MCRN¯003/MYX·1: A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma after 1-3 Prior Therapies

Abstract Background: Carfilzomib, a second generation proteosome inhibitor, is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Recent phase II and phase III trials have demonstrated the efficacy of weekly dosing strategies. The aim of this study was to examine high dose once weekly carfilzomib in combination with weekly dexamethasone and low dose weekly cyclophosphamide (wCCD) in RRMM. It was hypothesized that this may offer a potent yet convenient and more financially viable triplet-based treatment option than existing combinations. Methods: The MCRN-003/MYX.1 multi-centre single arm phase II clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had at least one but not more than three prior lines of therapy and who did not have proteosome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg on days 1, 8, 15 and 22. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. The total sample size of 76 patients includes a 6 patient lead-in phase where safety at 70 mg/m2 was evaluated. The primary objective was to observe an overall response rate (ORR) ≥ 80% after 4 cycles of protocol therapy. Secondary endpoints include safety, toxicity, kinetics of and maximal response depth and overall survival. This analysis is based on the locked data base of 2018 July 13. Results: Of the 76 patients accrued 1 was subsequently determined to be ineligible on the basis of bortezomib refractory disease, and 1 did not receive any protocol therapy due to a cardiac event occurring post-study registration but prior to treatment commencement. All patients who received therapy were included in the analysis as per protocol inclusive of the bortezomib exposed patient. Among these 75 patients, median age was 66 years with 33% being > 70 years of age. Thirty-seven percent were female. Thirty-nine percent received 1 prior line, 44% received 2 prior lines and 17% received 3 prior lines of therapy. High risk cytogenetics [(t4;14), t(14;16) and del P53] were identified in 32%. Twenty percent had ISS stage III disease and 11% had R-ISS stage III disease. Prior PI and immunomodulatory drug exposure was noted in 87% and 81% respectively. Within the first 4 cycles of therapy 84% (95% CI, 76-92%) of patients achieved PR or better, with ≥ VGPR achieved in 52% and ≥ CR in 9% (table 1, p = 0.0006). There was a trend toward a better ORR after 4 cycles based on the presence or absence of high-risk cytogenetics (75% vs 94% respectively, p = 0.051) not meeting statistical significance. The median duration of follow-up at the time of data analysis was 13.9 months (range 0.2 to 22.8 months). 18 patients have died with an estimated 1-year OS of 80%. The cause of death as assessed by the investigator was myeloma in 13 patients with 3 dying from a cause possibly or probably related to the study intervention. During the first 4 cycles of treatment, non-hematologic toxicity ≥ grade 3 occurred in 33% of patients; most commonly infection (16%) and fatigue (7%). Grade 3/4 anemia was observed in 17%, thrombocytopenia in 33% and neutropenia in 20%. Grade 3 or greater hypertension was seen in 4%, dyspnea in 1%, pulmonary edema in 1% and thrombotic microangiopathy in 4%; all resolved with no long-term sequelae. To date 37 (49%) patients have discontinued carfilzomib, 11 due to toxicity and 16 due to disease progression. Conclusion: This prospective phase II study demonstrates that wCCD is a safe and effective regimen in the treatment of RRMM. The study met its primary endpoint demonstrating a ≥ 80% ORR after 4 cycles of therapy. These results compare favourably to published phase III data examining weekly carfilzomib and dexamethasone as well as the established twice-weekly dosing strategies. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to immunomodulatory agents who would otherwise be ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sandhu:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Bioverativ: Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Chen:Amgen: Honoraria. Louzada:Celgene: Honoraria; Janssen: Honoraria; amgen: Honoraria; pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Kite: Research Funding.

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High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Blood ◽

10.1182/blood.v116.21.2271.2271 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2271-2271

Author(s):

Andreas L Petzer ◽

Dominic Fong ◽

Thomas Lion ◽

Irina Dyagil ◽

Zvenyslava Masliak ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

De Novo ◽

Chronic Phase ◽

Phase Iii ◽

High Dose ◽

Molecular Response ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 2271 Introduction: Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML. Methods: We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726. Results: From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B. Conclusions: Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients. Disclosures: Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Phase I/II Trial Of Everolimus, Bortezomib and Rituximab In Relapsed Or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v122.21.4402.4402 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4402-4402 ◽

Cited By ~ 3

Author(s):

Irene M. Ghobrial ◽

Erica N Boswell ◽

Stacey Chuma ◽

Ranjit Banwait ◽

Courtney Hanlon ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Complete Response ◽

