Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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A Multi-Center, Open-Label Phase II Study of Lenalidomide Plus Low-Dose Dexamethasone in Chinese Patients with Relapsed/Refractory Multiple Myeloma - the MM-021 Trial

Blood ◽

10.1182/blood.v120.21.1864.1864 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1864-1864

Author(s):

Jian Hou ◽

Jie Jin ◽

Zhen Cai ◽

Fangping Chen ◽

Li Yu ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Chinese Patients ◽

Open Label ◽

Advisory Committees ◽

Overall Response ◽

Best Response

Abstract Abstract 1864 Background: Previous studies (i.e. ECOG E4A03) have shown that lenalidomide plus low-dose dexamethasone (Rd) has a better safety profile compared with lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM patients. It is hypothesized that Rd may also provide benefits in patients with relapsed/refractory multiple myeloma (RRMM). The MM-021 trial is the largest study in Chinese patients with RRMM aimed to assess the efficacy, safety, and pharmacokinetics (PK) of Rd in patients who had progressed or were refractory to previous treatment. Methods: This was a phase II, multi-center, single arm, open-label study, RRMM patients received lenalidomide (25 mg/day on days 1–21) and dexamethasone (40 mg on days 1, 8, 15 and 22) in 28-day treatment cycles until disease progression. Thromboembolic prophylaxis with aspirin or other anti-thrombotic medication was required. The primary endpoint was the best overall response rate (partial response [PR] or better) based on the investigator's assessment. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), safety, and PK parameters. Results: As of April 23, 2012 (median follow-up of 10.8 months), 199 patients have completed at least 1 cycle, 134 patients have completed at least 6 cycles, and 187 patients were evaluable for efficacy. Median age was 59 years (range 35–81) and 63% were male. The majority of patients (86%) had Durie-Salmon stage III disease and 57% had received ≥4 prior anti-myeloma regimens including bortezomib (64%), thalidomide (69%), or both bortezomib and thalidomide (45%). After median treatment duration of 8 months (range 1–18) or 8 cycles (range 1–19), best overall response rate (≥PR) was 54% (100 patients); including 8% (14 patients) with a best response of complete response (CR). Overall disease control (≥stable disease [SD] or better) was 95%, including 42% (78 patients) with best response of SD. Nine patients (5%) had best response of disease progression. Best overall response rates were consistent across subgroups when analyzed according to baseline renal function (creatinine clearance ≥60 mL/min: 68 patients [54%], 330 to <60 mL/min: 26 patients [52%], <30 mL/min: 6 patients [50%]) and number of prior therapies (64% if ≤2 prior regimens, 50% if >2 prior regimens). Responses were also consistent regardless of prior therapy received; 50%, 52%, and 47% for patients who previously received bortezomib, thalidomide, or both, respectively. Of the 5% (10 patients) presenting with IgD at baseline, 7 patients achieved ≥PR. Median time to first response was 2 months (range 1–12) and median duration of response was 7 months (range 0–16). The median PFS was 8 months (95% CI: 6–9) and the OS rate was 86% at 6 months and 73% at 1 year. Among the 199 patients evaluable for safety, the most common grade 3–4 adverse events (AEs) were anemia (25%), neutropenia (24%), thrombocytopenia (15%), and pneumonia (13%). Only 1 patient experienced febrile neutropenia. AEs led to dose reduction/interruption of lenalidomide in 40% of patients, 41% for dexamethasone; and 6.5% discontinued treatment due to one or more AEs. No patient discontinued due to anemia or neutropenia. Sixty-one patients (31%) died on study and the most common cause of death was disease progression (15 patients, 8%). Conclusions: Based on a median follow-up of nearly 11 months, the Rd regimen achieved a substantial best overall response rate (54%) in heavily pretreated RRMM Chinese patients. Response rates were consistent across subgroups including patients with renal impairment. The combination of Rd regimen was generally well tolerated. Disclosures: Hou: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Xian: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jensen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mei:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment. Wortman-Vayn:Celgene Corporation: Employment.

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Update On the Phase IIb, Open-Label Study of Vorinostat in Combination with Bortezomib in Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.3890.3890 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3890-3890 ◽

Cited By ~ 1

Author(s):

David Siegel ◽

Sundar Jagannath ◽

Sagar Lonial ◽

Meletios A. Dimopoulos ◽

Thorsten Graef ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Cutaneous Manifestations ◽

