A Phase 1b, Dose-Finding Study Of Ruxolitinib Plus Panobinostat In Patients With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF): Identification Of The Recommended Phase 2 Dose

Abstract Background Myelofibrosis (MF) is a myeloproliferative neoplasm associated with progressive, debilitating symptoms that impact patient quality of life (QoL) and reduce survival. Ruxolitinib (RUX), a potent dual JAK1/JAK2 inhibitor, demonstrated superiority in spleen volume and symptom reduction, improved health-related QoL measures, and prolonged survival compared with traditional therapies or placebo in the phase 3 COMFORT studies. Panobinostat (PAN) is a potent oral pan-deacetylase inhibitor (DACi) that inhibits JAK pathway signaling through increased acetylation of the JAK2 protein chaperone HSP90. In phase 1/2 studies in MF, PAN has shown reduction in splenomegaly and JAK2 V617F allele burden, and improvement of marrow fibrosis. RUX and PAN demonstrated synergistic anti-MF activity in JAK2-mutation–driven MF murine models. Here, we present the results of a phase 1b study to determine the recommended phase 2 dose (RP2D) of the combination of RUX and PAN in MF patients. Methods Patients with intermediate-1, -2, or high-risk MF by International Prognostic Scoring System criteria and with palpable splenomegaly ≥ 5 cm below the costal margin were enrolled. Dose escalation was guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first cycle along with other safety findings. DLTs were defined as protocol-specified toxicities related to treatment but unrelated to disease progression, intercurrent illness, or concomitant medications, occurring up to and including cycle 1 day 28, that are considered severe enough to prevent continuation of treatment. Each dosing cohort consisted of ≥ 3 evaluable patients. Data for ≥ 9 patients were required to determine the preliminary RP2D and/or maximum tolerated dose (MTD). Following determination of the preliminary RP2D, additional patients were to be enrolled and treated at that dose in the safety-expansion phase. The range of dose levels tested for RUX was 5-15 mg twice daily (BID) and for PAN was 10-25 mg once daily, 3 times a week (TIW; days 2, 4, and 6), every other week (QOW) in a 28-day cycle. Serial blood samples collected following the first dose of RUX alone on day 1 and in combination with PAN on days 2 and 6 were evaluated for plasma concentrations of RUX (days 1, 2, and 6) and PAN (days 2 and 6) by LC-MS/MS. Pharmacokinetic parameters were derived using noncompartmental analysis. Spleen size was determined by palpation. Results A total of 38 patients have been enrolled across 6 cohorts in the dose-escalation phase. Preliminary data presented here are based on a cutoff date of March 7, 2013. Thirteen patients (34.2%) have discontinued study treatment. Reasons for discontinuation include disease progression (n = 4), adverse events (n = 7), withdrawal of consent (n = 1), and death due to pulmonary embolism (n = 1). The most common grade 3/4 adverse events were anemia (34.2%), thrombocytopenia (21.2%), abdominal pain (7.9%), and diarrhea (7.9%). QTc prolongation of > 500 ms was observed in 1 patient in cohort 4. DLTs are summarized in the Table. An approximate 50% increase in plasma exposure of both RUX and PAN on day 6 from respective baselines suggested drug-drug interaction (DDI) at 15 mg RUX and 25 mg PAN. The RP2D was defined at the cohort 6 dose and schedule. Evidence of preliminary activity was observed across all cohorts with 28 patients (73.7%) showing ≥ 50% decrease in palpable spleen length at some point during the study. Conclusions The combination of RUX and PAN has a tolerable safety profile, with few DLTs and acceptable rates of grade 3/4 anemia and thrombocytopenia. Also, encouraging splenomegaly reduction was seen in the dose-escalation phase. The MTD was not reached; however, due primarily to findings of anemia and potential DDI in dose cohort 6, preliminary RP2D was identified at RUX 15 mg BID/PAN 25 mg TIW/QOW and will be confirmed in the dose-expansion phase. Additional safety and efficacy data from patients in the expansion phase will be presented. Disclosures: Ribrag: Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson : Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is approved for MF but panobinostat is not approved anywhere globally at this time for any indication. Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Heidel:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kiladjian:AOP Orphan: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Acharyya:Novartis: Employment. Mu:Novartis: Employment. Liu:Novartis: Employment. Williams:Novartis: Employment. Giles:Novartis: Consultancy, Research Funding. Conneally:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees. Passamonti:sanofi-aventis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Blood ◽