Recommended Dose ◽

Advisory Committees ◽

Grade 3

Abstract Introduction The phase I aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab and the phase II study aimed to examine response and safety of the combination of all 3 agents in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM. Methods Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance until Progression. The phase I trial included two stages with a total of four dose levels. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. For the phase II study, patients received everolimus 10 mg daily, bortezomib IV 1.6mg/m2 on days 1, 8, 15 every 28 days, and rituximab 375mg/m2 IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression Results Forty-Six patients were enrolled in this phase I/II clinical trial from April 2009 to July 2013. The median age is 65 (range, 47–84) yrs and the median lines of prior therapy is 5 (range, 1–9) with 45 (98%) patients receiving prior rituximab and 23 (50%) receiving prior bortezomib. The median number of cycles on therapy was 19.5 (range, 0–39). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (4.3%), leukopenia (2.2%), thrombocytopenia (13%), lymphopenia (2.2%) and hypertriglyceridemia (2.2%). Grade 3 toxicities included: neutropenia (13%), leukopenia (13%), anemia (10.9%), lymphopenia (8.7%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), (2.2%) bacterial endocarditis, (2.2%) congestive heart failure, (2.2%) hearing loss, hyperglycemia (4.3%) hypernatremia (4.3%) and 1(2.2%) subject had an incarcerated inguinal hernia with small bowel obstruction. Two patients discontinued therapy due to grade 3 anemia. For the phase II study, sixteen patients are currently evaluable for response, including 2 (13%) complete response (CR), 11 (68%) partial response and 1 (6%) minimal response (MR), for an overall response rate including MR of 14/16 (88%) in this relapsed/refractory population. Furthermore, overall response including MR in phase I was 1/23 (4%) complete response, 7/23 (30%) partial response and 10/23 (43%) minimal response. In phase II 1/23 (4%) complete response, 14/23 (61%) partial response and 2/23 (9%) minimal response. Additionally, 8 (17%) patients achieved stable disease. Conclusions The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. The responses observed to date indicate that this combination is highly effective in this relapsed/refractory population. This study was supported from the FDA Office of Orphan Products Development and by Millennium/Takeda and Novartis Inc. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; BMS: Research Funding; Sanofi: Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees. Richardson: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; Novartis: Membership on an entity’s Board of Directors or advisory committees. Treon:Millennium: Consultancy. Matous:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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Bortezomib in Combination with Pegylated Liposomal Doxorubicin and Thalidomide (VDT), An Effective Steroid Independent Regimen for Previously Untreated Multiple Myeloma Patients: Final Result of a Phase II Study.

Blood ◽

10.1182/blood.v114.22.618.618 ◽

2009 ◽

Vol 114 (22) ◽

pp. 618-618

Author(s):

Taimur Sher ◽

Kena C Miller ◽

Sikander Ailawadhi ◽

Debbie Manfredi ◽

Margaret Wood ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Phase Ii ◽

Phase Ii Trial ◽

Phase Ii Study ◽

Pegylated Liposomal Doxorubicin ◽

High Dose ◽

Advisory Committees ◽

Significant Toxicity ◽

Grade 3

Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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A Lysa Phase II Study of Oral JAK1/2 Inhibitor Ruxolitinib in Advanced Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Blood ◽

10.1182/blood.v128.22.4160.4160 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4160-4160 ◽

Cited By ~ 2

Author(s):

Eric W Van Den Neste ◽

Marc Andre ◽

Thomas Gastinne ◽

Aspasia Stamatoullas ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Study Drug ◽

