A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

scholarly journals Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3892-3892
Author(s):  
Colin D. Godwin ◽  
Megan Othus ◽  
Mary-Elizabeth M. Percival ◽  
Bart L. Scott ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Left Ventricular Systolic Dysfunction ◽  
Phase 1 ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Background: We recently found that CLAG-M was safe and produced higher rates of CR/CRi and higher measurable residual disease (MRD)-negative CR (measured by multiparameter flow cytometry [MFC]) than standard "7+3" therapy in fit patients with newly-diagnosed AML or other high-grade myeloid neoplasm with ≥10% blasts (HG-MN). Since addition of the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) to chemotherapy reduces relapse risk and improves survival in some AML patients, we conducted a phase 1 study (NCT03531918) to determine the maximum tolerated dose (MTD) of GO with CLAG-M in fit adults with newly-diagnosed AML (APL excluded) or HG-MN. Patients and Methods: Adults ≥18 years were eligible if they were fit (treatment-related mortality [TRM] score ≤13.1, corresponding to < 13.1% risk of TRM within 1 month) and had LVEF ≥45%, creatinine ≤2.0 mg/dL, and bilirubin ≤2.5-times upper limit of normal. Patients with concomitant illness with expected survival <1 year, with uncontrolled infection, or in myeloid blast phase of chronic myeloid leukemia were excluded. Doses were escalated in cohorts of 6 patients over 2 dose levels of GO ("GO1": 3 mg/m2 on day 1; "GO3": 3 mg/m2 on days 1, 4, and 7 [doses capped 4.5 mg]); the highest dose level achieved could then enroll an additional 6 patients (12 total) if ≤2 dose-limiting toxicities (DLTs) were observed. CLAG-M consisted of cladribine 5 mg/m2/day (days 1-5), cytarabine 2 g/m2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative CR/CRi was not achieved. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. The protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. Results: We enrolled 18 patients, median age 66 (range: 28-77) years, median TRM score 3.92 (range: 0.14-10.3) with newly-diagnosed AML (n=14) or HG-MN (n=4); 7 were "favorable", 4 "intermediate and 7 "adverse" by 2017 European LeukemiaNet criteria. The first 6 patients were treated at GO1, with 1 DLT (grade 3 left ventricular systolic dysfunction). Two subsequent cohorts of 6 were treated at GO3. Three DLTs occurred at this second dose level (grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, grade 3 intracranial hemorrhage). As prespecified in the protocol, with ≤4/12 DLTs the MTD was formally not reached and GO3 was declared the recommended phase 2 dose. Among 18 evaluable patients, 13 achieved CR and 2 CRi for a CR/CRi rate of 83% (95% confidence interval: 59-96%). 13/15 CR/CRi patients were negative for MRD by MFC and cytogenetics for an MRDneg CR/CRi rate of 72% (49-88%). The 3 patients without CR/CRi had marrow aplasia without MFC evidence of AML at time of study removal. Two underwent allogeneic hematopoietic cell transplantation in aplasia; the other achieved later neutrophil recovery prior to AML recurrence 2.5 months following induction without interval therapy. 5/18 did not have platelet recovery to 100,000/µL prior to the next therapy/removal from study. Median time to absolute neutrophil count of 1000/µL (achieved in 16/18 patients) and platelet count of 100,000/µL (achieved in 13/18 patients) was 35 (range: 24-48) days and 31 (range: 26-48) days, respectively. Besides infections and neutropenic fever, hypertension and left ventricular systolic dysfunction were the most common adverse events. One patient had severe, self-limited liver toxicity characterized by weight gain and elevated aminotransferases without hyperbilirubinemia and did not meet typical clinical criteria for sinusoidal obstructive syndrome. There were no deaths within 56 days of starting induction in this study cohort. Conclusions: CLAG-M with fractionated-dose GO is feasible in patients with newly-diagnosed AML/HG-MN and appears to have high anti-tumor efficacy. CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint. Disclosures Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Scott:Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Gardner:Abbvie: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Walter:Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. OffLabel Disclosure: Cladribine is not approved for AML, only Hairy Cell Leukemia, however it is widely used for AML with literature supporting it.