Treatment Regimens ◽

Equity Ownership

Abstract Abstract 3890 Poster Board III-826 Introduction Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. MM accounts for approximately 1% of all new cancer diagnoses and is the second most common hematologic malignancy in adults. Despite recent advances in therapy, MM remains largely incurable and there is a need to develop new treatments or treatment regimens to combat MM. Vorinostat is an oral histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous manifestations of T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. As HDACs are over-expressed and involved in the regulation of transcription with recruitment by oncogenic transcription factors in a variety of tumor types, the efficacy of vorinostat is currently under investigation in a number of hematologic and solid malignancies, including MM. Bortezomib is a proteasome inhibitor that has provided significant survival advantages for patients with MM. Preclinical studies have shown that the combination of vorinostat and bortezomib synergistically induces MM cell apoptosis. Results from two Phase I studies showed that the combination of vorinostat and bortezomib (+/- dexamethasone) is well tolerated and achieves ∼ 40% objective response rate in a relapsed/refractory MM population, even in those patients who were refractory to prior bortezomib treatment (Weber et al. Clinical Lymphoma and Myeloma 2009;9:S44, abstract A248) (Weber et al. Clinical Lymphoma and Myeloma 2009; 9:S42, abstract A242). Encouraging results observed in these trials led to the design of a Phase IIb, international, multicenter, open-label study that will assess the efficacy and tolerability of vorinostat in combination with bortezomib in advanced MM patients. Methods Patients (aged ≥18 years) with relapsed and refractory MM after two prior treatment regimens, including at least one bortezomib-containing regimen, and who are relapsed, refractory, intolerant, or ineligible for other therapies, including immunomodulatory agents, were included in this trial. Patients received intravenous bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 and oral vorinostat 400 mg once daily on Days 1-14 of each 21-day cycle. The addition of oral dexamethasone (20 mg on the day of and day after each bortezomib dose) was permitted for patients who experienced disease progression after two treatment cycles or no change (stable disease) after four cycles, until further disease progression. The primary endpoint is objective response rate and secondary endpoints include assessment of: safety, time to disease progression, progression-free survival, and overall survival. Patient-reported outcomes were collected in this study as an exploratory objective. Study enrollment At the time of submission, 38 patients (out of 142) have been enrolled in the trial. A first interim futility analysis is planned after the 43rd patient has been enrolled. At the time of the meeting, safety data, along with enrollment status and timelines for future data read-outs, will be reported. Disclosures: Siegel: Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Dimopoulos:MSD: Honoraria; Celgene: Honoraria. Graef:Merck: Employment, Equity Ownership. Pietrangelo:Merck: Employment, Equity Ownership. Lupinacci:Merck: Employment, Equity Ownership. Reiser:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment. Anderson:Millennium: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding.

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Clinical Effectiveness of Combination Immunotherapy DPX-Survivac, Low Dose Cyclophosphamide, and Pembrolizumab in Recurrent/Refractory DLBCL: The Spirel Study

Blood ◽

10.1182/blood-2020-136751 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-16

Author(s):

Neil L Berinstein ◽

Isabelle Bence-Bruckler ◽

Nicholas Allen Forward ◽

Pierre Laneuville ◽

Joy Mangel ◽

...

Keyword(s):

