A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)

Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

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Impact of Somatic Gene Mutations on Response to Lenalidomide (LEN) in IPSS Lower-Risk Myelodysplastic Syndromes (MDS) Patients (Pts) without Del(5q) and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents (ESAs)

Blood ◽

10.1182/blood.v128.22.225.225 ◽

2016 ◽

Vol 128 (22) ◽

pp. 225-225 ◽

Cited By ~ 2

Author(s):

Valeria Santini ◽

Pierre Fenaux ◽

Aristoteles Giagounidis ◽

Uwe Platzbecker ◽

Alan F List ◽

...

Keyword(s):

Lower Risk ◽

Research Funding ◽

Response Rate ◽

Single Gene ◽

Gene Mutations ◽

Advisory Board ◽

Employment Equity ◽

Mutation Status ◽

Somatic Gene ◽

Equity Ownership

Abstract Background: Somatic gene mutations occur in the majority of MDS pts; specific mutations and high mutation frequency have prognostic relevance (Papaemmanuil et al. Blood. 2013;122:3616-27). Evaluation of somatic mutations may support the diagnosis of MDS and guide treatment (Tx) selection. The phase 3 randomized MDS-005 study compared LEN and placebo (PBO) Tx in red blood cell transfusion-dependent (RBC-TD) non-del(5q) lower-risk MDS pts ineligible for or refractory to ESAs. Deletions in chromosome 5q are associated with a high response rate to LEN in MDS pts; however, no mutations have been definitively associated with a predictable clinical response to LEN in non-del(5q) MDS. Aim:To investigate the relationship between somatic gene mutations detected by targeted next-generation sequencing (NGS) and response and overall survival (OS) in lower-risk non-del(5q) MDS pts treated with LEN in the MDS-005 study. Methods: Eligible pts were: RBC-TD (≥ 2 units packed RBCs/28 days 112 days immediately prior to randomization) with International Prognostic Scoring System defined Low-/Intermediate-1-risk non-del(5q) MDS; ineligible for ESA Tx (serum erythropoietin > 500 mU/mL); or unresponsive or refractory to ESAs (RBC-TD despite ESA Tx with adequate dose and duration). 239 pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40-60 mL/min) or PBO. DNA was isolated from bone marrow mononuclear cells or whole blood collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate tissue for analysis. Targeted NGS of 56 genes was performed at Munich Leukemia Laboratory; average sequencing coverage was 2,000-5,000-foldand the variant allele frequency detection cutoff was 3%. Target regions varied by gene, including all exons to hotspots. For association tests, mutant variants (heterozygous or homozygous) were scored as 1 (mutant) or 0 (wildtype) for gene-level analyses. A Fisher exact test was used to test association of mutation status with response. Median OS was calculated by the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were determined by a non-stratified Cox proportional hazards model. A log-rank test was used to test treatment effect with OS for single gene mutation status. Results: The biomarker cohort included 198 of 239 pts (83%; LEN n = 130, PBO n = 68). At least 1 mutation was detected in 30/56 (54%) genes and 173/198 (87%) pts. The most frequently mutated genes were SF3B1 (59%), TET2 (33%), ASXL1 (23%), and DNMT3A (14%); the most frequent co-mutations were SF3B1/TET2 (23%), SF3B1/DNMT3A (10%), SF3B1/ASXL1 (10%), and TET2/ASXL1 (9%) (Figure). Of 116 pts with SF3B1 mutations, 115 (99%) had ≥ 5% ring sideroblasts. The 56-day RBC transfusion-independence (RBC-TI) response rate was significantly lower in LEN-treated ASXL1 mutant pts vs wildtype pts (10% vs 32%, respectively; P = 0.031). At 168 days, the RBC-TI response rate was still lower in LEN-treated ASXL1 mutant pts vs wildtype pts (7% vs 22%); however, the difference was not significant (P = 0.101). LEN-treated DNMT3A mutant pts had a higher 56-day RBC-TI response rate vs wildtype pts (44% vs 25%); however, this difference did not reach significance (P = 0.133) due to the small sample size. RBC-TI response rate with LEN was similar regardless of total number of mutations per pt. Higher numbers of mutations were significantly associated (P = 0.0005) with worse median OS. Mutation in any of the genes associated with a negative prognosis reported by Bejar et al. (N Engl J Med. 2011;346:2496-506) was also significantly associated (P = 0.0003) with worse median OS.However, OS was not significantly different in LEN- vs PBO-treated pts based on any single gene mutation status. Conclusions: In this group of lower-risk RBC-TD non-del(5q) MDS pts, somatic mutations in genes recurrently mutated in myeloid cancers were detected in 87% of pts. SF3B1 mutations (alone or in combination) were most frequent and not associated with response to LEN. ASXL1 mutant pts had a significantly lower LEN response rate vs wildtype pts, whereas DNMT3A mutant pts had a trend for improved LEN response. Median OS was influenced by mutations, but not significantly modified by LEN. Determining predictive clinical markers for Tx response in non-del(5q) MDS pts remains challenging; nevertheless, there is a significant need to identify pt subsets who may be responsive to LEN Tx. Figure. Figure. Disclosures Santini: Novartis: Consultancy, Honoraria; Amgen: Other: advisory board; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astex: Other: advisory board. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding. Zhong:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Discitis DX: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding.

