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

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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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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Bortezomib, Melphalan, Prednisone and Thalidomide Followed by Maintenance with Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly Multiple Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors

Blood ◽

10.1182/blood.v116.21.620.620 ◽

2010 ◽

Vol 116 (21) ◽

pp. 620-620 ◽

Cited By ~ 6

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Maide Cavalli ◽

Roberto Ria ◽

Massimo Offidani ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Weekly Infusion ◽

Risk Of Disease ◽

Grade 3

Abstract Abstract 620 Background. The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for elderly newly diagnosed multiple myeloma. This phase 3 study compared the 4 drug combination bortezomib-melphalan-prednisone-thalidomide followed by maintenance bortezomib-thalidomide (VMPT-VT) with VMP alone. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day) or VMP (N=257) alone. In March 2007, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). The primary end point was progression-free survival (PFS). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were superior in the VMPT-VT group with a complete remission (CR) rate of 38% vs 24% (p=0.0008). After a median follow-up of 26.1 months, the 3-year PFS were 55% in patients receiving VMPT-VT and 38% in those receiving VMP (HR 0.65, 95% CI 0.49–0.85, P=0.002, Table). The 3-year time-to-next-therapy were 69% with VMPT-VT and 55% with VMP (HR 0.60, 95% CI 0.42–0.85, P=0.004). The 3-year overall survival was 86% with VMPT-VT and 84% with VMP (HR 0.88, 95% CI 0.53–1.45, P=0.62). The achievement of CR was a strong predictive factor of longer PFS in both groups (P=0.0001): in VMPT-VT arm, 3-year PFS was 66% in patients who obtained CR and 47% in those achieving PR; in VMP arm, it was 70% and 30%, respectively. The PFS benefit of VMPT-VT was seen consistently across different subgroups defined by creatinine clearance, LDH and bortezomib schedule; by contrast, in patients older than 75 years (HR 0.87; 95% CI 0.54–1.43, P=0.59) and in those at increased risk of disease progression, defined as presence of cytogenetic abnormalities [t(4;14) or t(14;16) or del17p] and ISS 3 (HR 1.35; 95% CI 0.45–4.06, P=0.60), VMPT-VT seemed not to add any significant PFS advantage to VMP. Grade 3–4 neutropenia (38% vs. 28%, p=0.02), cardiological events (10% vs. 5%, p=0.04) and thromboembolic events (5% vs. 2%, p=0.08) were more frequent among patients assigned to the VMPT-VT group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. In both groups, the once-weekly infusion of bortezomib significantly reduced the incidence of severe sensory peripheral neuropathy from 16% to 3% (p<0.0001). One hundred and forty-nine VMPT-VT patients were assessable for maintenance treatment. After a median duration of maintenance of 14.4 months, the PR rate was 90%, including 45% CR. The 1-year landmark analysis of PFS in patients completing the 9 induction cycles, showed a 2-year PFS of 63% in the VMPT-VT group and 40% in the VMP group, demonstrating that maintenance with VT reduced the risk of disease progression of 51% (HR 0.49, 95% CI 0.33–0.72, p=0.0003, Figure). This advantage was less evident in patients older than 75 years (HR 0.97, 95% CI 0.52–1.78, P=0.91) and in those with high-risk of disease progression, defined as presence of cytogenetic abnormalities and ISS 3 (HR 1.31, 95% CI 0.22–7.85, p=0.77). Continuous therapy with VT had favourable safety profile: 3% of patients experienced grade 3–4 hematological toxicity, 5% grade 3–4 peripheral neuropathy and 7% discontinued due to adverse events. Conclusion. In summary the current results indicate that: 1. VMPT-VT prolonged PFS with an unprecedented 3-year PFS of 55% in elderly patients; 2. once-weekly infusion of bortezomib improved safety without affecting outcome; 3. higher dose-intensity regimens seemed to be less effective in frail patients (≥ 75 years) and 4. maintenance therapy with VT further improved PFS with a good safety profile. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Patriarca:Celgene: Honoraria; Janssen Cilag: Honoraria; Roche: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Petrucci:Celgene: Honoraria; Janssen Cilag: Honoraria. Musto:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

Blood ◽

10.1182/blood.v124.21.409.409 ◽

2014 ◽

Vol 124 (21) ◽

pp. 409-409 ◽

Cited By ~ 8

Author(s):

Valeria Santini ◽

Antonio Almeida ◽

Aristoteles Giagounidis ◽

Stephanie Gröpper ◽

Anna Jonasova ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Efficacy And Safety ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Double Blind ◽

Equity Ownership ◽

Grade 3

Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

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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

Blood ◽

10.1182/blood.v122.21.4045.4045 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4045-4045 ◽

Cited By ~ 10

Author(s):

Vincen t Ribrag ◽

Claire N Harrison ◽

Florian H Heidel ◽

Jean-Jacques Kiladjian ◽

Suddhasatta Acharyya ◽

...