Median Number ◽

Primary Objective ◽

Additional Treatment ◽

Advisory Committees ◽

Grade 3

Abstract Background: JAK2 constitutive activation/overexpression is frequent in classical HL tumor cells and many autocrine/paracrine cytokines stimulate HL cells by recognizing JAK1- or JAK2-bound receptors. Thus, JAKs blockade may be of therapeutic value in HL. Methods: A phase II study (HIJAK study)was conducted to evaluate safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in R/R HL, given at 20 mg bid for 6 cycles of 28 days. Dosage at 15 mg bid was planned for patients with platelets comprised between 75 and 200 x 109/L at inclusion. Patients with platelets < 75 x 109/L, neutrophils < 1000 x 109/L were excluded. Maintenance beyond 6 cycles was permitted if disease control. The primary objective was overall response rate (ORR, Cheson 2007) at 6 cycles. Secondary objectives were safety, B symptoms relief, best ORR, response duration, PFS and OS. To be evaluable for response and survivals, patients had to receive at least one cycle of the study drug. The safety set included all patients who received at least one dose of ruxolitinib. Median follow-up was 27.1 months (95% CI: 14.4-27.1). Results: 33 patients were included between Jul 2013 and Dec 2014 in 10 LYSA centers in France and Belgium: M/F, 21/12; median age 37 (range 19-80) years; stage III/IV, 75.8%; B symptoms, 51.5%; median number of prior lines, 5 (range 1-16); prior transplantation, 60.6%; prior radiotherapy, 54,5%; prior brentuximab vedotin (BV), 82%; refractory to last therapy, 81.8%. Overall, median number of ruxolitinib cycles was 4. Nine (27.3%) patients received at least 6 cycles and 6 (18.2%) maintenance. ORR at the end of induction was 3/32 (9.4%) patients, all PRs. Best ORR at any time during study was 18.8% (6/32) with five PRs and 1 patient who converted into CR beyond 6 cycles. Transient stable disease was noted in 11 patients. Rapid and durable alleviation of B-symptoms (pruritus, fever, sweating) was frequently noted, especially pruritus which was present in 35.5% of patients before treatment and 6.6% of them after one cycle of ruxolitinib. Median duration of response was 7.7 months (95% CI: 1.8-NA). Two patients remain on therapy. Median PFS was 3.5 months (95%CI: 1.9-4.6) and median OS was 27.1 months (95%CI: 14.4-27.1). Using bead-based immunoassays, plasma levels of 27 cytokines related to the immune system were measured at baseline and after cycle 1. Before ruxolitinib, there was no difference in cytokine levels between responders and non-responders. In responders, the only cytokine that significantly decreased was CX-CL10 (P.01). In patients presenting with pruritus (n=11), PDGF-BB, IL-5, IL-10, IL-12, IL-13, IL-17, eotaxin, FGF basic, MIP1b, rantes, and VEGF were significantly increased. In the latter patients, ruxolitinib treatment significanlty decreased PDGF-BB, IL-10, IL-12, IL-13, IL-17, FGF basic and VEGF. Among patients who were analyzable for JAK2 amplification in RS cells (n=12), polysomy was detected in all of them and specific JAK2 amplification in one. Further analysis of Jak2 targets by IHC will be performed. 40 adverse events (AEs) were reported in 14/33 patients (42.4%), of which 18 were related to ruxolitinib and 18 were grade ≥ 3. One AE led to permanent treatment discontinuation. No AE leading to death was reported. 87.5% of AEs recovered without sequelae. Eight SAEs (infection, 3; anemia, 1; diarrhea, 1; subdural hematoma, 1; bone pain, 1; pulmonary embolism, 1) were reported in 4 patients (12.1%), of which 2 were related to ruxolitinib. No grade 4 neutropenia and 1 grade 3/4 thrombocytopenia was observed. Five patients had grade 3 anemia. Twelve patients died due to lymphoma (83.3%) or toxicity of additional treatment (8.3%) or other reason (8.3%). Among 30 patients who progressed (initial site in 97% and/or new site in 60%), 25 (83.3%) were retreated: with chemotherapy in 19 (comprising bendamustine in 10) and/or immunotherapy in 9 (rituximab, n=4; BV, n=3; nivolumab, n=2). Transplantation was eventually performed in 5/25 (4 allogenic, 1 autologous). In the 25 patients who were retreated, CR/PR rates were 10/15%, respectively. Conclusions: Ruxolitinib shows hints of activity beyond simple anti-inflammatory action in highly advanced, mostly refractory, HL patients, although most responses are short-lived. Toxicity was limited suggesting potential to be combined with other modalities. Further treatment, beyond ruxolitinib, was possible in most patients, even with chemotherapy. Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Ghesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Roche France: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria.

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Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL) for Relapsed/Refractory WaldenstrÃ¶m Macroglobulinemia Patients

Blood ◽

10.1182/blood-2018-99-114023 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1607-1607 ◽

Cited By ~ 1

Author(s):

Giulia Benevolo ◽

Simone Ferrero ◽

Alessandro Andriani ◽

Anna Castiglione ◽

Anna Baraldi ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Salvage Treatment ◽

First Line ◽

Advisory Committees ◽

Grade 3 ◽

Line Of Therapy

Abstract BACKGROUND: Standard rituximab plus chemotherapy salvage treatment has shown moderate activity in patients with relapsed/refractory Waldenström's macroglobulinemia (RR-WM), with 18-months progression free survival (18-PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi (F.I.L.) we designed a multicenter phase II study to assess the efficacy of a combination of bendamustine, rituximab and bortezomib (BRB) in improving these results. METHODS and PATIENTS: This single-arm phase II study tested the hypothesis that 18-PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan was: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months. Patients with RR-WM after first line of therapy were enrolled in 18 F.I.L. centers, from October 2014 to November 2017. In the last 23 patients MYD88L265Pwas tested by the recently described droplet digital PCR (ddPCR) assay both on bone marrow (BM) and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). RESULTS: At the time of analysis, 29 patients completed the six cycles of therapy, six patients stopped therapy for toxicity, two patients died and one had just finished therapy and was not yet evaluated. 18-PFS was 84% (95%CI: 61-94%), with two progressions and two deaths without evidence of progression (one cerebrovascular accident during the fifth cycle and one pulmonary embolism at three months follow up). On an intention-to-treat analysis (N=37), overall response rate was 70%, (N=26) including 4 (11%) complete, 11 (30%) very good partial, 10 (27%) partial responses and 1 (3%) minimal response according to IWM response criteria. Overall, treatment was well tolerated, the most common adverse events of any grade included 13 patients (34%) experiencing grade 3-4 neutropenia, especially in cycle 4 (leading in four cases to treatment discontinuation). Peripheral nervous system toxicity was observed in five patients (13%; 4 of grade 1-2 and 1 of grade 3-4), with no discontinuations. Serious adverse events were observed only in three patients, mainly rash, all resolved. All the 23 patients assessed for MYD88L265Pat baseline scored positive in BM, while only 18/23 (78%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. Among the 21 patients monitored for MRD after treatment 5 scored MRD negative in BM and 13 in PB, highlighting the deep activity of the BRB regimen in clearing the disease. CONCLUSIONS: Among patients with RR-WM after first line of therapy, BRB regimen is a well-tolerated salvage treatment, resulting in high rates of PFS at 18 months. Moreover, the deep anti-tumor activity of this regimen is highlighted by the promising rates of both clinical and molecular responses. More complete and mature results will be presented during the meeting. (ClinicalTrials.gov number: NCT02371148). Disclosures Gaidano: AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vitolo:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Phase I/II Clinical Trial of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas