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Update on a Phase 2 Study of Idelalisib in Combination with Rituximab in Treatment-Naïve Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽

10.1182/blood.v124.21.1994.1994 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1994-1994 ◽

Cited By ~ 15

Author(s):

Susan O'Brien ◽

Nicole Lamanna ◽

Thomas J. Kipps ◽

Ian W. Flinn ◽

Andrew D. Zelenetz ◽

...

Keyword(s):

Research Funding ◽

Tp53 Mutation ◽

Lymphocytic Leukemia ◽

Extension Study ◽

Primary Study ◽

Small Lymphocytic Lymphoma ◽

Employment Equity ◽

Treatment Naïve ◽

Equity Ownership ◽

Systemic Therapies

Abstract Background: The selectivePI3K-delta inhibitor Idelalisib (Zydelig®, IDELA), in combination with rituximab (R), has been previously reported to yield a 97% ORR in treatment naïve patients (pts) ≥65 years with CLL or SLL (O’Brien, ASCO 2013). This report is an update on that initial cohort of study pts. Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m2 weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 weeks without progression could continue to receive idelalisib on an extension study. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, based on modified IWCLL guidelines (Hallek 2008, Cheson 2012). Results: 64 pts were enrolled, 59 CLL/5 SLL, median age 71 yrs (range: 65-90), 63% male, Rai stage III/IV 13/30 (%), nodes ≥5 cm in 11%, WHO 0/1/2 in 42/56/2 (%). Adverse risk factors: del(17p) and/or TP53 mutation in 14%, del(11q) in 16%, IGHV unmutated in 58%, median β2-microglobulin 4.0 mg/L (range 1.9-15.8). Disposition: 43 pts completed the 48 wk primary study and 41 entered the extension study. 21 pts discontinued from the primary study (17 AE, 1 withdrawn consent, 3 deaths [pneumonitis; sepsis; metastatic melanoma with pneumonia]); an additional death occurred within 30 days of discontinuation due to pneumonitis. There were 17 discontinuations from the extension study (9 AE, 2 withdrawn consent, 1 investigator request, 4 PD, 1 death [myocardial infarction]), leaving 24 pts ongoing. The median IDELA exposure is 22.9 mos (range 0.8-45.3), with 13 (20%) pts treated for more than 36 months. The ORRis 97% (78% PR, 19% CR) with 3% nonevaluable; median time to response is 1.9 mos (range 1.6-5.7). The Kaplan-Meier (KM) estimated median PFS is not reached (NR), 95% CI (37.3 mo, --). The KM estimated DOR is NR, 95% CI (35.4,--). Of note, 9/9 pts with del(17p) and/or TP53 mutation responded (3 CR, 6 PR); 5 discontinued for AE (4) or investigator request (1) and 4 remain on treatment for 28, 34, 40 and 41 months. The most frequent Gr ≥3 AEs (%) were diarrhea/colitis (42), pneumonia (19), rash (13), dehydration (8), UTI (6), dyspnea (5) and respiratory failure (5). In addition, pneumonitis developed in 2 pts (3%), both Gr 5, and one pt with diverticulitis developed bowel perforation. The median time to onset of Gr ≥3 diarrhea/colitis was 9.5 mo, (range 3-29). Rechallenge was attempted in 21 of the 27 pts with Gr ≥3 diarrhea/colitis, and 12 pts were able to resume IDELA for ≥ 120 days. 15 (23%) pts developed Gr ≥3 ALT or AST elevation, all recovering, with successful resumption of IDELA, at a reduced dose, in 12. In total, 29 (45%) pts had one or more treatment-emergent AEs leading to IDELA dose reduction. Conclusions: IDELA + R is highly active, rapidly inducing responses in 97% of treatment-naïve older pts with CLL and SLL. The responses are durable, including in those with del(17p)/TP53 mutation. Diarrhea/colitis was the most common Gr ≥3 AE, and IDELA was successfully reintroduced in 44% of the affected pts. Ongoing studies are further investigating the role of IDELA in the frontline setting. Disclosures O'Brien: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Burger:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.