T Cell ◽

Cell Carcinoma ◽

Board Of Directors ◽

Cell Response ◽

Research Funding ◽

Low Dose ◽

Response Rate ◽

Objective Response ◽

T Cell Response ◽

Advisory Committees

Background: Recurrent/refractory (r/r) DLBCL presents a major treatment challenge, especially in the setting of patients who are ineligible for, or relapsing after, potentially curative treatments such as autologous stem cell transplant (ASCT) and chimeric antigen receptor T cell (CAR-T) therapy. Efficacious treatment options that are well-tolerated and easily accessible in this population represent a critical unmet medical need. DPX-Survivac is a targeted T cell activation therapy against cancers expressing survivin. Survivin plays an essential role in cancer biology and represents a target of choice to disrupt tumour progression. DPX-Survivac's mechanism of action relies on its ability to generate robust and durable survivin-specific T cells that migrate to, infiltrate and kill tumour cells. DPX-Survivac is administered with intermittent, low dose cyclophosphamide (CPA) used as an immunomodulator. In nonclinical studies, treatment with DPX-Survivac increases PD-L1 and PD-1 expression providing the rationale for combination with pembrolizumab. Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with r/r DLBCL with confirmed survivin expression are eligible for participation. Subjects must also be ineligible for potentially curative therapy. The treatment and testing regimen is shown in the figre below. The primary objective of SPiReL is to document a minimum Objective Response Rate (ORR) of 24% (in 6/25 subjects) using the modified Cheson criteria (2007). Secondary objectives include safety, duration of response and time to next treatment. Exploratory endpoints include T cell response, tumour immune cell infiltration, and biomarker analysis. Results: At data cut-off, 22 subjects have been enrolled in the study. The median age is 75.5 years (50-82). Thirteen of 22 subjects (59.1%) are GCB sub-type, 8 subjects (36.4%) are non-GCB and 1 subject (4.5%) has primary cutaneous DLBCL, leg type. The median number of prior therapies is 2 (1-7), with 4 subjects having previously undergone ASCT and 5 subjects with transformed disease. Of the 22 enrolled subjects, 8 are not evaluable per protocol for clinical efficacy due to early disease progression. Four subjects are active on treatment, 3 of which have not yet reached the first time point for assessment. Clinical outcome was analyzed for the Full Analysis Set (FAS) (n=19) and in the Per Protocol (PP) analysis (n=11). Of 11 subjects in the PP, 7 subjects (63.6%) have achieved an objective response, meeting the study's primary endpoint; 3 subjects (27.3%) with a CR and 4 subjects (36.4%) with a PR. Three subjects (27.3%) achieved SD and thus clinical benefit was demonstrated in 10/11 (90.9%) of evaluable subjects. Two subjects (18.2%) have completed the 1 year treatment period, 8 subjects (72.7%) discontinued treatment due to disease progression, and 1 subject (9.2%) discontinued treatment due to an unrelated Adverse Event (AE). Including the entire FAS, the objective response rate was 7/19 (36.8%). This treatment combination is well-tolerated, only 11% of Treatment Related AEs (TRAEs) were assessed as Grade 3 or higher. The majority of the Grade 1 and 2 TRAEs were Injection Site Reactions (ISRs) related to DPX-Survivac. Ten serious AEs were reported, of which 3 were considered related to study treatment. No subjects have discontinued study treatment due to a TRAE. Analyses of peripheral blood T cell responses to survivin by ELISpot assay shows that 7/7 subjects who achieved an objective response have survivin-specific T cell response. One subject with PD also showed a survivin-specific T cell response, supporting the mechanism of action and the role of DPX-Survivac in anti-tumor activity. Summary: DPX-Survivac and low dose CPA in combination with pembrolizumab, demonstrates promising clinical activity in recurrent/refractory DLBCL with 10/11 (90.9%) of evaluable subjects deriving clinical benefit with minimal toxicity. The primary endpoint of this study has been reached with 7/11 (63.6%) of evaluable subjects achieving an objective response warranting further exploration of DPX-Survivac in this population. Enrollment is continuing to further define the patient population most likely to benefit from this well-tolerated therapy. Figure 1 Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Forward:Seattle Genetics: Research Funding; IMV: Research Funding; Merck: Research Funding; Astellas: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Stewart:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria. Bramhecha:IMV Inc.: Current Employment. Conlon:IMV Inc.: Current Employment. OffLabel Disclosure: Keytruda (pembrolizumab). Indicated for use in melanoma, nonÃƒÆ'Ã'Â¢ÃƒÂ¢Ã¢â'¬Å¡Ã¢â€šâ'¬ÃƒÂ¢Ã¢â€šâ'¬Ã…â€œsmall cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), and renal cell carcinoma (RCC).

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Expand: a Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis and Baseline Platelet Counts Between 50 × 109/L and 99 × 109/L

Blood ◽

10.1182/blood.v120.21.177.177 ◽

2012 ◽

Vol 120 (21) ◽

pp. 177-177 ◽

Cited By ~ 2

Author(s):

Claire N Harrison ◽

Heinz Gisslinger ◽

Carole B. Miller ◽

Jean-Jacques Kiladjian ◽

Edric Atienza ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Dose Finding ◽