10.1182/blood.v120.21.2737.2737 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2737-2737 ◽

Cited By ~ 1

Author(s):

Naokuni Uike ◽

Michinora Ogura ◽

Yoshitaka Imaizumi ◽

Norio Asou ◽

Atae Utsunomiya ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets <10,000/uL or bleeding requiring platelet transfusion); ALT/AST elevation of Grade 4 or that of Grade 3 lasting 7 or more days; and/or clinically unacceptable Grade 3 or higher other non-hematological adverse events (AEs). Treatment was continued until the development of unacceptable toxicity or progressive disease (PD). Response was assessed by internationally accepted standard criteria for ATL and PTCL. Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets <10,000/uL) and 4 patients received lenalidomide for 37, 56, 138, and 387 days, respectively, until PD in 3 patients and unrelated death in one. The sixth patient is still receiving lenalidomide for 28+ days without a DLT. In Cohort 3, 2 patients had DLTs (thrombocytopenia, platelets <10,000/uL in one patient and Grade 3 prolongation of QTc interval in one patient on concomitant fluconazole with preexisting cardiac disease and grade 1 QTc prolongation at baseline), 1 patient received lenalidomide for 71 days before withdrawal of consent, and 1 patient is still receiving lenalidomide for 323+ days without a DLT. Based on these results, 25 mg daily per 28-day cycle was regarded as the MTD. Other Grade 3/4 non-DLT AEs occurring in 2 or more patients included neutropenia (n=8), lymphocytopenia (n=7), thrombocytopenia (n=3), skin rash (n=3), hyperbilirubinemia (n=2), and increased ALT/AST (n=2). Among the 9 ATL patients, 3 achieved partial responses (PR) with hematological complete response in 2 patients, including the disappearance of skin lesions in 1 patient. These responses occurred between 54 and 57 days, and lasted for 92, 279+ and 505 days. Among the 4 PTCL patients, 1 achieved a PR at day 106 with >75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

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Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.639.639 ◽

2016 ◽

Vol 128 (22) ◽

pp. 639-639 ◽

Cited By ~ 21

Author(s):

Jeffrey A. Jones ◽

Jennifer Woyach ◽

Farrukh T. Awan ◽

Kami J. Maddocks ◽

Thomas Whitlow ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Response Assessment ◽

Phase 2 ◽

Advisory Committees ◽

Once Daily ◽

Phase 1B

Abstract BACKGROUND Venetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination. METHODS Patients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14. RESULTS Twelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200). CONCLUSIONS G, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. Table. Table. Disclosures Jones: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

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Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results.

Blood ◽

10.1182/blood.v114.22.432.432 ◽

2009 ◽

Vol 114 (22) ◽

pp. 432-432 ◽

Cited By ~ 5

Author(s):

Sagar Lonial ◽

Ravi Vij ◽

Jean-Luc Harousseau ◽

Thierry Facon ◽

Jonathan Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Advisory Board ◽

Advisory Committees ◽

Expansion Phase ◽

Grade 3

Abstract Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.

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A Phase 2 Study of Elotuzumab (Elo) in Combination with Lenalidomide and Low-Dose Dexamethasone (Ld) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R MM): Updated Results

Blood ◽

10.1182/blood.v120.21.202.202 ◽

2012 ◽

Vol 120 (21) ◽

pp. 202-202 ◽

Cited By ~ 12

Author(s):