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A Phase 2 Study of Idelalisib Monotherapy in Previously Untreated Patients ≥65 Years with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽

10.1182/blood.v124.21.1986.1986 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1986-1986 ◽

Cited By ~ 19

Author(s):

Andrew D. Zelenetz ◽

Nicole Lamanna ◽

Thomas J. Kipps ◽

Steven E. Coutre ◽

Susan O'Brien ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Lymphoid Tissues ◽

Small Lymphocytic Lymphoma ◽

Employment Equity ◽

Treatment Naïve ◽

Equity Ownership ◽

Systemic Therapies

Abstract BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (Zydelig, IDELA,), a potent and selective orally administered inhibitor of PI3Kδ, in combination with rituximab weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report describes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy. METHODS: Enrollment began in November, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measurable lymphadenopathy, were treated with IDELA 150 mg bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012). RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microglobulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisib exposure was 4.8 months (range 0.9-8.5). There has been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median absolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluable for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluable pts and hepatomegaly in 75% of 4 evaluable pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was observed in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent lab abnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thrombocytopenia. One pt had a TEAE leading to dose reduction. CONCLUSIONS: IDELA has substantial single agent activity in treatment-naïve pts with CLL or SLL. Early lymphocytosis is observed with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximab. IDELA was well tolerated and had a manageable safety profile in this preliminary analysis. Disclosures Zelenetz: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.

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BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽

10.1182/blood-2021-145936 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3742-3742

Author(s):

Anthony R. Mato ◽

William G. Wierda ◽

John M. Pagel ◽

Matthew S. Davids ◽

Pier Luigi Zinzani ◽

...

Keyword(s):

Research Funding ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Fixed Duration ◽

Small Lymphocytic Lymphoma ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Free Survival ◽

Prior Therapy

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today's standard of care. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population. Study Design and Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure). Eligible patients are adults with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Disclosures Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Genmab: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding. Wierda: GSK/Novartis: Research Funding; Xencor: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Gilead Sciences: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy. Davids: Astra-Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding. Zinzani: ROCHE: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; MSD: Consultancy, Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau. Lu: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Liu: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tam: Beigene: Honoraria; Loxo: Honoraria; Abbvie: Research Funding; Janssen: Research Funding; Beigene: Research Funding; Janssen: Honoraria; Abbvie: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Eyre: Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding.

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Evaluation of Ofatumumab, a Novel Human CD20 Monoclonal Antibody, as Single Agent Therapy in Rituximab-Refractory Follicular Lymphoma.

Blood ◽

10.1182/blood.v114.22.935.935 ◽

2009 ◽

Vol 114 (22) ◽

pp. 935-935 ◽

Cited By ~ 15

Author(s):

Anton Hagenbeek ◽

Luis Fayad ◽

Vincent Delwail ◽

Jean Francois Rossi ◽

Eric Jacobsen ◽

...