Blood ◽

10.1182/blood-2020-134750 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Ajay Major ◽

Justin Kline ◽

Theodore G. Karrison ◽

Paul A S Fishkin ◽

Amy S Kimball ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

The Other ◽

Advisory Committees ◽

Grade 3

Background Targeting the PI3K/Akt/mTOR axis in relapsed lymphomas is of interest based on constitutive activation in many lymphoma subtypes, and has had varying degrees of success. We previously showed that the first generation mTOR inhibitor, temsirolimus (TEM), has activity across histologies with an acceptable toxicity profile (Smith, et al., JCO 2010). Lenalidomide (LEN) is currently approved for use in indolent non-Hodgkin lymphomas, and has several potential synergistic and overlapping targets with PI3K/mTOR/Akt inhibition. We designed this phase I/II clinical trial to evaluate the efficacy and tolerability of the combination of TEM and LEN in relapsed/refractory lymphomas. Methods The phase I dose-finding study utilized a standard "3+3" design and was open to all patients with mature B-cell malignancies. TEM was 25 mg IV weekly for all dose levels. LEN was dosed orally on D1-D21 every 28 days at three dose levels: 15 mg, 20 mg, and 25 mg. The phase II study accrued patients in a two-stage "minimax" design with stratification into three histologically-defined cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR), and secondary endpoints were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results In the phase I study, 18 patients were enrolled and available for toxicity assessment. Patients were treated to intolerance, progression, or discontinuation at physician discretion. Of these, 15 patients were evaluable for dose-limiting toxicity (DLT) assessment. At dose level 3, there were 2 DLTs: grade 3 diarrhea and grade 3 HSV mucositis. Dose level 2 was thus established as the recommended phase II dose: TEM 25 mg weekly and LEN 20 mg on D1-D21 every 28 days. Of the 18 patients, there were 5 partial responses, 4 stable disease, 3 progressive disease, 4 on active treatment, and 2 not adequately assessed. The phase II study enrolled an additional 93 patients (Table 1): 39 DLBCL, 15 FL, and 39 other lymphomas which included 20 relapsed/refractory Hodgkin lymphoma (HL) patients. The median number of prior treatments was 4 (range, 1-14), and 31 patients (33%) had relapsed following prior autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-21). The FL cohort closed prematurely due to slow accrual. The ORR were 25.6% (12.8% CR) and 64.1% (17.9% CR) for DLBCL and other lymphoma cohorts, respectively (Table 2). The ORR for HL patients in the other lymphoma cohort, the majority of whom had relapsed after brentuximab vedotin (BV) and autologous stem cell transplantation (ASCT), was 80% (35% CR). Eight HL patients (40%) proceeded to allogeneic transplantation after TEM and LEN therapy. The high response rate in the other lymphoma cohort was sufficient to reject the null hypothesis of a 30% response rate under the minimax design. Median PFS was 7.0 mo (90% CI 3.5-8.0) and 7.0 mo (90% CI 4.6-9.9) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median OS was 9.1 mo (90% CI 6.0-16.0) and 25.5 mo (90% CI 10.8-60.6) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median DOR was 13.8 mo (90% CI 4.1-19.0) and 5.5 mo (90% CI 2.6-23.7) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median PFS, OS and DOR for HL patients in the other lymphoma cohort were 9.2 mo (90% CI 4.6-25.5), 39.6 mo (90% CI 17.4-NR), and 8.1 mo (90% CI 5.1-38.3), respectively. Kaplan-Meier curves are displayed in Figure 1. Grade ≥3 non-hematologic adverse events (AE) related to treatment were uncommon, with no cases of pneumonitis and one grade 3 thromboembolism. Grade ≥3 hematologic AEs were common and reversible. Three Grade 5 AEs occurred (colonic perforation, myocardial infarction and sepsis). Conclusions Combination therapy with TEM and LEN demonstrated encouraging activity in heavily-pretreated and relapsed/refractory lymphomas. Survival in the other lymphoma cohort was primarily driven by favorable activity in relapsed/refractory HL. TEM and LEN may be a suitable option for treatment of HL after BV and ASCT, including as a bridge to allogeneic stem cell transplantation. Further study of PI3K/Akt/mTOR inhibition in combination with lenalidomide is warranted, particularly in relapsed HL. Disclosures Kline: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kite/Gilead: Speakers Bureau. Kimball:Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company. Petrich:Daiichi-Sankyo: Current Employment; AbbVie: Current equity holder in publicly-traded company. Smith:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; Acerta: Research Funding. OffLabel Disclosure: Temsirolimus is FDA-approved for renal cell carcinoma.