Paul G. Richardson ◽

Sundar Jagannath ◽

Philippe Moreau ◽

Andrzej Jakubowiak ◽

Marc S Raab ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Phase 2 ◽

Phase 3 ◽

Advisory Committees ◽

Infusion Reactions ◽

Grade 3

Abstract Abstract 202 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of MM cells, with lower expression on natural killer (NK) cells and little to no expression on normal tissues. The mechanism of action of Elo is primarily NK cell-mediated antibody-dependent cellular cytotoxicity against MM cells. In the Phase 1 portion of this 1703 study, Elo escalated from 5 to 20 mg/kg intravenously (IV) plus Ld resulted in an 82% objective response rate (ORR) in pts with R/R MM (Lonial, J Clin Oncol 2012). Historically, lenalidomide plus high dose dexamethasone provided a 61% ORR and a median 11.1 months (mos) progression free survival (PFS) in a similar pt population (Dimopoulos, Weber, N Engl J Med 2007). At the time of previous presentation (Moreau, ASCO 2012), median PFS in the Phase 2 portion the 1703 study of Elo + Ld was not reached (NR) with 10 mg/kg after a median follow-up of 17.2 mo and was 18.6 mo with 20 mg/kg. Methods: Pts with R/R MM previously treated with 1–3 prior therapies were randomized to Elo 10 or 20 mg/kg IV (days 1, 8, 15, 22 every 28 days in cycles 1–2 and days 1, 15 in cycles ≥3) plus lenalidomide 25 mg (PO) (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on Elo dosing days. All pts received a premedication regimen of methylprednisolone or dexamethasone, diphenhydramine, ranitidine, and acetaminophen prior to elo dosing to minimize infusion reactions. Treatment continued until disease progression, unacceptable toxicity, or death. Pts were monitored for PFS until 60 days post-treatment follow-up. The primary objective was efficacy (ORR ≥partial response) according to the International Myeloma Working Group criteria. Results: 73 pts were treated (10 mg/kg, n=36; 20 mg/kg, n=37). Median age was 63 (range, 39–82) years, 55% received ≥2 prior therapies, 60% prior bortezomib, and 62% prior thalidomide. Median (range) duration of treatment was 20.5 (3.0–31.0) and 16.0 (1.0–32.0) cycles with 10 and 20 mg/kg, respectively. At the data cutoff (July 10 2012), 27 pts (10 mg/kg, n=15; 20 mg/kg, n=12) were ongoing and 46 pts discontinued (disease progression, n=26; adverse events, n=11; investigator/pt decision, n=9). ORR was 84% overall; 92% with 10 mg/kg (chosen as the Phase 3 dose) and 76% with 20 mg/kg (see Table). Overall median time to objective response was 1 month (range, 0.7–19.2). After a median follow-up of 18.1 mos, median PFS in the 10 mg/kg cohort was 26.9 mos (95% confidence interval [CI]: 14.9–NR); however, 15 pts are still ongoing with a median follow-up of 23.9 mos, and the PFS data will likely mature further with longer follow up. Median PFS in the 20 mg/kg cohort was 18.6 mos (95% CI: 12.9–NR). In subgroup analyses combining 10 and 20 mg/kg cohorts, ORRs for pts with 1 (n=33) or ≥2 prior therapies (n=40) were 91% and 78%, respectively, and overall median PFS were 25.0 (95% CI: 15.7–NR) and 21.3 mos (95% CI: 14.0–NR), respectively. Pts with prior thalidomide (n=45) had an ORR of 82% and median PFS of 26.9 mos (95% CI: 14.9–NR). Fifty-six (78%) pts experienced ≥1 treatment emergent grade ≥3 event. Most common were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), anemia (12%), leukopenia (10%), hyperglycemia (10%), pneumonia (7%), diarrhea (7%), fatigue (7%), and hypokalemia (6%). Two deaths occurred on study (multiple adverse events [n=1; pneumonia, multiple organ failure and sepsis]; disease progression [n=1]). Investigator-designated (any grade) infusion reactions were reported in 12% of pts; 1 pt had a grade 3 event (rash). There were 4 cases of second primary malignancies (prostate; bladder; myelodysplastic syndrome; nasal squamous cell); all were deemed unrelated to Elo. Conclusions: In pts with R/R MM, Elo + Ld was generally well tolerated. Elo at 10mg/kg (the phase 3 dose) + Ld resulted in a high ORR and an encouraging median PFS of 26.9 mos after 18.1 mos of median follow-up. Phase 3 trials of Elo 10 mg/kg ± Ld are ongoing in newly diagnosed MM (ELOQUENT-1; CA204-006; NCT01335399) and R/R MM (ELOQUENT-2; CA204-004; NCT01239797). Disclosures: Richardson: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Elotuzumab is not currently approved for any indication. Jagannath:Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Facon:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Celgene: Honoraria, Research Funding. Reece:Johnson & Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Deng:Abbott Biotherapeutics Corp: Employment. Kroog:BMS: Employment. Singhal:Abbott Biotherapeutics: Employment, Equity Ownership. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy.