Open Label ◽

Advisory Committees ◽

Starting Dose ◽

Finding Study ◽

Label Dose ◽

Phase 1B

Abstract Abstract 177 Background: Ruxolitinib (rux) is a potent oral JAK1 and JAK2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of myelofibrosis (MF). In the two phase 3 COMFORT studies, rux demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. Although there has been considerable experience in patients (pts) who developed thrombocytopenia in the COMFORT studies, there has been limited experience in pts with baseline thrombocytopenia as those with platelet counts (PLTs) < 100 × 109/L were excluded. The aims of EXPAND are to evaluate the safety of rux and to establish the maximum safe starting dose (MSSD) in thrombocytopenic MF pts. Methods: Phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLTs 50–99 × 109/L. A Bayesian logistic regression model will be used to guide dose-escalation decisions; intra-pt dose modification is allowed during the study. The study consists of 2 phases: dose escalation and safety expansion. Starting dose of rux is 5 mg bid with a maximum of 15 mg bid. In the dose-escalation phase, cohorts will be: 5 mg bid, 5 mg AM/10 mg PM, 10 mg bid, 10 mg AM/15 mg PM, and 15 mg bid. Pts are assigned to 1 of 2 strata based on their baseline PLTs: stratum 1, 75–99 × 109/L; stratum 2, 50–74 × 109/L. Each dose level in the second stratum will be open only if both that dose and the following one are deemed safe in the first stratum. In the safety-expansion phase, 20 additional pts (10 in each stratum) will be treated at the respective MSSD for their stratum. Results: 14 pts (PMF, n = 10; PPV-MF, n = 3; PET-MF, n = 1) have been enrolled in 4 cohorts: 4 pts in stratum 1/cohort 1 (5 mg bid), 3 in stratum 1/cohort 2 (5 mg AM/10 mg PM), 4 in stratum 1/cohort 3 (10 mg bid), and 3 in stratum 2/cohort 1 (5 mg bid). At baseline, all pts had an ECOG performance status of 0–2, and spleen length ranged from 5–30 cm below the costal margin. 12 pts have completed > 28 days of treatment and are evaluable. 2 pts were nonevaluable: 1 pt discontinued at day 6 due to granulocytic sarcoma, and 1 pt took an incorrect dosage from day 1 to 7 but treatment is ongoing. Reported adverse events (AEs) were similar to those previously seen with rux. 7 pts experienced grade 3/4 AEs (only 2 anemia events were study-drug related), and 4 pts experienced serious AEs (Table). The majority of hemoglobin and absolute neutrophil count (ANC) abnormalities were grade 1 or 2. No pt had a grade 4 decrease in PLTs or ANC; 2 pts experienced a grade 4 decrease in hemoglobin. No pt discontinued due to anemia, neutropenia, or thrombocytopenia. No hemorrhagic events were observed. The lowest PLTs across all pts ranged from 29–96 × 109/L. No dose-limiting toxicities (DLTs) were observed. Reductions in spleen length were reported for all 12 evaluable pts and 1 ongoing nonevaluable pt. Splenomegaly completely resolved in 3 pts. Spleen length reductions were rapid and occurred within the first few weeks of therapy. Conclusions: In this study, no DLT has occurred with the first 3 dose levels in pts with PLTs 75–99 × 109/L or with the first dose level in pts with PLTs 50–74 × 109/L. Rux was generally well tolerated, similar to results reported in previous studies, and no pt has discontinued because of thrombocytopenia. The study is ongoing, and additional pts are being recruited for both strata. Pts are receiving dose levels approaching those approved for nonthrombocytopenic MF pts. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Atienza:Novartis Pharmaceuticals Corporation: Employment. Stalbovskaya:Novartis Pharma AG: Employment, Equity Ownership. Sirulnik:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Al-Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. McMullin:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Shire: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.

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Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2677.2677 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2677-2677

Author(s):

Madeleine Duvic ◽

Steven M Horwitz ◽

Youn H Kim ◽

Pier Luigi Zinzani ◽

Gajanan Bhat ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Dose Finding ◽

Advisory Committees ◽

Finding Study ◽

Dose Finding Study ◽

Grade 3 ◽

Ecog Ps

Abstract Background: Cutaneous T-cell Lymphomas (CTCL) include several variants of extra-nodal non-Hodgkin's lymphomas characterized by their skin lesions and T-cell surface markers. The most common, mycosis fungoides (MF), often has an indolent course but can transform and rapidly disseminate. While skin-directed therapies are effective for early-stage MF, patients with refractory, transformed or late-stage disease require systemic therapy. Methods: Adult patients with CTCL including MF, transformed MF (T-MF), Sézary syndrome (SS), primary cutaneous anaplastic large cell lymphoma (ALCL), ≥ 1 prior systemic therapy, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were eligible and signed consent. FOL was administered weekly via intravenous push for 3 of 4 weeks; BEX was self-administered orally with food. The standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD), with cohort expansion for dose-limiting toxicities (DLTs). The MTD was the highest dose with < 33% DLT incidence in any cohort. DLTs included the following in Cycle 1: ≥ Grade 3 neutropenia (or G-CSF administered), thrombocytopenia, treatment-related non-hematologic toxicity, hyperlipidemia, or hypothyroidism, and treatment-related adverse events (AEs) causing BEX dose omission for ≥10/28 days or FOL dose omission/reduction. Results: In Cohort 1 (15 mg/m2 FOL + 150 mg/m2 BEX), 0/3 patients had DLTs. In Cohort 2a (15 mg/m2 FOL + 300 mg/m2 BEX), 2/3 patients had DLTs: Grade 3 neutropenia and Grade 2 hypotension (n = 1) and Grade 4 neutropenia and thrombocytopenia (n = 1). Therefore, the combination MTD was identified as 15 mg/m2 + 150 mg/m2. An additional 28 patients were enrolled at the MTD for a total of 34 patients (53% male, 47% female) in the study; all have discontinued treatment. The median age was 66 (range 39-85) years, and the median number of prior therapies was 4 (range 2-14). Histology included MF (53%), T-MF (32%), SS (12%), and ALCL (3%). ECOG PS was 0 (68%), 1 (18%), or 2 (15%). Patients received a median of 6 (range 1-33) cycles of therapy. All patients reported ≥ 1 AE. The most common (>20%) FOL-related AEs were mucositis or mucosal inflammation (68%), fatigue (41%), neutropenia and nausea (32% each), and anemia (24%). The most common (>20%) BEX-related AEs were hypertriglyceridemia (56%), fatigue (44%), neutropenia (32%), nausea (26%), and uncorrected hypothyroidism (24%). Grade 3 and 4 AEs were reported for 79% and 9% of patients, respectively: neutropenia (29% and 6%), hypertriglyceridemia (29% and 0%), and stomatitis (21% and 0%) and one Grade 5 AE of respiratory failure. Serious adverse events (SAEs) were reported for 35% of all patients; SAEs in > 1 patient were neutropenia and hypotension (6% each). Dose omissions and reductions for AEs were required for 74% and 21% of patients, respectively. AEs led to discontinuation for 32% of all patients, most commonly stomatitis (9%) and anemia, fatigue, and neutropenia (6% each). The overall Objective Response Rate was 61% (20/33 evaluable patients); 18/30 [60%] in Cohort 1 and 2/3 [67%] in Cohort 2. Four [12%] patients had a complete response, 16 [48%] partial response, 11 [33%] stable disease, and 2 [6%] progressive disease. Duration of Response ranged from 0-29+ months; median Response Duration was not reached, as 14 patients (3 CRs, 11 PRs) remained in response. Median PFS at the MTD was 12.8 (range 0.5-29.9+) months. Table 1. Response by CTCL Subtype Objective Response Rates CTCL Subtype Overall CR PR All Evaluable, n=33 20 (61%) 4 16 ALCL, n = 1 1 (100%) 1 0 MF, n = 19 12 (63%) 2 10 T-MF, n = 10 5 (50%) 1 4 SS, n = 3 2 (67%) 0 2 Conclusions: The combination of FOL + BEX was well tolerated and efficacious in patients with various CTCL subtypes, as measured by response rates (61% including patients with durable CRs) in this dose-finding study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Therakos: Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Oncoceutics: Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy. Bhat:Spectrum Pharmaceuticals, Inc: Employment.

