretreatment baseline (both p<0.0001), whereas no such change was observed in matched T cells (n ranging between 62 to 652 per experimental group, p>0.05), suggesting that cells with high expression of IKZF3 were selected by ibrutinib treatment. Moreover, we showed that ibrutinib treatment resulted in consistent upregulation of BCR-signaling genes (e.g., CD79B, LYN, GRB2, FOS, RAC1, PRKCB and NFKBIA) (n ranging between 362 to 1374 per experimental group, all p<0.0001), which were likewise activated by mutant IKZF3. Altogether, these data imply that IKZF3 mutation or overexpression may influence upregulation of BCR-signaling genes and enhance cellular fitness even during treatment with BCR-signaling inhibitors. We highlight our observation that IKZF3 mutation appears to be phenocopied by elevated IKZF3 expression, and suggest that alterations in mRNA or protein level that mimic genetic mutations could be widespread in human cancers. Disclosures Kipps: Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding.

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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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Increased Activity of Aldehyde Dehydrogenase, a Stem/Progenitor Cell Marker, in Chronic Lymphocytic Leukemia,

Blood ◽

10.1182/blood.v118.21.3867.3867 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3867-3867

Author(s):

Raymond P. Wu ◽

Christina C.N. Wu ◽

Tomoko Hayashi ◽

Laura Z. Rassenti ◽

Thomas J. Kipps ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Progenitor Cell ◽

Lymphocytic Leukemia ◽

Cell Marker ◽

Aldh Activity ◽

Advisory Committees ◽

Aldefluor Assay

Abstract Abstract 3867 Introduction: Despite their mature appearance, the B cells from chronic lymphocytic leukemia (CLL) possess immature characteristics both functionally and biochemically. CLL B cells display known biochemical markers characteristic of cells early in the blood lineage, including ROR1, Wnt16, and LEF1. In addition, CLL B cells have higher levels of Reactive Oxygen Species (ROS) and of the oxidant-induced transcription factor Nrf2 [NFE2L2], compared to normal peripheral blood mononuclear cells (PBMC). Intracellular ROS status has been suggested to be a marker of cancer stem/progenitor cells possibly due to their high expression of oncogenes. Downstream targets of Nrf2 include the Aldehyde dehydrogenase [ALDH] enzymes, which are believed to play a crucial role in stem cell biology because they protect the cells against oxidative stress caused by accumulation of aldehydes. Here, we use ALDH activity to visualize populations of CLL B cells that may have stem/progenitor properties. Materials and Methods: Isolated PBMC from normal donors and CLL patients with aggressive and indolent disease were stained for ALDH activity with an Aldefluor assay kit (StemCell Technologies). The ALDH inhibitor, diethylaminobenzaldehyde (DEAB), was used to confirm that the fluorescent activity was due to ALDH activity. At the end of the Aldefluor assay, the cells were stained for cell surface markers, CD19, CD5, CD38 and CD34. 50,000 total events were collected for FACS analysis. Normalized Mean Fluorescence Intensity (MFI) values were calculated by dividing each MFI value to average MFI value of normal CD19+ cells for each experiment. Data analyses were performed by FlowJo software and Prizm. P-values were calculated by One-Way ANOVA analysis with Post-Bonferroni's multiple comparison test. Results: We examine the level of ALDH expression and activity in CD19+ cells of healthy donors (n = 9), CLL samples that expressed unmutated IgVH and that were ZAP-70 positive (defined as “aggressive”, n = 14) or samples that expressed mutated IgVH and were ZAP-70 negative (defined as “indolent”, n=12). CLL B cells from patients with aggressive disease had significantly higher ALDH activities compared to normal B cells (p < 0.001) and indolent CLL B cells (p < 0.05) (Figure1). Indolent CLL B cells also have higher level of ALDH activities compared to normal B cells (p < 0.01) (Figure1). Treatment with the ALDH inhibitor, DEAB, suppressed the increased fluorescence observed in CLL B cells. In addition, ALDH high CLL B cells are CD34 negative. These data show that CLL B cells express a marker known to be associated with stem/progenitor cells, but these populations are different from CD34 positive hematopoietic stem cells. In addition, our data show that a stem/progenitor cell marker is associated with the pathogenesis of CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding.

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