Keyword(s):

Follicular Lymphoma ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Advisory Board ◽

Employment Equity ◽

Duration Of Response ◽

Heavily Pretreated ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 935 Introduction: Patients with follicular lymphoma (FL) who are refractory to rituximab-based therapy have a need for new non-cytotoxic treatment options. Ofatumumab targets a unique small-loop epitope on CD20 and elicits rapid and efficient in vitro cell lysis via complement-dependent cytotoxicity, even in rituximab-resistant B cells that express high levels of complement inhibitory proteins. Ofatumumab as single agent showed activity in relapsed/refractory FL, including in some patients previously exposed to rituximab (Hagenbeek et al, Blood 2008). Here we report preliminary results from an international, single-arm trial assessing ofatumumab monotherapy in patients with rituximab-refractory FL. Methods: Eligible patients (aged ≥18 years), with Grade 1 or 2 CD20+ FL considered refractory to rituximab alone or in combination with chemotherapy, were enrolled between Sept 2006 and Sept 2008 (N=116). Refractoriness to rituximab (at least 4 doses) was defined as failure to achieve at least a partial response, disease progression during rituximab treatment, or disease progression following a response within 6 months of last treatment with rituximab-containing regimens. Patients received 8 weekly infusions of ofatumumab (Dose 1, 300 mg; Doses 2–8, 500 or 1000 mg); glucocorticoid premedication was required before infusions 1 and 2, and acetaminophen and antihistamine were administered before every infusion. The primary endpoint was objective response (International Working Group criteria) in the 1000 mg dose group over 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee. Secondary endpoints included duration of response, progression-free survival (PFS) and adverse events (AEs). Results: Table 1 summarizes the baseline characteristics; 90% of patients received all 8 ofatumumab doses. The median follow-up time on the study was 4.7 months overall and 5.5 months for the 1000 mg group. The overall response rate (ORR) in the 1000 mg group was 10% (95% CI: 4, 17%), including 1 complete response. Stable disease was observed in 50% of patients. In the 1000 mg group, the median duration of response was 6.0 months (95% CI: 2.8, upper limit not estimable) and median PFS was 6.0 months (95% CI: 4.9, 9.1). The ORR in the total population was 11% (95% CI: 5, 17%). Among patients who were refractory to prior rituximab monotherapy (n=27), the ORR was 22% (95% CI: 7, 38%). The ORR among patients who were refractory to rituximab maintenance therapy (n=44) and rituximab combined with chemotherapy (n=45) was 9% (95% CI: 1, 18%) and 7% (95% CI: 0, 14%), respectively. During treatment and up to 30 days following the last dose, the most common AEs (>10% of patients) included rash (15%), urticaria (14%), fatigue (14%), pruritis (13%), nausea (12%), pyrexia (11%) and cough (11%); grade 3–4 infusion-related reactions occurred in only 3 patients (all grade 3 events), none of which were considered serious events; grade 3–4 hematologic AEs included neutropenia in 5% of patients, anemia in 3% and thrombocytopenia in 1%; grade 3 infections (sepsis, febrile neutropenia) occurred in 2 patients. Conclusions: The majority of patients with rituximab-refractory FL in this study were heavily pretreated, were also refractory to chemotherapy and had high-risk FLIPI scores. Although response rates were low with single-agent ofatumumab in patients refractory to rituximab-chemotherapy, a higher response rate was observed in patients who were refractory to rituximab monotherapy, indicating activity despite being refractory to single-agent rituximab. Ofatumumab was well tolerated in this heavily-pretreated population. Infusion reactions were manageable and no unexpected toxicities were observed. Further investigations with ofatumumab are warranted, including in combination with other therapies in patients with FL. Disclosures: Hagenbeek: Roche, Bayer Schering Pharma, Genmab: Advisory roles. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis).. Fayad:GlaxoSmithKline, Genmab: Research Funding. Rossi:GlaxoSmithKline: Investigator on trial funded by GSK. Kuliczkowski:GlaxoSmithKline: Investigator on trial funded by GSK. Link:Genentech: Advisory Board, Research Funding; Genmab, GlaxoSmithKline: Research Funding. Radford:GlaxoSmithKline: Equity Ownership. Hellmann:Novartis, BMS: Consultancy, Honoraria. Gupta:GlaxoSmithKline: Employment. Arning:GlaxoSmithKline: Employment, Equity Ownership. Begtrup:Genmab: Employment, Equity Ownership. Schultz:Genmab: Employment. Bang:Genmab: Employment. Russell:Genmab: Employment, Equity Ownership. Czuczman:GlaxoSmithKline: Advisory Board, Honoraria, Research Funding; Genmab: Advisory Board, Research Funding.