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Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.508.508 ◽

2015 ◽

Vol 126 (23) ◽

pp. 508-508 ◽

Cited By ~ 27

Author(s):

Ajai Chari ◽

Sagar Lonial ◽

Attaya Suvannasankha ◽

Joseph W. Fay ◽

Bertrand Arnulf ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Institutional Research ◽

Advisory Committees ◽

Multicenter Phase ◽

Phase 1B ◽

Grade 3

Abstract Introduction : Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody with remarkable safety and activity as monotherapy in heavily treated relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512). DARA has demonstrated clinical activity in combination with lenalidomide (LEN) and dexamethasone (D) in relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This ongoing 4-arm, multicenter, phase 1b study (NCT01998971) evaluated the safety and efficacy of DARA in combination with various backbone therapies and pomalidomide plus D (POM-D). Results in newly diagnosed patients treated with DARA and backbone therapies were previously reported (Mateos MV, et al. Haematologica 2015;100(s1):84). Methods : Patients in the DARA + POM-D arm had relapsed or RR MM with ≥2 prior lines of therapy including ≥2 consecutive cycles of LEN and bortezomib. During 28-day treatment cycles patients received DARA 16 mg/kg qw for 2 cycles, then q2w for 4 cycles, and q4w until disease progression (PD). Pomalidomide 4 mg was administered qd for 21 days with D 40 mg qw (20 mg for patients >75 years of age). The primary endpoint was safety and tolerability of DARA in combination with POM-D. Overall response rate (ORR) was a secondary endpoint. Disease responses were evaluated by an independent data safety monitoring board. Results: A total of 77 patients were enrolled into the DARA + POM-D arm. The median (range) age was 64 (35-86) years and the median number of prior therapies was 3.5 (2-10). Sixty-five percent of the patients were refractory to bortezomib, 30% to carfilzomib, 88% to lenalidomide, and 65% to both a PI and IMiD. With a median (range) duration of follow-up of 72 (1-423) days, 28 (36%) patients have discontinued treatment due to PD (15 [20%]), adverse events (AEs; 6 [8%]), death or physician's decision (3 [4%] each), and one (1%) patient withdrawal. The median (range) duration of treatment was 69 days (1-416), and the median (range) number of infusions was 7.5 (1-25). Forty-nine (64%) patients continue on study treatment and enrollment is ongoing. There was little additional toxicity when DARA was added to POM-D other than DARA-specific infusion related reactions (IRRs; 47/77 patients). Most occurred on Cycle 1 Day 1 (45/47 patients), and the most common (>10%) IRRs were chills (13%), cough (13%), and dyspnea (11%). The most common (>10%) and grade ≥3 adverse events (AEs) are presented in Table 1. Five patients died within 30 days of receiving study treatment due to AEs (4[5%]) or progressive disease (1 [1%]). In 53 patients with >1 post-baseline assessment, the ORR was 58.5%, with 3 stringent complete responses (sCR), 1 complete response (CR), 12 very good partial responses (VGPR), 15 partial responses (PR), 2 minimal responses, 18 stable disease, and 2 PD. Many responses deepened over time. Median (range) time to first response was 30 (28-92) days. After a median follow-up of 148 days, 4 out of 31 responders developed PD. Among the evaluable double refractory patients (n = 40), there was 1 sCR, 1 CR, 10 VGPRs, and 11 PRs with an ORR of 57.5%. Conclusions : The addition of DARA to POM-D was well tolerated and did not result in additional toxicities with the exception of DARA-related infusion reactions. Deep and durable responses were observed quickly, along with a high response rate. Study enrollment is ongoing and data will be updated at the meeting. Table 1. Most Common (>10%) Adverse Events (N = 77) Adverse Event, n (%) Any Grade Grade ≥3 Neutropenia 42 (54.5%) 39 (50.6%) Anemia 28 (36.4%) 16 (20.8%) Fatigue 28 (36.4%) 4 (5.2%) Cough 24 (31.2%) 0 Nausea 21 (27.3%) 0 Dyspnea 20 (26.0%) 5 (6.5%) Diarrhea 19 (24.7%) 1 (1.3%) Leukopenia 19 (24.7%) 12 (15.6%) Thrombocytopenia 17 (22.1%) 8 (10.4%) Pyrexia 16 (20.8%) 1 (1.3%) Dizziness 15 (19.5%) 0 Chills 14 (18.2%) 0 Nasal Congestion 14 (18.2%) 0 Upper Respiratory Tract Infection 14 (18.2%) 1 (1.3%) Back Pain 13 (16.9%) 2 (2.6%) Constipation 13 (16.9%) 0 Tremor 13 (16.9%) 2 (2.6%) Insomnia 12 (15.6%) 1 (1.3%) Lymphopenia 11 (14.3%) 7 (9.1%) Muscle Spasms 11 (14.3%) 0 Vomiting 11 (14.3%) 0 Arthralgia 9 (11.7%) 1 (1.3%) Pruritus 9 (11.7%) 0 Throat Irritation 9 (11.7%) 0 Anxiety 8 (10.4%) 0 Headache 8 (10.4%) 0 Hypertension 8 (10.4%) 4 (5.2%) Musculoskeletal Chest Pain 8 (10.4%) 2 (2.6%) Peripheral Edema 8 (10.4%) 1 (1.3%) Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Onyx: Consultancy, Research Funding. Lonial:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Suvannasankha:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Arnulf:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Qin:Janssen: Employment. Masterson:Janssen: Employment. Nottage:Janssen: Employment. Schecter:Janssen: Employment. Ahmadi:Janssen: Employment. Weiss:Janssen and Millennium: Consultancy; Janssen and Onclave: Research Funding. Krishnan:Millenium: Speakers Bureau; BMS: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lentzsch:Celgene: Consultancy; Janssen: Consultancy; Axiom: Honoraria; Novartis: Consultancy; BMS: Consultancy.