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A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.848.848 ◽

2013 ◽

Vol 122 (21) ◽

pp. 848-848 ◽

Cited By ~ 22

Author(s):

Nancy L. Bartlett ◽

Jeff P. Sharman ◽

Yasuhiro Oki ◽

Ranjana H. Advani ◽

Celeste M. Bello ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Objective Response ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Board Membership

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from <1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in >20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in >10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of >8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

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Seven Year Follow up and Comparison of Dosing Strategies from the Pivotal Phase II Clinical Trial of Lenalidomide Plus Rituximab (R2) in Previously Untreated Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-119592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1594-1594

Author(s):

Nathan H. Fowler ◽

Preetesh Jain ◽

Loretta J. Nastoupil ◽

F. B. Hagemeister ◽

Sheryl G Forbes ◽

...

Keyword(s):

Clinical Trial ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Best Response

Abstract Introduction: We have previously reported the results of cohort A from a single arm, phase II clinical trial of lenalidomide with rituximab (R2) as frontline treatment for patients with previously untreated follicular lymphoma (FL), Fowler N et al Lancet Oncology 2014. Recent randomized studies (RELEVANCE) did not demonstrate superiority of either R2 or R-Chemo in untreated, high GELF FL, but follow up is short. We now report outcomes of an additional extended dosing cohort (12 mo of R2) and the long term follow up of the both dosing schedules in untreated FL. Methods: A total of 154 pts were included in the original clinical trial (FL, n=80; MZL, n=31; SLL, n=43). Characteristics were collected at the time of starting R2 treatment. Patients received lenalidomide 20 mg/day on days 1-21 of each 28-day cycle and rituximab 375 mg/m2 on day 1 of each cycle (6 cycles; schedule A) and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for cycles 1-6 then lenalidomide 10 mg/day on days 2-22 for cycles 7-12 with rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle (12 cycles; schedule B). Responders continued treatment for at least 6 but up to 12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. Results: Eighty pts with FL were enrolled in study and followed a median of 86 months. Median age was 58 years (range, 29 to 84); 50% were males. 61% pts had grade 1 FL and 39% had grade 2 FL. Schedule A was administered in 50 pts and schedule B in 30 pts. Seventy seven pts were evaluable for initial response assessment and 76 (98%) responded. The best response rate was 95% (87% CR/CRu). At the time of last follow up, 23 patients experienced disease progression, 13 lost to follow up (all had CR as best response and had completed tx), 4 came off study due to pt choice/financial and 4 due to intolerance (2 arterio-thrombotic event, 1 respiratory failure, 1 intolerance) during therapy. After a median follow up of 86 mo, 23 pts (29%) progressed, 5 yr PFS was 75%. Five yr PFS was 70% and 82% for pts on cohort A vs B respectively (P=.30). Overall, 2 pts died, with a 5 year survival 97%, Figure-1 (A-B). The median event free survival in pts with FL was 85 months with a 5 year EFS of 59%. Subgroup analysis showed no statistically significant difference in PFS with FLIPI score, bulky disease and by initial bone marrow involvement. Pts who achieved CR had significantly longer PFS compared to those who did not achieve CR (not reached vs 78 months; p = 0.004), however the OS was not significantly different between the two groups Figure-1 (C-F). Grade 3 or 4 hematologic AEs included neutropenia (28%), thrombocytopenia (3%), and no anemia. Count recovery occurred in all pts with follow up and/or dose modification. Nine pts developed second primary cancers, including one melanoma in-situ, 3 localized skin cancers, and 2 secondary hematologic malignancies. Conclusions: A combination of lenalidomide with rituximab produced durable responses in pts with FL. At a follow up of 7 years, the majority of pts remain in remission and patients who achieved CR had the best outcomes. Five year PFS may be longer in pts who received 12mo of therapy, but will need larger analysis to confirm. Further studies are ongoing to analyze mutation dynamics and genomic profile to identify molecular biomarkers. Disclosures Fowler: Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Nastoupil:Novartis: Honoraria; Juno: Honoraria; Gilead: Honoraria; TG Therappeutics: Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Merck: Honoraria, Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Kite Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding. Samaniego:ADC Therapeutics: Research Funding.