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MAGNIFY: Phase IIIb Randomized Study of Lenalidomide Plus Rituximab (R2) Followed By Lenalidomide Vs. Rituximab Maintenance in Subjects with Relapsed/Refractory Follicular, Marginal Zone, or Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1798.1798 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1798-1798 ◽

Cited By ~ 7

Author(s):

David J. Andorsky ◽

Abdulraheem Yacoub ◽

Jacob D. Bitran ◽

Jason Melear ◽

Heather D. Brooks ◽

...

Keyword(s):

Research Funding ◽

Randomized Study ◽

Treatment Withdrawal ◽

Clinical Activity ◽

Open Label ◽

Employment Equity ◽

Prior Therapy ◽

Rituximab Maintenance ◽

Phase Iiib ◽

Equity Ownership

Abstract Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received >=1 prior therapy and had stage I-IV, measurable disease (>1.5 cm). Subjects received 12 cycles of R2 induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R2 vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (<=2 vs. >2), and age (<65 vs. >=65 years).Maintenance R2 consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R2 maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03. Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for <6 months with prior rituximab). The most common prior regimens were rituximab (41%), BR (25%), R-CHP (14%), R-CHOP (11%), and R-CVP (7%). At data cut-off, 45 (33%) subjects discontinued treatment before the maintenance period. Primary reasons for discontinuation of lenalidomide and/or rituximab, respectively, were due to AEs in 16 (12%) and 14 (10%) subjects, PD in 15 (11%) subjects for either treatment, withdrawal by subject in 6 (4%) and 7 (5%) respectively, and death 3 (2%) in either treatment. In the safety population (n=124), treatment-emergent adverse events (AE) during induction that led to dose reduction/interruption of lenalidomide or rituximab occurred in 55% or 24% of subjects, respectively, mainly due to neutropenia for lenalidomide and infusion-related symptoms for rituximab. The most common grade 3/4 AEs during induction were 27% neutropenia, 9% leukopenia, 6% thrombocytopenia, and 5% fatigue. 11 subjects have died (5 due to PD, 3 AEs, 3 other). At a median duration of 23.1 weeks (range, 0.1-51.1) of induction, 90 subjects were evaluable for response. Best responses to induction were 56 (62%) subjects with ORR, 8 (9%) CR, 12 (13%) CRu, 36 (40%) PR, and 22 (24%) SD. Responses with R2 treatment were observed in all histologies (Table 1). At data cut-off, 19 subjects have completed induction and 18 have proceeded to maintenance (n=7 R2, n=11 rituximab alone). Continued study and follow-up are ongoing to enroll more subjects in the induction and maintenance arms. Conclusions: R2 induction therapy shows favorable activity and a tolerable safety profile in subjects with advanced-stage, relapsed/refractory FL, MZL, MCL, and TL. Continued study is ongoing to determine the effect of R2 vs. rituximab maintenance following 1 year of R2 induction. Disclosures Andorsky: Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI: Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Bitran:Oncology Specialists: Employment. Melear:Texas Oncology: Employment. Foon:Celgene: Employment. Rizvi:Celgene: Employment, Equity Ownership. Llorente:Celgene: Employment. Li:Celgene: Employment, Equity Ownership. Sharman:Genentech: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy; Gilead: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy.