Lenalidomide, Bortezomib, and Dexamethasone (RVD) In Combination with Vorinostat as Front-Line Therapy for Patients with Multiple Myeloma (MM): Initial Results of a Phase 1 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3034-3034 ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Jatin J Shah ◽  
Jacob P. Laubach ◽  
Leonard Heffner ◽  
Dixil Francis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Patient Choice ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Upfront Therapy ◽  
Grade 3

Abstract Abstract 3034 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate. The goal of the current trial is to improve on the CR rate compared with RVD by adding a novel targeted agent. Preclinical studies have demonstrated that vorinostat (Vor), an HDAC inhibitor, is synergistic with bortezomib, immunomodulatory (IMiD®) compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study is to determine the tolerability and preliminary efficacy of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (Pts) received the current standard RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5-8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. DLT (≥ G3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of ANC to ≥1,000/μL or platelets to ≥50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified EBMT and Uniform criteria. Pts with PR or better could proceed to autologous transplant after ≥ 4 cycles. Results: Eleven pts (median age 54, 82% men, 54.5% ISS Stage II/III) have been enrolled to date with n=4 pts each in cohorts 1 (Vor 100mg) and 2 (Vor 200mg), and 3 pts in cohort 3 (Vor 300 mg). One patient has completed 8 cycles, 1 pt completed 4 cycles and proceeded to transplant, 6 pts remain on study treatment and 3 pts have discontinued therapy (1 for significant peripheral neuropathy {grade 3}, 1 for patient choice unrelated to toxicity and 1 for non adherence). Two DLTs have occurred: syncope (cohort 1) and asymptomatic grade 3 elevation of ALT (cohort 2) with none in cohort 3.The episode of syncope was not related to cardiac arrhythmia. One study related SAE has occurred (syncope). One other episode of grade 3 elevation of ALT occurred in a pt in cycle 3 in cohort 1. Both episodes of increased ALT resolved and patients remained on study with dose modification. One patient developed grade 3 diarrhea in cohort 1. No patients have developed a grade 4 toxicity. Treatment emergent peripheral neuropathy occurred in 6 patients (4 grade 1, 1 grade 2 and 1 grade 3). No episodes of study related grade 3 fatigue, nausea, or vomiting have occurred. The MTD has not been reached. Eight patients are evaluable for response. All have responded to study therapy with 3 CRs, 1 VGPR and 4 PRs. Three patients went on to stem cell collection after 4 cycles and all collected an adequate dose for transplant of >5 ×106 CD34+ cells/kg. Conclusion: The combination of RVD with vorinostat has been generally well tolerated to date. No unexpected toxicity has been noted with side effects commensurate with prior experience with each of the drugs and no additive toxicity seen to date. While asymptomatic elevation of ALT has been seen and will require ongoing monitoring, grade 3 ALT elevation was a DLT in the original RVD study and related to dexamethasone, so may not be related to the addition of vorinostat. Early efficacy data is promising with 50% of patients achieving a VGPR or higher. Accrual is ongoing to determine the MTD. Disclosures: Kaufman: Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Off Label Use: Use of lenalidomide as upfront therapy. Use of vorinostat as upfront therapy. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding. Heffner:Millenium: Consultancy, Honoraria, Research Funding. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau.

PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4304-4304
Author(s):  
Caspar Da Cunha-Bang ◽  
Rudy Agius ◽  
Arnon P. Kater ◽  
Mark-David Levin ◽  
Anders Österborg ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Severe Infection ◽  
Newly Diagnosed ◽  
Risk Of Infection ◽  
Advisory Committees ◽  
Educational Grant ◽  
Travel Grant ◽  
Grade 3

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

scholarly journals Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 397-397 ◽  
Author(s):  
Paolo Caimi ◽  
Deepa Jagadeesh ◽  
Kirsten Marie Boughan ◽  
Robert M. Dean ◽  
Brenda Cooper ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Second Line ◽  
Advisory Committees ◽  
Line Therapy ◽  
Grade 3

Abstract Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically <45%). The RP2D of VEN is 800 mg. Hematologic toxicity - particularly neutropenia - is common, and G-CSF support as well as antibiotic prophylaxis are necessary to prevent infectious complications. Updated safety, progression-free survival and response data will be presented at the meeting. Disclosures Caimi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 123-123 ◽  
Author(s):  
Ravi Vij ◽  
Nitya Nathwani ◽  
Thomas G. Martin ◽  
Mark A. Fiala ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Hematologic Toxicity ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Oral Regimen ◽  
Grade 3