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Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase R, in Subjects with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE)

Blood ◽

10.1182/blood-2021-150234 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2047-2047

Author(s):

Myrthe J. van Dijk ◽

Minke A.E. Rab ◽

Anita W. Rijneveld ◽

Erfan Nur ◽

Marije Bartels ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Health Research ◽

Research Funding ◽

Oxygen Affinity ◽

Dose Finding ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

2,3 Dpg

Abstract Background Sickle cell disease (SCD) is one of the most common and devastating inherited blood disorders characterized by a single nucleotide mutation in the beta-globin chain leading to the production of mutant hemoglobin S (HbS). HbS polymerizes upon deoxygenation causing red blood cells (RBC) to sickle which results in extremely painful episodes of vaso-occlusive crisis (VOC), severe hemolytic anemia, chronic multiorgan failure and a reduced life span. An important metabolic feature directly associated with RBC sickling is increased intracellular levels of the glycolytic intermediate 2,3-diphosphyglycerate (2,3-DPG) which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb). Pyruvate kinase R (PKR) is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, membrane integrity and deformability, and modulates 2,3-DPG levels. Mitapivat (AG-348) is an oral, small molecule allosteric activator of PKR and shows promise as an anti-sickling agent in addition to its effect in PK deficiency and thalassemia. The safety and efficacy of mitapivat in subjects with SCD was evaluated in the dose finding period of this ongoing phase 2 study. Methods The ESTIMATE study is a phase 2, open-label study in which subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+) with a baseline hemoglobin >6.1 g/dL and ≤11.1 g/dL, no chronic transfusion and adequate organ function were eligible. In the 8-week Dose Finding Period, initial dosing of mitapivat was 20 mg twice daily (BID). Subjects received a maximum of two sequential dose escalations of mitapivat (i.e. from 20 mg BID to 50 mg BID and 100 mg BID) depending on safety. The primary endpoints were safety, evaluated by frequency and severity of adverse events (AEs), and efficacy of mitapivat on RBC sickling. RBC sickling was evaluated by change in Point of Sickling (PoS), the pO2 at which sickling occurs as measured by oxygen gradient ektacytrometry on the Lorrca (RR Mechatronics). Secondary endpoints included changes in hematological parameters, levels of 2,3-DPG and ATP, Hb-oxygen affinity (p50) and surrogate markers of organ damage and mortality. Subjects who safely tolerated mitapivat and showed evidence of clinical improvement, were eligible to continue a 52-week follow-up period (Fixed Dose Extension Period). Results Six subjects have been enrolled as of September 2020 and completed the Dose Finding Period. All had homozygous HbSS except one patient who had HbS/β0-thalassemia. Baseline characteristics were: median age of 36 years (range 20-59 years), 4 (66.7%) were female and 5 (83.3%) were on stable-dose hydroxyurea. All subjects received dose escalation to a maximum dose of 100 mg BID. No serious adverse events (SAEs) occurred. Adverse events (AEs) were mild and often transient, with the most common treatment emergent AEs: transaminase increase (n=3 [50.0%], Grade 1), gastrointestinal disorders including dyspepsia, diarrhea and abdominal discomfort (n=3 [50.0%], Grade 1) and headache (n=2 [33.3%], Grade 1). One VOC occurred without hospital admission and did not require dose reduction or discontinuation. Table 1 summarizes the anti-sickling effect as well as the hematological and biochemical response to mitapivat treatment. Sickling occurred at lower pO2 levels in all 6 patients during the Dose Finding Period reflected by a significant decrease in treatment week 8 mean PoS compared to baseline. 5/6 subjects (83.3%) achieved a Hb increase of ≥1 g/dL during this period, which was accompanied by a decrease in hemolytic markers. Consistent with activation of PKR, 2,3-DPG levels decreased and ATP levels increased. Additional results including biomarker data will be presented. Conclusion Mitapivat demonstrated an adequate safety profile during the 8-week Dose Finding Period in patients with SCD. The data show promising efficacy in terms of a decrease in the pO2 at which RBCs start to sickle, as well as increase in Hb from baseline and a concomitant decrease in markers reflecting hemolysis. The observed changes in 2,3-DPG and ATP levels are consistent with the proposed mechanism of the drug. The study is ongoing and further data including follow-up data, patient-reported outcomes, PKR activity and thermostability will be reported at a later stage. Figure 1 Figure 1. Disclosures van Dijk: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Rijneveld: Servier: Research Funding; Amgen: Research Funding. Nur: Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Roche: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Novo Nordisk: Research Funding; OctaPharma: Research Funding; Pfizer: Research Funding; Shire/Takeda: Research Funding; Bayer: Research Funding. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers: Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding.