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Safety and Efficacy of Ibrutinib in Combination with Rituximab and Lenalidomide in Previously Untreated Subjects with Follicular and Marginal Zone Lymphoma: An Open Label, Phase II Study

Blood ◽

10.1182/blood-2018-99-113721 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 447-447 ◽

Cited By ~ 1

Author(s):

Loretta J. Nastoupil ◽

Hun Ju Lee ◽

F. B. Hagemeister ◽

Jason R. Westin ◽

Felipe Samaniego ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Marginal Zone ◽

Phase Ii Study ◽

Open Label ◽

Advisory Committees ◽

Common Grade ◽

Open Label Phase ◽

Grade 3

Abstract Introduction Given the relapsing nature of indolent non-Hodgkin lymphomas (iNHL), the prolonged natural history suggests many patients will undergo multiple lines of therapy over the course of their disease. Combination approaches with rational selection of synergistic mechanisms of action are desirable to improve outcomes and minimize overlapping toxicity. Rituximab and lenalidomide (R2) has resulted in favorable efficacy and manageable toxicity in phase II and III studies (Fowler et al, Lanc Oncol 2014; Fowler et al, ASCO abstract 2018) in untreated iNHL. Ibrutinib, a BTK inhibitor and active B-cell receptor signaling pathway inhibitor, is an attractive agent to build upon R2 given the therapeutic activity in the microenvironment via enhanced T cell activation and function, reduction in inflammatory cytokines, and diminished interaction with macrophages (Niemann et al, Clin Can Res 2015). We hypothesized that the addition of ibrutinib to R2 (IR2) would result in enhanced efficacy; the concern from the Phase I study was the potential for excess grade 3 rash (Ujjani et al, Blood 2016). In an attempt to reduce the incidence of grade 3 rash observed in the phase 1 study, an alteration in the cycle 1 dose of lenalidomide was done to assess the efficacy and safety of IR2 in untreated follicular (FL) and marginal zone lymphoma (MZL) in an open-label phase II, single center study. Methods In this phase II study, adults with untreated stage II, III, or IV FL (grade 1, 2, or 3a) or MZL, who were in need of therapy, received an initial cycle of lenalidomide 15mg/day (days 1-21 of a 28 day cycle), ibrutinib 560mg/day, and 4 weekly doses of rituximab (375mg/m2). For cycles 2-12, patients received 20mg of lenalidomide on days 1-21, 560mg of ibrutinib daily, and rituximab (375mg/m2) on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) at 2 years. Secondary endpoints include: complete response (CR), partial response (PR), overall response (ORR), duration of response (DOR) and overall survival (OS). Results Forty-eight patients with FL (N=38) and MZL (N=10; nodal MZL N=4; splenic ZML N=3; MALT N=3) were enrolled. Median age was 60 years (range 37-81), 67% were male (N=32), 3 (6%) had stage II disease, 12 (25%) stage III, and the remainder had stage IV disease (69%). With a median follow up of 19 months, the estimated 2 year PFS rate was 76% (95% CI: 60-96%). Among FL patients, the ORR according to Lugano criteria was 97%, with a CR rate of 78%. Among MZL patients, the ORR was 80% with a CR rate of 60%. No deaths have been observed to date. Seven (15%) subjects discontinued therapy due to treatment related adverse events (AEs), 3 due to recurrent grade 3 rash, 2 due to pneumonitis (1 grade 2, 1 grade 3), 1 due to pneumonia (grade 3), and 1 due to ventricular arrhythmia (grade 4). The most common grade ≥3 AEs were rash (46%), neutropenia (15%), and diarrhea (13%). The majority of patients with grade 3 rash were managed with interruption in study drugs and antihistamines with successful re-challenge. The most common grade 2 AEs included fatigue (23%), diarrhea (15%), myalgias (17%), rash and edema (each 10%). One patient experienced atrial fibrillation (grade 2) and 1 had an upper GI bleed (grade 3); both successfully resumed treatment without dose reduction. Correlative and minimal residual disease studies are currently underway and will be presented at the meeting. Conclusions Ibrutinib in combination with rituximab and lenalidomide for untreated FL and MZL was associated with promising efficacy. The toxicity profile was manageable. Modification of lenalidomide dose did not significantly impact the incidence of grade 3 or higher rash. Biomarkers are underway to identify patients most likely to benefit from triplet therapy. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; TG Therappeutics: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Spectrum: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Juno: Honoraria. Westin:Celgen: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Samaniego:ADC Therapeutics: Research Funding. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

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Phase II Study of the Combination of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3155.3155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3155-3155 ◽

Cited By ~ 5

Author(s):

Jatin J. Shah ◽

Lei Feng ◽

Donna Weber ◽

Sheeba K Thomas ◽

Michael Wang ◽

...