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Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽

10.1182/blood-2019-123406 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3512-3512

Author(s):

Rachael F. Grace ◽

D. Mark Layton ◽

Frédéric Galactéros ◽

Wilma Barcellini ◽

Eduard J. van Beers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

The Core ◽

Equity Ownership ◽

Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses >25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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TROPICS 2: A Phase III, Open-Label, Single-Arm Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Catheters.

Blood ◽

10.1182/blood.v114.22.1074.1074 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1074-1074

Author(s):

Cameron Tebbi ◽

John Costanzi ◽

Robert J Shulman ◽

Luke Dreisbach ◽

Brian R Jacobs ◽

...

Keyword(s):

Intracranial Hemorrhage ◽

Major Bleeding ◽

Thrombolytic Agent ◽

Treatment Success ◽

Central Venous Catheters ◽

Phase Iii ◽

Central Venous ◽

Open Label ◽

Employment Equity ◽

Equity Ownership

Abstract Abstract 1074 Poster Board I-96 Introduction: For many patients, central venous catheters (CVCs) are the only option for vascular access. Thrombotic occlusion is a common complication of CVCs and can prevent delivery of treatment. The objectives of this phase III, open-label, single-arm study were to evaluate the safety and efficacy of the thrombolytic agent tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, in restoring function to occluded CVCs. Methods: Pediatric and adult subjects with dysfunctional non-hemodialysis CVCs, defined by the inability to withdraw 3 mL of blood (1 mL of blood for subjects weighing <10 kg) were eligible. Subjects received intraluminal tenecteplase at a dose of up to 2 mL (2 mg); subjects weighing <30 kg received instillations of tenecteplase equal to 110% of the internal lumen volume (maximum volume, 2 mL). Tenecteplase was allowed to dwell in the lumen for up to 120 minutes. CVC function, defined as the ability to both withdraw 3 mL of blood or fluid and infuse 5 mL of normal saline (1 mL and 3 mL, respectively, for subjects <10 kg), was assessed at 15, 30, and 120 minutes after drug instillation. If function was not restored at 120 minutes, the initial dose was withdrawn, and a second dose was instilled for up to 120 minutes. CVC assessments were repeated as for the first dose. The primary efficacy endpoint was restoration of CVC function within 120 minutes after a single administration of tenecteplase. All adverse events (AEs) were documented from instillation of the first tenecteplase dose through 48-96 hours after treatment. Targeted AEs (intracranial hemorrhage, major bleeding, embolic events, thrombosis, catheter-related bloodstream infection [CRBSI], and catheter-related complications) and study-drug–related serious AEs were recorded through 7 days after treatment. Results: Tenecteplase was administered to 246 subjects (mean age 43.6 years; range, 0-92 years), 72 (29.2%) of whom were under 17 years of age. Most subjects had a port catheter (69.5%), and the most frequent indication for catheter insertion was chemotherapy (78.0%). Most subjects (186; 75.6%) received only a single dose of tenecteplase, and 60 (24.3%) subjects required a second dose of tenecteplase. Restoration of CVC function was achieved in 177 (72.0%) subjects within 120 minutes after the first dose of tenecteplase. Following instillation of up to 2 doses of tenecteplase, CVC function was restored in 200 (81.3%) subjects, with similar restoration rates observed in pediatric (83.3%) and adult (80.5%) subjects. Among those who had treatment success and underwent catheter assessment within 7 days of treatment, 111 (81.0%) subjects maintained catheter patency. Thirty-one (12.6%) subjects experienced a treatment-emergent AE; the most common events were pyrexia (6 subjects), neutropenia (3 subjects), and nausea (2 subjects).Two targeted AEs were reported, both CRBSIs, but neither event was judged by the investigator to be related to tenecteplase; and in both cases, blood cultures were subsequently reported negative. No cases of intracranial hemorrhage, major bleeding, thrombosis, embolism, or catheter-related complications were reported. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase; however, this subject was concurrently receiving a chemotherapeutic agent, which the investigator also considered to be related to the AE. Conclusions: Serial administration of up to 2 doses of tenecteplase into CVCs is safe and effective for restoration of catheter function in pediatric and adult subjects with dysfunctional CVCs. Disclosures: Off Label Use: Tenecteplase is a thrombolytic agent under study for clearance of dysfunctional central venous catheters. Shulman:Takeda Pharmaceuticals: Research Funding; NPS Pharmaceuticals: Consultancy. Jacobs:Speaking engagements unrelated to commercial activity: Honoraria. Blaney:Genentech: Employment, Equity Ownership. Ashby:Genentech: Employment, Equity Ownership. Gillespie:Quintiles: Employment, Quintiles is a contract research organization contracted by Genentech to execute the TROPICS trials.. Begelman:Genentech: Employment, Equity Ownership.