Keyword(s):

Adverse Events ◽

Disease Progression ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Expansion Phase ◽

Phase 1B ◽

Grade 3

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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A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up

Blood ◽

10.1182/blood-2018-99-111712 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1957-1957

Author(s):

Dickran Kazandjian ◽

Neha Korde ◽

Sham Mailankody ◽

Yong Zhang ◽

Jennifer Hsu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Risk Profile ◽

Phase 2 ◽

Time To Progression ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Abstract Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity. Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Updated Results of Phase 2 Study of Ruxolitinib in Combination with 5-Azacitidine in Patients with Myelofibrosis

Blood ◽

10.1182/blood-2018-99-120251 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 352-352 ◽

Cited By ~ 2

Author(s):

Lucia Masarova ◽

Srdan Verstovsek ◽

Jorge E. Cortes ◽

Naveen Pemmaraju ◽

Prithviraj Bose ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Bone Marrow Fibrosis ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Abstract Background: JAK1/2 inhibitor ruxolitinib (RUX) abrogates symptoms and organomegaly in patients with myelofibrosis (MF). Combination with azacitidine (AZA) may further improve its efficacy. Methods: We initiated a single institutional, single arm, prospective, phase 2 study of RUX AZA combination in adult patients with MF and < 20% blasts. Previous therapy with RUX or AZA was not allowed. RUX 5 - 20 mg orally twice daily was given continuously since cycle 1. AZA 25 - 75 mg/m2 on days 1 - 5 of each 28-day cycle was added starting cycle 4. Responses were assessed per International Working Group for Myelofibrosis Research and Treatment 2013 criteria (IWG-MRT). Enrollment cut-off for this analysis was December 31st, 2017 to allow > 6 months of follow-up for all enrolled patients. We plan to present updated results with additional 5 months of enrollment at the meeting. Results: Fifty two pts were enrolled on study between 03/2013-12/2017, and were evaluable for responses. Forty seven pts (84%) were treated with both agents (RUX and AZA), with a median of 25 cycles (range, 1-55). Median age was 66 years (range, 48-87). Thirty four pts (65%) had int-2/high DIPSS score, 40 pts (77%) had spleen ≥5 cm. Thirty pts (58%) were JAK2V617F positive. Among 36 pts tested for non-driver mutations (28-gene panel); 7 pts had ASXL1, 6 had TET2, 3 had IDH1/2 and 2 had EZH2 and TP53. After a median follow-up of 22+ months (range, 1-59+); 21 pts (40%) are on therapy with a median overall follow-up of 30+ months. The most common reasons for therapy discontinuation were elective stem cell transplantation (n=12), and uncontrolled disease (n=8), including progression to acute leukemia (n=4). Four pts (8%) primarily discontinued therapy due to drug related toxicity (cytopenias). Three treatment unrelated deaths occurred on study; one each due to sepsis, meningitis and metastatic melanoma. Thirty eight pts (73%) had objective response on a study (Table). Median time to response was 1.8 months (range, 0.7-19). Seven responses (21% of responders) occurred after the addition of AZA with a median time to response of 2 months. These responses included spleen and symptom clinical improvements in 26% and 16% of pts, respectively. In total, 26 (65%), and 23 (58%) pts had palpable spleen reduction by > 50% at any time on study, and at week 24, respectively. JAK2V617F allele reduction was noted in 13 (81%) of 16 evaluable pts. Thirty one pts (60%) had available bone marrow for sequential evaluation. Nineteen pts (61%) had a documented improvement in bone marrow fibrosis, collagen or osteosclerosis, with a median time to first response of 12 months (range, 6-18). The most common grade ≥3 non-hematologic toxicity on a study was infection (34%), constipation (21%), and nausea (14%). New onset of grade ≥3 anemia, thrombocytopenia and neutropenia occurred in 33%, 30% and 16% of pts, respectively. Conclusion: Concomitant RUX with AZA was feasible with overall IWG-MRT response rate of 73%, including >50% spleen reduction in 65% of pts. Moreover, 61% of pts achieved improvement in bone marrow fibrosis, collagen or osteosclerosis. ClinicalTrials.gov Identifier: NCT01787487. Table. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:novartis: Research Funding. Pemmaraju:novartis: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; SagerStrong Foundation: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding. Daver:Pfizer: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; Sunesis: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy; Daiichi-Sankyo: Research Funding; ARIAD: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide Combined with Melphalan and Prednisone In Patients ≥ 65 Years with Newly Diagnosed Multiple Myeloma (NDMM): Continuous Use of Lenalidomide Vs Fixed-Duration Regimens