Keyword(s):

Respiratory Failure ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Dose Reduction ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Advisory Committees ◽

Grade 3

Abstract Background: The role of maintenance lenalidomide (Len) in the post autologous stem cell transplant (ASCT) setting has been based on a significant benefit in progression-free survival (PFS) and time to progression (TTP) in the CALBG 100104 and IFM 2005-02 trials, and overall survival (OS) benefit in the CALBG100104 trial. To date, the use of a proteasome inhibitor (PI) as maintenance therapy has been limited by the inconvenience of its IV/subcutaneous administration. Ixazomib, an oral PI, may provide an alternative maintenance therapy. Here we report the results of a single arm phase II study combining ixazomib and lenalidomide as post ASCT maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM). Methods: This is a single arm phase II study of the combination of lenalidomide/ixazomib (LI) maintenance therapy for NDMM paients post ASCT. The primary objective was to establish safety and efficacy of Len as maintenance therapy. The secondary objectives were to evaluate the incidence of secondary primary malignancies (SPMs), overall response rate (sCR/nCR/VGPR/PR), TTP, time to next therapy, and toxicity profile. Eligible patients had undergone ASCT, with melphalan as a preparative regimen, within 12 months of initiation of induction therapy. Patients were required to start maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of ixazomib 4 mg on days 1, 8, 15, and lenalidomide 10 mg daily on days 1-28. Len was increased to 15 mg after 3 months if well tolerated. Based on clinical experience from ongoing phase III studies, the protocol was later amended to reduce the starting dose of ixazomib to 3 mg. Adverse events were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: 65 patients (pts) were enrolled with a median age of 60 (range 39-74); 65% (42/65) were male. 39 pts had ISS stage I disease, 13 had Stage II; and 13 had stage III. Of the 65 pts, 47 remain on therapy and as of June 2015, pts have received a median of 10 cycles (range 1-30). The median PFS has not been reached however, the estimated 2-year PFS was 83%. 18 pts are off study: 7 due to progressive disease (PD), 3 at PI discretion, and 8 due to consent withdrawal. 6/7 pts with PD had high risk disease and received 2, 5, 7, 7, 9, 11, and 24 cycles of study therapy. Among the 7 pts with PD, the median PFS post ASCT was 13 months (6-34 months); 3 pts have died with an OS of 15, 27 and 31 months. Grade 3/4 hematologic adverse events (AEs) included: grade 3 (G3) anemia (2), G3 neutropenia (13), G4 neutropenia (2); and G3/4 thrombocytopenia (7). Grade 3/4 drug-related non-hematologic AEs included: G3 elevated aspartate aminotransferase (3); G3 back pain (2); G3 constipation (4); G3 creatinine increase (2); G3 nausea and diarrhea (2); G3 fatigue (4). 10 pts had G1/2 rash and 8 pts had G3 rash. 42 patients had G1/2 peripheral neuropathy (PN); 1 pt had G3 PN; and 2 pts had G3/4 respiratory failure. There were no second primary malignancies. Infectious complications included G3 urinary tract infections (2); G3/4 upper respiratory tract infections (4); G3 sinusitis (1); G3 pneumonia (7); G3 influenza (2); G4 infection (1). Other AEs included G4 renal failure due to progressive disease (1); G3 non cardiac chest pain (1); G3 emesis (1); G4 respiratory failure and G4 sepsis/respiratory failure (2). 10 patients required a dose reduction of ixazomib for PN (5); neutropenia (3); thrombocytopenia (1), and hearing loss (1). 1 pt discontinued ixazomib and remained on Len due to persistent PN. 11 pts had a dose reduction in Len to 10 mg for 21 of a 28 day cycle due to cytopenias (neutropenia or thrombocytopenia); 5 pts had a dose reduction to 5 mg due to rash/pruritus in 4 pts and 1 pt due to neutropenia. Conclusions: Long term administration of combination of lenalidomide/ixazomib as maintenance therapy post ASCT is feasible with pts ongoing at 30+ cycles. The incidence of adverse events was similar to historical experience with lenalidomide alone; hematologic adverse events were manageable with dose reductions. The incidence of PN was limited to grade 1/2 events and 1 grade 3 event with no other unexpected toxicity. The combination is safe, feasible, well tolerated and experience to date supports further exploration in phase III studies. Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Celgene: Research Funding; Novartis: Research Funding; Idera Pharmaceuticals: Research Funding. Wang:Celgene: Research Funding. Orlowski:Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Ixazomib, Thalidomide and Dexamethasone (IxaThalDex) in Relapsed/Refractory Multiple Myeloma (RRMM): An Interim Analysis of a Phase II Trial