Abstract Background: Maintenance therapy post-autologous stem cell transplantation (ASCT) has shown to improve progression-free and overall survival in multiple myeloma (MM) and has largely become the standard of care. Consolidation therapy, a brief duration of more-intensive chemotherapy administered prior to maintenance, has been shown to further deepen responses and may improve long-term outcomes. Ixazomib, lenalidomide and dexamethasone (IRd) is an all oral regimen that has been shown to be active in newly diagnosed MM as well as relapsed disease. In this study, we are analyzing the safety and efficacy of IRd as consolidation therapy after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, are being consented prior to ASCT. Approximately 4 months following ASCT, patients receive 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. The primary end point is minimal residual disease (MRD) status. MRD is being assessed by ClonoSEQ where possible and by multi-color flow where not. Toxicity, IMWG response rate, PFS, and OS are secondary end points. One month after the last consolidation cycle, patients are randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15) or lenalidomide (15 mg daily). In total, 240 patients will be enrolled on the trial. This presentation coincides with planned interim analysis 2 which included data from the consolidation phase only. Results: As of July 2018, 172 patients with NDMM have been enrolled from 10 centers within the US. The median age was 57 (range 28-70) and 67% were male. 76% were white, 10% African-American/Black, and 13% were another race. 39% were ISS Stage I, 30% were Stage II, and 20% were Stage III. All patients received proteasome inhibitors and/or IMIDs as front-line induction and melphalan as conditioning for ASCT. IRd consolidation started at a median of 110 days post-ASCT (range 80-138). IRd has been well tolerated. Only 4% (6/154) of patients have been unable to complete the 4 cycles of consolidation to date due to toxicity. Grade 3 hematologic toxicity has been uncommon; 4% neutropenia, 3% thrombocytopenia, and 2% anemia. There has been no grade 4 hematologic toxicity. Non-hematologic grade 3-4 toxicities have included: infection (8%), nausea/vomiting/diarrhea (3%), and transaminitis (1%). No grade 3-4 peripheral neuropathy has been reported. One case of grade 5 pneumonia was reported but was not considered related to study treatment. Following ASCT, the MRD-negative rate was 26% and this improved to 37% following consolidation. In the subset of patients with Clonoseq results available, the MRD negative rate improved from 19% to 27%. Clinical response rate improved similarly; prior to consolidation the VGPR or better rate was 76% including 39% CR/sCR. Following consolidation, the VGPR or better rate was 85% including 56% CR/sCR. 137 patients went on to receive maintenance with either ixazomib (n = 71) or lenalidomide (n = 66). At time of submission, the median follow-up from start of IRd is 14 months and 28 patients have relapsed/progressed and 6 have expired. An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance. Conclusion: IRd consolidation following ASCT appears to be safe and effective. The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. Study enrollment is scheduled to complete in Q1 of 2019. Disclosures Vij: Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Amgen: Research Funding; Sanofi: Research Funding; Roche: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kaufman:Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gregory:Poseida Therapeutics, Inc.: Research Funding. Berdeja:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Chari:Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; The Binding Site: Consultancy.

scholarly journals Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1413-1413
Author(s):  
David Belada ◽  
Jacob Haaber Christensen ◽  
Kristina Drott ◽  
Sylvia Snauwaert ◽  
Joshua Brody ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Metabolic Response ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL. Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks. Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts. Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. Disclosures Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase 1 Study Update of the Novel Pan-Pim Kinase Inhibitor LGH447 in Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 301-301 ◽  
Author(s):  
Marc S Raab ◽  
Enrique M Ocio ◽  
Sheeba K. Thomas ◽  
Andreas Günther ◽  
Yeow-Tee Goh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Once Daily ◽  
Grade 3 ◽  
Dose Levels

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

Comparison of Sequential Vs Alternating Administration of Bortezomib, Melphalan, Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) in Elderly Pts with Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 178-178 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Joaquin Martinez-Lopez ◽  
Miguel-T Hernandez ◽  
Rafael Martinez ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Sequential Approach ◽  
Grant Support ◽  
Similar Survival