Blood ◽

10.1182/blood.v116.21.622.622 ◽

2010 ◽

Vol 116 (21) ◽

pp. 622-622 ◽

Cited By ~ 20

Author(s):

Antonio Palumbo ◽

Michel Delforge ◽

John Catalano ◽

Roman Hajek ◽

Martin Kropff ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Fixed Duration ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Risk Of Progression ◽

Grade 3

Abstract Abstract 622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients with NDMM. Methods: 459 patients aged ≥ 65 years with NDMM, stratified by age and International Staging System (ISS) stage were randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), with or without lenalidomide 10 mg/day (D1-21) for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/day; D1-21) or placebo until progression; MP patients received placebo until progression. Patients with progressive disease (PD) could enroll in the open-label extension phase (OLEP) and receive lenalidomide at 25 mg/day (D1-21) with or without dexamethasone at 40 mg/day (D1-4, 9–12, and 17–20). The primary comparison for this trial was MPR-R vs MP. Updated data from a pre-planned interim analysis at 70% of events (median follow-up of 21 months) are presented. Results: MPR-R compared with MP resulted in a higher overall response rate (ORR; 77% vs 50%, P <.001) as well as higher rates of complete response (16% vs 4%, P < .001) and very good partial response (VGPR) or better (32% vs 12%, P < .001). Responses were more rapid in patients receiving MPR-R compared with MP (median 2 vs 3 months, P < .001), and improved over time. Overall, MPR-R reduced the risk of disease progression by 58% compared with MP (hazard ratio [HR] = 0.423, P < .001) with a higher 2-year progression-free survival (PFS) rate (55% vs 16%). PFS was extended in patients receiving continuous lenalidomide therapy vs fixed-duration MP regardless of gender, ISS stage (stage I/II vs III), kidney function (creatinine clearance ≥ 60 vs < 60 mL/min), or baseline β2-microglobulin (≤ 5.5 vs > 5.5 mg/L). A landmark analysis comparing MPR-R and MPR initiated at the beginning of cycle 10 demonstrated that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo (HR = 0.314, P < .001). In addition, regardless of induction response (≥ VGPR or PR), patients who received maintenance lenalidomide had longer PFS compared with placebo. Importantly, patients relapsing during MPR-R had similar second-line treatment duration (median 55 weeks) compared with those relapsing while on placebo following MPR or MP (median 68 and 54 weeks, respectively). Additionally, PD rates during the OLEP were similar across all treatments (13% for each). Thus, outcomes of patients who relapse following continuous lenalidomide are similar to those who relapse following fixed-duration regimens, suggesting maintenance lenalidomide is not associated with more aggressive relapse. Follow-up remains too short to identify significant overall survival differences between the 3 groups. MPR-R had a manageable safety profile with minimal cumulative toxicities. Discontinuation rates due to adverse events (AEs) for patients treated with MPR-R and MP were 20% and 8%, respectively. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 71%, 38%, and 24% of patients receiving MPR-R and 30%, 14%, and 17% of those receiving MP; no grade 3/4 peripheral neuropathy was observed. Importantly, maintenance lenalidomide was as well tolerated as placebo, with few grade 3/4 AEs. During maintenance, low rates of thrombocytopenia (3% vs 2%, respectively), neutropenia (2% vs 0%), deep vein thrombosis (1% vs 0%), and fatigue (1% vs 0%) were observed. Conclusions: MPR-R achieved a higher ORR, as well as better quality and more rapid responses vs MP. Furthermore, MPR-R compared with fixed-duration regimens of MP and MPR resulted in an unprecedented reduction in the risk of progression with a manageable safety profile, and similar rates of PD in subsequent OLEP treatment. These data suggest that continuous lenalidomide therapy with MPR-R is superior to regimens of limited duration by providing sustained disease control in transplant-ineligible patients with NDMM. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria. Kropff:OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Dimopoulos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Lenalidomide In Combination With R-CHOP (R2-CHOP) In Patients With High Burden Follicular Lymphoma: Phase 2 Study

Blood ◽

10.1182/blood.v122.21.248.248 ◽

2013 ◽

Vol 122 (21) ◽

pp. 248-248 ◽

Cited By ~ 5

Author(s):

Herve Tilly ◽

Franck Morschhauser ◽

Olivier Casasnovas ◽

Thierry Jo Molina ◽

Nicolas Mounier ◽

...