Blood ◽

10.1182/blood.v128.22.3335.3335 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3335-3335 ◽

Cited By ~ 3

Author(s):

Heinz Ludwig ◽

Eberhard Gunsilius ◽

Michael Fridrik ◽

Richard Greil ◽

Andreas Petzer ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Clinical Benefit ◽

Research Funding ◽

Phase Iii ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Clinical Benefit Rate ◽

Grade 3

Abstract Introduction Ixazomib, a second generation proteasome inhibitor provides the advantage of combining oral administration with pronounced activity and a favorable toxicity profile. Phase II studies employing ixazomib-dexamethasone established a once weekly dosing regimen and showed substantial activity in RRMM yielding response rates of up to 58% when combined with lenalidomide-dexamethasone (Ld). A recent phase III trial proved the superiority of the triple combination ixazomib-Ld compared to Ld in patients with RRMM. Here, we evaluate the activity and tolerability of the all oral combination ixazomib-thalidomide-dexamethasone in patients with RRMM. Methods Patients with RRMM with at least 1 prior line of therapy were enrolled. Patients had to have measurable disease, ECOG performance status ≤2, ANC ≥1000/µL, platelet count ≥50000µL, GFR ≥15mL/min. The treatment regimen consisted of ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg daily) and dexamethasone (40mg once weekly). Patients aged ≥75 years received a reduced dose of both thalidomide (50mg daily) and of dexamethasone (20mg, once weekly). A total of 8 cycles was planned, followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in patients aged ≥75 years) for one year. Progression-free survival curves were estimated using the Kaplan-Meier method. The EORTC Q30 instrument was used for evaluation of changes in overall health and global QoL during therapy. Results Thirty-nine of 77 planned patients have been enrolled so far. Intent-to treat group (ITT), age, median: 67, range 42 to 85; ISS stage I: 13, II 14, III: 10, not known: 2, number of prior treatment lines, median: 2, (range: 1-5). Seven patients have discontinued treatment before completion of 2 cycles (early death: 3, progressive disease: 2, protocol violation: 1, patients request: 1). At present, 8 patients are too early (not yet completed 2 cycles) for evaluation per protocol (PP). Full documentation of at least 2 cycles of therapy is available for 24 patients. In this group, the median number of cycles administered is 4, and the median follow up is 4.5 months. Responses to IxaThalDex were seen in 14 patients (35.8% and 58.3% of ITT and PP group, respectively), 3 achieved ≥ VGPR (8%/ITT, 13%/PP), 10 PR (26%/ITT, 42%/PP) and 2 MR (5%/ITT, 8%/PP), yielding a clinical benefit rate of 38.5%/ITT, 62.5%/PP. FISH data are available in 17 of the 24 PP patients. Responses (≥PR) were seen in 5/6 patients with t (4;14) and/or t (14;16) and/or del17p and in 5/8 with standard risk cytogenetics. Median PFS at the time of reporting is 5.7 and 6.4 months in the ITT and PP group, respectively. An improvement in overall health and of general QoL was noted in 6 and 7 of the 14 responders, respectively. Toxicity data are presented for the PP group. Neutropenia was the most common hematologic toxicity noted in 20 (83.3%) patients; all of them had grade 1/2, and none higher grade neutropenia. Leukopenia was seen in 15 (62.5%) patients, (14 grade 1/2 and one grade 3). Sixteen (66.7%) had grade 1/2 anemia. Grade 1/2 thrombocytopenia was noted in 8 (33.3%) patients. The most frequent non hematological toxicity was infection seen in 7 (29%) patients. Six were grade 3; pneumonia was seen in 4, sepsis in 1 and other infections in 2 patients. Polyneuropathy at baseline was seen in 7 patients (grade 1 in 2, and grade 2 without pain in 6 patients). During the study the incidence of new PNP was relatively rare (3 new and one worsening PNP) with presently 9 (37.5%) patients with grade 1-2 and only 1 (4.2%) with grade 3. Other notable toxicities were acute renal failure (grade 3) in 2 (8.3%), fatigue in 8 (4 grade 1, 4 grade 2), constipation and diarrhea (all grade 1) each in 4, and edema and vision impairment (all grade 1), each in 3 patients. Conclusion The entirely oral IxaThalDex regimen resulted in an ORR of 58.3 in the PP and of 35.8% in the ITT population (with 8 patients being too early for PP evaluation and not having reached 2 cycles as yet). The clinical benefit rate was 62.5% and 38.5% for the PP and ITT group, respectively. Median PFS was 6.4 months in the PP group. General health and QoL improved in 42.8% and 50% of the responders. The ixazomib-thalidomide-dexamethasone regimen was well tolerated and with relatively few side effects being noted. As exposure to therapy is still short at this point of time it is anticipated that efficacy data will further improve with longer therapy and follow up. Updated results will be presented at the meeting. Disclosures Ludwig: Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: 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. Greil:Celgene: Research Funding; Takeda: Honoraria, Research Funding; Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Petzer:Roche: Honoraria. Knop:Takeda: Consultancy. Poenisch:Mundipharma: Research Funding.