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A Phase II Study of Oral Tamibarotene in Acute Promyelocytic Leukemia (APL) Patients (PTS) Who Have Received Prior Therapy with All-Trans Retinoic Acid and Arsenic Trioxide (STAR-1 trial).

Blood ◽

10.1182/blood.v114.22.2050.2050 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2050-2050

Author(s):

Jorge Cortes-Franco ◽

Steven Coutre ◽

Eros Di Bona ◽

Francesco Lo-Coco ◽

Meir Wetzler ◽

...

Keyword(s):

Retinoic Acid ◽

Arsenic Trioxide ◽

Treatment Interruption ◽

Initial Therapy ◽

Qtc Interval ◽

Employment Equity ◽

Prior Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Equity Ownership

Abstract Abstract 2050 Poster Board II-27 BACKGROUND: Most patients with APL have a favorable outcome after treatment with all-trans-retinoic acid (ATRA), and most of those who fail can be successfully treated with arsenic trioxide (ATO). However, a few patients may not respond or eventually relapse after therapy with these agents. Tamibarotene is a synthetic retinoid that has been reported to be well-tolerated and effective in APL in studies in Japan. Treatment with tamibarotene is associated with a low incidence of differentiation syndrome and it has no effect on QTc interval. METHODS: Patients with APL refractory or relapsed after treatment with both ATRA and ATO (sequential or concomitant) were eligible, with no limit on the total number of prior therapies. Pts received tamibarotene orally at a daily dose of 6 mg/m2 divided in two doses until remission or a maximum of 56 days. After remission, patients could continue consolidation courses with the same dose for 4 weeks every 8 weeks for a maximum of 3 courses. RESULTS: Nine patients have been treated, 4 female, median age 57 years (range, 45-60). Patients had received a median of 7 prior therapies, and 1 had received two prior stem cell transplants (SCT). At the start of therapy the median WBC was 2.6 ×109/L (0.29 to 16.7) and platelet count 50 ×109/L (22 to 121). Of the 9 pts treated, 3 (33%) achieved a hematologic CR and 4 (44%) a morphologic leukemia-free state. After induction, 3 (33%) patients had achieved a cytogenetic remission and 1 (11%) had undetectable PML-RARα transcript levels. One patient went to SCT after achieving CR and died in CR of GVHD. The two other CRs continued with consolidation therapy and received 2 and 3 cycles, respectively. One of them relapsed after completing all treatment. Remissions have been sustained for 3+ and 8 months, respectively. Treatment was well tolerated. Differentiation (“ATRA”) syndrome was observed in 1 patient that resolved with medical management without requirements for treatment interruption. Other toxicities possibly related to tamibarotene include dry mouth in 2 (22%) patients, neutropenia in 1 (11%), generalized weakness in 1 (11%), joint pains in 1 (11%), hypertriglycerdemia in 1 (11%), vomiting in 1 (11%), diarrhea in 1 (11%), leg edema in 1 (11%), and bone pain in 1 (11%) patient. Grade 3-4 adverse events possibly related included neutropenic fever in 1 patient (11%), syncope in 1 patient (11%), and somnolence in 1 patient (11%). CONCLUSION: These results suggest that tamibarotene is an effective agent for management of APL. Based on the favorable results observed in this heavily pre-treated population, studies of tamibarotene in combination with other agents as initial therapy are being planned. Disclosures: Wieland: CytRx Corporation: Employment, Equity Ownership. Barber:CytRx Corporation: Employment, Equity Ownership.

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