Keyword(s):

Complete Remission ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Tumor Burden ◽

Phase 2 ◽

Advisory Committees ◽

High Burden ◽

Grade 3

Abstract Background Single-agent studies of lenalidomide in relapsed/refractory follicular lymphoma (FL) have demonstrated significant activity. Recent studies reported that the combination of lenalidomide and rituximab yields high response rates in patients with FL. Three recent phase 1 studies have shown that lenalidomide administered on 10 to 14 days of 21-day cycle of R-CHOP could be safe in the initial treatment of aggressive or indolent B-cell lymphomas. Two of these studies determined 25 mg of lenalidomide as the recommended daily dose. This multicenter, open label, phase 2 trial (NCT01393756) investigated the combination of lenalidomide with R-CHOP in patients (pts) with high burden FL. Methods Pts with previously untreated FL grade 1, 2 or 3a and a high tumor burden according to GELF criteria were eligible. Pts received an induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg oral lenalidomide on days 1-14) followed by two additional rituximab infusions. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the cycles. Lenalidomide dose was adapted to toxicities. Pts responding to induction therapy received rituximab maintenance every 8 weeks for 2 years. The primary endpoint was the complete remission (CR/CRu) rate, according to IWRC 99, at the end of induction treatment. Secondary endpoints were safety, progression free survival, duration of response and overall survival. Results Eighty pts were enrolled from 16 LYSA centres between December 2010 and January 2012. Median age was 57 y (range 29-71); 50% were male; 92% Ann Arbor stage III-IV; 28% B symptoms, 69% ECOG performance status = 0; 25% mass >10cm; 53% bone marrow involved; 40% LDH elevated; 63% FLIPI 3-5. Sixty-eight pts (85%) received the complete induction regimen. Median interval between R2-CHOP cycles remained 21 days during treatment. Thirty-three pts (41%) experienced at least one dose reduction of lenalidomide. The complete remission (CR/CRu) rate was 74% (CI 95%: 63%-83%) and ORR was 94% (CI95%: 86%-98%).Current median follow-up is 13 months. So far, 9 pts (11%) experienced a progression/relapse. Hematologic toxicity was in the range of that observed with R-CHOP regimen with 65% grade 4 neutropenia; 12.5% grade 4 thrombocytopenia; 7.5% febrile neutropenia and no toxic death. Grade 1-2 sensory neuropathy was observed in 28 pts (36%), one pt had a grade 3 neuropathy. Twenty-nine pts (36%; grade 1-2: 27; grade 3: 2) had reversible skin toxicity, usually during the course of the first cycle. Five episodes of thrombosis occurred during treatment or follow-up, 3 were related to venous access devices and only one required discontinuation of lenalidomide. Three cases of neoplasm were observed during follow-up. Conclusion The combination of 25mg of lenalidomide for 14 days with 21-day R-CHOP cycles is well tolerated and yields a high rate of complete remission in patients with high tumor burden follicular lymphoma. Disclosures: Tilly: Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Off Label Use: Use of lenalidomide to enhance R-CHOP efficacy in follicular lymphoma. Morschhauser:Celgene: advisory boards Other, Honoraria, Research Funding, Speakers Bureau. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Molina:Merck: Honoraria. Salles:roche: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Haioun:Roche: 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; Takeda: 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.

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Phase 2 Study of Carfilzomib (CFZ) with or without Filanesib (FIL) in Patients with Advanced Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v126.23.728.728 ◽

2015 ◽

Vol 126 (23) ◽

pp. 728-728 ◽

Cited By ~ 7

Author(s):

Jeffrey A Zonder ◽

Saad Usmani ◽

Emma C. Scott ◽

Craig C. Hofmeister ◽

Nikoletta Lendvai ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Heavily Pretreated ◽

Grade 3

Abstract Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

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A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽

10.1182/blood-2021-147112 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3722-3722

Author(s):