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Treatment of Relapsed/Refractory Waldenström Macroglobulinemia Patients: Final Clinical and Molecular Results of the Phase II Brb (Bendamustine, Rituximab and Bortezomib) Trial of the Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood-2021-148424 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 48-48

Author(s):

Giulia Benevolo ◽

Simone Ferrero ◽

Nicoletta Villivà ◽

Anna Castiglione ◽

Federico Monaco ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Residual Disease ◽

Phase Ii Study ◽

Hematological Toxicity ◽

Advisory Committees ◽

Mutational Screening ◽

Grade 3 ◽

Myd88 L265p

Abstract Introduction Symptomatic patients with relapsed/refractory Waldenström Macroglobulinemia (RR-WM) treated with standard rituximab plus chemotherapy as second-line salvage therapy, generally show a 18-months progression free survival (PFS) of about 50%. On behalf of the Fondazione Italiana Linfomi, a multicenter phase II study was designed to assess whether a combination of bendamustine, rituximab and bortezomib (BRB) (EudraCT Number:2013-005129-22) could be considered a promising new treatment in this setting. Patients and Methods This single-arm phase II study tested the hypothesis that 18-months PFS is at least 65%. The required sample size was 38 patients (alpha=0.10; beta=0.25; minimum follow up=24 months). Treatment plan provided: rituximab 375 mg/m2 intravenously on day 1 followed by intravenously bendamustine 90 mg/m2 on day 1 and 2 and subcutaneous bortezomib 1.3 mg/m2 on day 1, 8, 15 and 22, every 28 days for 6 months (6 cycles). MYD88 L265P and CXCR4 S338X mutations were tested by ddPCR in bone marrow (BM), plasma and peripheral blood (PB) samples, both at baseline (as mutational screening) and at the end of treatment (for minimal residual disease purposes, MRD). Results Median age was 66.8 years (8 patients were older than 75 years). Many patients had features of advanced disease such as cytopenia (anemia 71%, thrombocytopenia 20%), systemic symptoms (40%) and symptomatic splenomegaly (24%). Sixteen (42%) patients had at least one comorbidity, mostly cardiovascular disease (21%) or metabolic disorders (16%), such as diabetes mellitus. Thirty patients completed six cycles, 7 patients stopped therapy for toxicity and 1 for progressive disease. Overall response rate at the end of therapy was 82%, including 4 (11%) complete, 15 (39%) very good partial, 12 (32%) partial responses according to IWM response criteria. At 18, 24, and 30 months PFS was 84% (95% CI 68-92%), 81% (95%CI 65-91) and 79% (95%CI 62-89) respectively. At 18 months OS was 92% (95%CI 77-97%) and no deaths were observed between 18 and 30 months. Nineteen patients (50%) experienced grade ≥3 hematological toxicity, mainly thrombocytopenia, 12 patients (31.5%) developed grade ≥3 extra-hematological toxicity of which only one cutaneous toxicity related to bendamustine. Bortezomib-related nervous system disorders were observed in 6 patients (5 of grade 1-2 and 1 of grade 3), with no discontinuations. Mutational data were available for 21 patients: all patients scored MYD88 L265P in BM, 18/19 (95%) in plasma and only 18/21 (86%) in PB, prospectively confirming the risk of false negative results when only PB of rituximab pre-treated patients is analyzed. CXCR4 S338X was detected only in one patient at baseline. MRD negativization rates after treatment differed across investigated tissues: in detail, 5/17 (29%) in BM, 6/14 (43%) in plasma and 12/16 (75%) in PB. Overall, a good concordance was observed between BM and plasma (Cohen's kappa= 0.714), suggesting the possibility of avoiding BM aspiration for mutational screening and MRD analysis. Conclusion The final results of FIL BRB phase II trial showed that BRB regimen, used as second-line therapy, is an effective and well-tolerated salvage treatment for RR-WM patients. The deep anti-tumor activity of the novel combination is highlighted by an absolute increase of PFS rate in comparison to historical controls (30-months PFS of 79%), as well as by high rates of clinical response, with an ORR (CR+VGPR+PR) of 82% (95%CI 66-92). Moreover, MRD monitoring showed promising efficacy of BRB regimen in clearing the residual disease. Disclosures Benevolo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau. Ferrero: Morphosys: Research Funding; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Gaidano: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Varettoni: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Vitolo: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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