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Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase 1b Study

Blood ◽

10.1182/blood-2020-140752 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Erlene K. Seymour ◽

Yiwei Li ◽

Amro Aboukameel ◽

Radhakrishnan Ramchandren ◽

Golbon Sterbis ◽

...

Keyword(s):

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Blood Samples ◽

Prior Therapy ◽

Phase 1B ◽

Grade 3 ◽

Dose Reductions

Introduction: The chemoimmunotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is curative for many patients (pts) with diffuse large B cell lymphoma (DLBCL), but a subset of high-risk pts, including those with transformed and double-hit lymphomas, are less likely to be cured by R-CHOP. Exportin-1 (XPO1), a nuclear export protein, is overexpressed in NHL and correlates with chemotherapy-resistance and poor prognosis. Overexpression of XPO1 results in increased nuclear export of tumor suppressor proteins (TSPs) leading to their functional inactivation, and enhanced expression of Bcl-2 family members and c-Myc. Inhibition of XPO1 leads to TSP activation and oncoprotein reduction. Selinexor, a novel, oral selective inhibitor of XPO1, was approved by the FDA for DLBCL after 2 prior therapies based on an overall response rate (ORR) of 29% including a 13% complete response (CR) rate. Our previous preclinical results in vitro and in vivo showed potent additive or synergistic cytotoxicity of selinexor with chemotherapy in xenograft NHL mouse models. We evaluated the safety and preliminary efficacy of the combination of selinexor with R-CHOP chemotherapy in pts with untreated NHL. Methods: This is an open-label phase 1b study to determine the safety, tolerability, recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of selinexor in combination with R-CHOP in pts with NHL. Pts with stage III/IV DLBCL (including transformed DLBCL) who had no prior therapy, and pts with indolent lymphomas who had either no prior therapy or received one prior therapy not containing an anthracycline, were included. A standard 3 + 3 dose escalation design in which pts received 6 cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 IV, vincristine 0.5 mg/kg on day 1, prednisone 100 mg po on days 1-5 in a 21 day cycle) and 60 mg or 80 mg selinexor on days 1, 8, and 15 of each cycle was used. Weekly selinexor maintenance, at the dose employed at the conclusion of R-CHOP, was continued for an additional year. Blood samples were obtained on days 0, 3, 5, 8 and 15 for RNA isolation followed by RT-PCR to evaluate the expression of targets or downstream effectors including XPO1, AABCG2, AKT, Bcl-2, Bax and ERK. Results: A total of 12 pts were enrolled: 10 pts had DLBCL (1 GCB, 5 non-GCB, 4 transformed from indolent NHL); 2 pts had follicular lymphoma. Median age was 55 years. Six pts received selinexor 60 mg weekly + R-CHOP and 6 pts received selinexor 80 mg weekly + R-CHOP. Among the first 3 pts in the 60 mg cohort, there was an episode of grade 3 supraventricular tachycardia and an episode of grade 3 syncope. No further cardiac events occurred amongst these 3 pts, and this cohort was expanded by 3 pts. No further serious cardiac adverse events (AEs) occurred for the entire cohort. Among the first 3 pts in the 80 mg cohort, 1 DLT occurred: grade 3 nausea and vomiting. There were more discontinuations and dose reductions in the 80 mg cohort than in the 60 mg cohort; The majority of AEs were grade 1 or 2 and included nausea (100%), fatigue (67%), skin and nail changes (58%), constipation (42%), dizziness (42%), sinus congestion (42%), and vomiting (42%) with nausea and fatigue lasting ~1-2 days. AEs leading to selinexor discontinuation in 5 pts included fatigue +/- nausea. Dose reductions occurred in 3 pts, all due to fatigue. 8 pts completed all 6 cycles of R-CHOP with Selinexor, and 6 continued maintenance therapy. 2 pts came off study for non-compliance. MTD was not reached, however because of the higher frequency of selinexor discontinuation and dose reductions in the 80 mg cohort, selinexor 60 mg weekly + R-CHOP is the recommended RP2D. Among 10 efficacy evaluable pts (6 at 60 mg and 4 at 80 mg), the ORR was 100%: 9 pts with a CR (including 4 non-GCB pts) and 1 with a PR. Median follow up is 476 days. In line with previous reports, XPO1 mRNA expression was consistiently increased in all pt blood samples at day 3. Conclusions: R-CHOP in combination with weekly selinexor showed encouraging preliminary efficacy with an ORR of 100% and CR of 90%. At the 60 mg selinexor dose level, AEs were manageable and milder (grade 1/2) than those previously reported with selinexor. The results of correlative studies performed were consistent with our preclinical findings. A phase 2 study of this combination is ongoing in frontline DLBCL and Richter's transformation (NCT03147885). Disclosures Seymour: Incyte: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle Genetics, Janssen, Genentech: Research Funding. Yang:Protagonist: Research Funding; AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding. Bhutani:Sanofi: Consultancy, Research Funding. Azmi:Rhizen Phamaceuticals Inc, EISAI: Research Funding; GLC, Guidepoint: Consultancy. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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

Blood ◽

10.1182/blood-2019-123954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2831-2831 ◽

Cited By ~ 1

Author(s):

Swaminathan P. Iyer ◽

Brad M. Haverkos ◽

Jasmine Zain ◽

Radhakrishnan Ramchandren ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽

10.1182/blood.v114.22.4937.4937 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4937-4937

Author(s):

Meletios A. Dimopoulos ◽

Huw Roddie ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Romualdas Jurgutis ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Safety Data ◽

Phase 2 ◽

Advisory Committees ◽

Ortho Biotech ◽

Function Group ◽

Grade 3 ◽

Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

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