John F. Seymour ◽

Priyanka Gaitonde ◽

Ugochinyere Emeribe ◽

Ling Cai ◽

Anthony R. Mato

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

The Difference ◽

Grade 3 ◽

Definition Of

Abstract Background: Acalabrutinib (Acala) is a next-generation, highly selective, covalent BTK inhibitor (BTKi) approved for the treatment of CLL. The phase 3 ASCEND study demonstrated significant progression-free survival (PFS) benefit with Acala vs investigator's choice of chemoimmunotherapy (bendamustine + rituximab [BR]) or pi3K inhibitor (idelalisib) + rituximab (IR) in R/R CLL patients (pts) (Ghia et al. J Clin Oncol. 2020). In ELEVATE-RR, Acala demonstrated non-inferior PFS vs a first-generation BTKi (ibrutinib [Ibr]) in R/R CLL pts with high-risk genomics (Byrd et al. J Clin Oncol. 2021). Acala was well tolerated in both trials. Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis balances risks (toxicity) and benefits (prolonged survival without symptoms of disease progression or adverse events [AEs]) of oncology treatments. We conducted a Q-TWiST analysis using data from these trials to assess risk-benefit of Acala vs comparators among R/R CLL pts. Methods: Patient survival time with 16 months (ASCEND) and 41 months (ELEVATE-RR) of median follow-up data were partitioned into 3 states: time with toxicity before disease progression (TOX); time without progression or toxicity (TWiST); and time from disease progression until death or end of follow-up (relapse [REL]). Toxicity was defined as grade 3/4 AEs and, for the comparison vs Ibr, an additional definition of toxicity included AEs of any grade with frequency ≥10% (AE ≥10%). Sensitivity analyses with toxicity defined as grade 2-4 AEs will be presented. Kaplan-Meier survival curves were constructed for TOX, PFS, and overall survival (OS). For the TOX curve, event time for each pt was calculated by summing days with AEs (per toxicity definition) before disease progression, with no pt censored. Restricted means were calculated for the longest PFS time among treatment arms. Restricted mean TWiST duration was estimated using the difference between restricted means of PFS and TOX. Restricted mean REL duration was estimated using the difference between restricted means of OS and PFS. Q-TWiST was calculated by summing weighted restricted mean durations of TOX, TWiST, and REL. Utility of 1.0 for TWiST and 0.5 for TOX and REL (Gelber et al. Am Statistician. 1995) were applied. Sensitivity analysis was conducted using utility measures from trial data. Two-sided p<0.05 indicated statistical significance. Results: Among Acala vs IR/BR-treated pts, significantly longer duration of TWiST (mean diff, 3.58 months [95% CI, 2.42, 4.74]) and shorter duration of REL (mean diff, −2.51 months [95% CI, −3.50, −1.60]) and TOX (mean diff, −0.73 months [95% CI, −1.24, −0.24]) were found, indicating Acala vs IR/BR-treated pts had longer time without disease progression and toxicity and shorter time with toxicity. Q-TWiST was significantly different (1.96 months [95% CI, 1.13, 2.81]) between Acala (17.48 months) and IR/BR (15.52 months). In the Acala and Ibr comparison, differences in durations of TWiST and TOX varied based on the toxicity definition while the difference in REL durations remained consistent (mean diff, 0.37 months [95% CI, −1.82, 2.60]; p=0.33]). With the toxicity definition of AE ≥10%, Q-TWiST was significantly different (2.56 months [95% CI, 0.19, 4.83]) for Acala (33.02 months) vs Ibr (30.46 months). When toxicity was defined as grade 3/4 AEs, Q-TWiST had higher estimates for Acala but the difference was not statistically significant (1.28 months [95% CI, −1.34, 3.80]). In the sensitivity analysis, Q-TWiST gains were not statistically significant, most likely because the study was not designed to collect EQ-5D data post-treatment discontinuation. Conclusions: Q-TWiST analyses integrate efficacy, safety, and quality of life into a more appropriate measure useful for detailed benefit-risk assessment of cancer treatment. This analysis demonstrated that Acala treatment is significantly superior to IR/BR treatment. Quality-adjusted survival gains of Acala over Ibr varied by toxicity definition, but was numerically higher for Acala. Overall, Acala demonstrated a favorable benefit-risk profile vs different comparators in R/R CLL. Figure 1 Figure 1. Disclosures Seymour: Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: 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. Gaitonde: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Cai: Celgene Corporation: Ended employment in the past 24 months; Google: Current equity holder in publicly-traded company; AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Mato: Johnson and Johnson: Consultancy, Research Funding; MSKCC: Current Employment; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genmab: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AstraZeneca: Consultancy.

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