Abstract Background: VMP and Rd are two of the most effective regimens in the treatment of elderly newly diagnosed MM pts. In order to further improve its outcome, one possibility would be to use regimens including all these drugs simultaneously, but this may result toxic. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of these pts. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and Rd in a sequential vs an alternating scheme. Pts and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). Both arms were well balanced according to the baseline characteristics. Of note, 55% of pts in the sequential and 44% in the alternating arm were older than 75 yrs. Fifty-one percent in the sequential arm and 52% in the alternating had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles, the sCR/CR rate was lower in the sequential (20%) than in the alternating arm (32%)(p=0.02). However, among the 179 pts that were evaluable for efficacy after the 18 planned cycles of treatment, the pattern reversed: 51% achieved sCR/CR in the sequential vs 38% in the alternating arm (p=0,05). The flow-CR rate among patients in sCR/CR was 66% and 48% in the sequential vs alternating arms, respectively (P=0.16). To achieve flow-CR was associated with a significantly longer TTP (median not reached vs 15 months since the end of treatment; P=.01). After a median f/u of 27 months, median PFS was of 30 months in both sequential and alternating arms (p=NS). Median OS has not been reached, and 68% and 67% of pts are alive at 3 yrs (p=NS). Pts who achieved sCR/CR had significantly longer PFS and OS as compared with pts who did not (3-yrs PFS for sCR/CR of 76% vs 18% for <CR (p<0.0001), and 3-yrs OS of 94% vs 53% for sCR/CR vs <CR (p<0.0001)) in both arms. The achievement of flow-CR has been also associated with 3-yrs PFS of 84% vs 38% months for pts who did not achieve flow-CR. This benefit has been observed in both arms. Pts younger than 75 yrs showed a significantly longer survival as compared to pts ≥75y (3-yrs PFS of 55% vs 27m, p=0.04) and 3-yrs OS of 89% vs 35m, p<0.0001 ) , with no significant differences between sequential and alternating arms. No differences were observed in overall response rates and sCR/CR rates in standard and high risk pts, but there was a trend toward shorter PFS and OS in the subgroup of high-risk CA (median PFS of 28 months and 3-yrs OS of 64%, pNS) vs standard-risk (3-yrs PFS of 54% and 3-yrs OS of 80%, pNS). Regarding hematologic toxicity, no significant differences were observed between the sequential and alternating arms in the frequency of G3-4 neutropenia (19% and 22%) or thrombocytopenia (21% and 20%). Concerning non-hematologic toxicity, 3% and 6% of the pts in the sequential and alternating arms had G3-4 infections. No differences were observed neither in the the incidence of peripheral neuropathy in the sequential and alternating arms (4% and 3%, respectively) nor in the rate of grade 3-4 thrombotic events (1% and 2%). The rate of early discontinuations (15%) and deaths (4%) before the cycle 9 were identical in both arms; of note 71% of early discontinuations occurred in pts aged over 75 yrs and all early deaths but one were also in pts older than 75 yrs. Conclusions: The alternating regimen has demonstrated to be not superior to the sequential approach. Toxicity profile is acceptable. This Total Therapy approach, including the four active anti-myeloma agents (melphalan, bortezomib, lenalidomide and steroids) is particularly active in pts between 65-75 years old, with similar survival to that of transplant candidate pts with outstanding outcome when sCR/CR is achieved. Disclosures Mateos: Celgene: 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. Off Label Use: Lenalidomide as first-line combination therapy for AL amyloidosis.. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Ocio:Celgene Corporation: Honoraria, Research Funding. Pérez de Oteyza:Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Oriol:Celgene Corporation: Consultancy. De La Rubia:Janssen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.

Phase I/II Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 187-187 ◽  
Author(s):  
Jatin J. Shah ◽  
Lei Feng ◽  
Elisabet E. Manasanch ◽  
Donna Weber ◽  
Sheeba K Thomas ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Depth Of Response ◽  
High Risk Disease ◽  
Grade 3