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Outcomes and Toxicities of Ibrutinib in Marginal Zone Lymphoma: A Retrospective Cohort Study at a Single Institution

Blood ◽

10.1182/blood-2019-128556 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5250-5250

Author(s):

David M. Weiner ◽

Nathaniel D. Robinson ◽

Steven M. Bair ◽

Hatcher J. Ballard ◽

Mitchell E. Hughes ◽

...

Keyword(s):

Clinical Trial ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Response Rate ◽

Marginal Zone Lymphoma ◽

Advisory Committees ◽

Bruton's Tyrosine Kinase ◽

Anti Cd20

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for treatment of patients (pts) with relapsed/refractory marginal zone lymphoma (MZL) who have already received one or more anti-CD20 containing treatment regimens and require systemic therapy. Approval was based on a clinical trial in 60 pts that showed durable responses and a median progression-free survival (PFS) of 14.2 months (mos) (Noy et al., Blood 2017). Since pts outside clinical trials may have different disease and demographic characteristics, our study investigates the safety and efficacy of ibrutinib when implemented in a non-trial setting. Materials and Methods: This is a retrospective analysis of MZL pts who received ibrutinib monotherapy as part of their treatment at the University of Pennsylvania. Subjects were identified by a database search for any MZL pts prescribed ibrutinib. Primary endpoints were PFS and overall survival (OS) since initiation of ibrutinib. Secondary endpoints were overall response rate (OR) and complete response rate (CR), adverse events, and reasons for discontinuation. The first patient was treated on April 10, 2014, and the data cutoff was July 1, 2019. Analyses were performed using STATA 15.0 software. Results: There were 28 pts included in this study with a median age of 69 years (range 36-90) and median ECOG performance status at diagnosis of 0 (range 0-2). All pts had advanced disease (all stage III/IV & 68% with bone marrow involvement). The distribution of MZL subtypes was 43% extranodal, 25% nodal, and 32% splenic. Most pts (89%) had received one or more treatments prior to ibrutinib (32% received first-line rituximab only). The median number of previous therapies was 2 (range 0-5), and 43% of pts were refractory to the previous line of therapy. A minority of pts (11%) received rituximab or another anti-CD20 antibody concurrently with ibrutinib. Pts started ibrutinib a median of 56 mos after their initial diagnosis (range 0.5-221 mos) with a median duration of therapy of 7 mos (range 0.7-62 mos). The median starting dose was 420 mg daily (range 70-560 mg daily). In 26 pts with response data available, the OR was 73% with CR 15%. The 12-mo PFS and OS were 77% and 87% respectively (see Figures 1 & 2, median PFS and OS not yet reached). PFS and OS at median follow-up were 55% and 69% respectively. There was no significant difference in response or survival rates among MZL subtypes. Pts who received rituximab only prior to ibrutinib had an OR of 86% compared to 69% in those with more than one previous therapy (Χ2 = 0.73, p = 0.39). Ibrutinib was discontinued in 43% of pts after a median of 2.9 mos (range 0.7-13.7 mos) due to disease progression (50%), intolerance (42%), or other reasons (8%). Most (67%) pts subsequently received other therapies. All pts who stopped due to toxicity were responding at the time of discontinuation. Ibrutinib was also temporarily held or dose-reduced in 46% of pts due to toxicity (77%), preparation for surgery (15%), or drug interactions (8%). One patient experienced acute rebound of symptoms until ibrutinib was restarted. Most commonly reported toxicities are summarized in Table 1. Grade 3 toxicities included pneumonia (7%), sepsis (4%), hemorrhage (4%), arthralgia (4%), fatigue (4%), URI (4%), and hepatitis (4%). Toxicities responsible for cessation of treatment were arthralgia, hepatitis, thyroiditis, and hemorrhage. There were no reported treatment-related deaths. Conclusion: To our knowledge, this is the first study to report the efficacy and safety of ibrutinib in a large cohort of MZL pts treated outside of a clinical trial. We found that the therapy was well-tolerated and observed response rates that compared favorably to those shown in the prospective clinical trial. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. OffLabel Disclosure: This paper looked at the effectiveness of ibrutinib, a Bruton's tyrosine kinase inhibitor, in treating patients with marginal zone lymphoma (MZL). Ibrutinib is FDA approved for MZL patients who have received at least one anti-CD20 containing therapy and now require systemic treatment. Some patients in the study had not previously received an anti-CD20-based therapy and received ibrutinib off-label.

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A Phase 2 Study of Futibatinib (TAS-120) in Patients with Myeloid or Lymphoid Neoplasms Harboring Fibroblast Growth Factor Receptor (FGFR) 1 Rearrangements

Blood ◽

10.1182/blood-2021-150630 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3656-3656

Author(s):

Jean-Jacques Kiladjian ◽

Kohei Shitara ◽

Lee Stephen Rosen ◽

Sun Young Rha ◽

Aiwu He ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Phase 1 ◽

Objective Response ◽

Phase 2 ◽

Advisory Committees ◽

Oncology Research ◽

Phase 2 Study ◽

Clinically Significant

Abstract Background: Myeloid and lymphoid neoplasms (MLNs) with FGFR1 rearrangements are very rare but aggressive myeloproliferative malignancies, characterized by eosinophilia, lymphoid aggregates, and often myelofibrosis, and are recognized as a distinct disease group by the World Health Organization (WHO). In these neoplasms, FGFR1 rearrangements drive oncogenesis via dysregulation of downstream FGFR signaling. Allogenic hematological stem cell transplant (HSCT) is the recommended treatment for patients with FGFR1-rearranged MLNs, as these malignancies are often refractory to chemotherapy and tyrosine kinase inhibitors. Currently, no effective molecularly targeted treatments are available for these patients. Futibatinib is an oral, highly selective, irreversible inhibitor of FGFR1-4 that has shown antitumor activity against FGFR-deregulated tumors in preclinical experiments and in phase 1 studies. Recent results from a phase 2 study demonstrated the efficacy (42% objective response rate) and manageable safety of futibatinib in patients with FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In addition to cholangiocarcinoma, futibatinib treatment resulted in objective responses across tumor types harboring various FGFR aberrations in the phase 1 study. In a separate report, a patient with an FGFR1-driven myeloid neoplasm treated with futibatinib achieved complete hematologic and cytogenetic remission. Based on these data, a multicohort phase 2 study (NCT04189445) was designed to evaluate the efficacy and safety of futibatinib in patients with tumors harboring specific FGFR aberrations. Here, we describe the cohort of patients with MLNs harboring FGFR1 rearrangements. Study Design and Methods: In this global, open-label, multicohort phase 2 study, patients (≥18 years, with Eastern Cooperative Oncology Group performance status 0-1 and adequate organ function) will be enrolled into 1 of 3 cohorts by type of tumor and/or FGFR aberration. The cohort of patients with MLNs harboring FGFR1 rearrangements (as defined by WHO criteria) will include patients who are not candidates for HSCT or other therapies or who have disease progression following HSCT. Patients with clinically significant alterations in calcium-phosphorus homeostasis, ectopic mineralization/calcification, clinically significant retinal/corneal disorder, untreated or clinically/radiologically unstable brain metastases, or prior FGFR inhibitor treatment will be excluded. Approximately 20 patients will be enrolled in this cohort (sample size considerations based on differentiating a ≤10% historical control complete response [CR] rate with a 50% target CR rate with 95% power). Patients will receive futibatinib 20 mg once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criterion is met. The primary endpoint is CR rate. Secondary endpoints include objective response rate, CR with incomplete hematological recovery (CRi) rate, complete or partial cytogenetic response rate, and safety. Additional secondary endpoints are duration of CR, CR+CRi, and response; as well as event-free (leukemia presentation only), progression-free, relapse-free, and overall survival. The study was initiated in August 2020, and patient enrollment is ongoing. Disclosures Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Shitara: Lilly, Ono Pharmaceutical, Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharm, Astellas Pharm, Medi Science, Eisai, Taiho Oncology: Research Funding; Astellas Pharma, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Taiho, MSD, Novartis, Abbvie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim: Consultancy; Novartis, Abbvie, Yakult: Other: Speaker fee. Rosen: Taiho Oncology: Research Funding. Rha: Taiho Oncology, Inc.: Research Funding. He: Taiho Oncology, Inc.: Research Funding. Oh: Taiho Oncology, Inc.: Research Funding; AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok: Other: Grants or contracts from any entity; AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point: Other: Participation on a data safety monitoring board or advisory board. Melisi: Taiho Oncology, Inc.: Research Funding. Iwasa: Taiho Oncology, Inc.: Honoraria, Research Funding. Jiang: Taiho Oncology, Inc.: Research Funding. Liu: Taiho Oncology, Inc.: Current Employment. Takahashi: Taiho Oncology, Inc.: Current Employment. Ribrag: Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

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