Abstract Background: Induction therapy prior to autologous stem cell transplantation (ASCT) continues to improve with the use of multi-drug combination regimens. Panobinostat (pano), a deacetylase inhibitor, was recently approved in combination with bortezomib/dexamethasone for relapsed myeloma based on the phase III PANORMA I trial for RRMM. The addition of pano in PANORAMA demonstrated a near doubling in CR rate from 15 to 27%. We previously reported phase I trial data of RVD + pano in newly diagnosed myeloma (NDMM) and demonstrated the pano can be safely combined with RVD. Based on the encouraging preliminary data we pursued a phase II dose expansion to further explore the potential improvement in depth of response with RVD + pano in NDMM. Methods: The primary objective was to determine the safety/tolerability of pano and RVD in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Patients had to have NDMM with indication for therapy and be eligible for ASCT with adequate organ function. Panobinostat 10 mg was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4 and responses were assessed by the modified International Uniform Response Criteria. Results: 42 patients (pts) were enrolled; 12 in the dose escalation and 30 in the dose expansion. The median age was 60 (range 44-79); male (n=30); ISS stage I (n=28); ISS stage II (n=10); ISS stage III (n=4); 14/42 pts had high risk myeloma (1 pt with t(4:14) and del17p; 1 pt with del 17p and 1q21; and 12 pts with only 1q21 amplification). Among 42 pts, 2 completed only 1-2 cycles and 1 pt was inevaluable for response. Among the 39 pts who completed 4 cycles and were evaluable for efficacy the ORR (≥PR) after 4 cycles was 93% (36/39) including nCR/CR in 17/39 (44%), VGPR in 10/39 (26%), PR in 9/39 (23%), and SD in 3/39 (8%) pts. In 12 of 14 pts with high risk disease, who were evaluable for response, the ORR was 100% (12/12); the nCR/CR in 6/12 pts; VGPR in 4/12 pts; and 2/12 pts achieved a PR. 25/42 (59%) pts completed induction therapy and underwent consolidation with ASCT; 5 pts completed induction therapy, came off study and did not proceed to ASCT. 8 pts choose a delayed transplant approach, completed induction therapy and stem cell collection. 6 of those 8 pts remain on trial with maintenance therapy (len/dex/pano) per protocol. 2 pts, neither with high risk disease, progressed after cycles 10 and 11 with extramedullary disease and plasma cell leukemia/central nervous system involvement, respectively. 4 additional patients have completed 2, 3, and 5 cycles of therapy and are pending ASCT. Grade 3-4 hematologic adverse events included anemia (5); neutropenia (10); thrombocytopenia (16). Grade 3-4 nonhematologic toxicities included ALT elevation (1); AST elevation (1); constipation (2); diarrhea (4); dyspnea (2); fatigue/muscle weakness (5); syncope (2); MI (1); nausea (3); peripheral neuropathy (2); rash (1); DVT/VTE (3). Infectious complications included grade 2 (G2) urinary tract infection (2); G2 upper respiratory tract infection (5); pneumonia (5); osteomyelitis/musculoskeletal (3); infection (3). Treatment emergent serious adverse events related to therapy observed were: G3 pneumonia (9); G2 fever (5), G3-4 venous thromboembolic events (2); G3 diarrhea (2); atrial fibrillation (2). Other events included 1 pt each with G3 cellulitis, G3 myocardial infarction (MI), G3 febrile neutropenia, G2 diarrhea, G2 seizure, G3 hypotension and G3 sinusitis. 1 pt had a second primary malignancy - a newly diagnosed breast cancer during cycle 9 of therapy. Conclusions: Panobinostat 10 mg can be safely combined with full dose RVD in NDMM. The side effect profile with use of subcutaneous bortezomib demonstrated minimal gastrointestinal toxicity/diarrhea and was a well-tolerated combination. The combination of RVD+ pano lead to rapid disease control with high response rate after 4 cycles of therapy and ORR of 93% and significant depth of response with a 4 cycle nCR/CR rate of 44%. Enrollment in dose expansion is near completion and full data will be presented at ASH and supports the study of panobinostat in a randomized trial for NDMM. Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Celgene: Research Funding; Novartis: Research Funding; Idera Pharmaceuticals: Research Funding. Orlowski:Genentech: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy.

scholarly journals Ixazomib or Lenalidomide Maintenance Following Autologous Stem Cell Transplantation and Ixazomib, Lenalidomide, and Dexamethasone (IRD) Consolidation in Patients with Newly Diagnosed Multiple Myeloma: Results from a Large Multi-Center Randomized Phase II Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 602-602 ◽  
Author(s):  
Ravi Vij ◽  
Thomas G. Martin ◽  
Nitya Nathwani ◽  
Mark A. Fiala ◽  
Feng Gao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Advisory Board ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of &gt;1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.

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