New Film-Coated Tablet Formulation of Deferasirox Is Well Tolerated in Patients with Thalassemia or MDS: Results of the Randomized, Phase II E.C.L.I.P.S.E. Study

Abstract Background : Patients (pts) compliant with iron chelation therapy (ICT) experience improved organ function and survival (Delea et al. Transfusion 2007;47:1919-29). Once-daily deferasirox (DFX) dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater adherence, pt satisfaction, and quality of life (Cappellini et al. Clin Ther 2007;29:909-17). However, barriers exist to pt adherence to DFX DT, including GI tolerability and palatability, leading to development of a film-coated tablet (FCT) that can be taken with or without a light meal. The FCT contains the same active substance as DT but different excipients (lactose and sodium lauryl sulfate removed). Here we present results of the randomized, open-label, Phase II ECLIPSE study that evaluated safety of DFX FCT and DT formulations in pts with transfusion-dependent thalassemia (TDT) or IPSS-R very low-, low- or intermediate-risk MDS. Methods : ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. Exclusion criteria: creatinine clearance below contraindication limit per local label (<60 mL/min or <40 mL/min), serum creatinine >1.5xULN, alanine aminotransferase >5×ULN, urine protein/urine creatinine ratio (UPCR) >0.5 mg/mg, or impaired GI function. ICT-naïve pts received DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. FCT doses are 30% lower than DT doses due to improved bioavailability, conversion factor 1.43. Dose was adjusted based on SF and investigator's judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time. Primary endpoint was overall safety, measured by frequency and severity of AEs and changes in laboratory values from baseline (BL) over 24 wks. A secondary endpoint was evaluation of selected GI AEs. Results: 173 pts were randomized 1:1 to DT or FCT (Table 1). Mean actual daily DFX dose ± SD over 24 wks was 27.5 ± 7.7 mg/kg/day (DT) and 20.8 ± 5.4 mg/kg/day (FCT). More FCT pts were started on a dose higher than the protocol-specified dose than DT pts (26.4% vs 9.3%). Mean/median duration of exposure was 155/168 days with DT and 163/169 days with FCT. 73 (84.9%; DT) and 77 (88.5%; FCT) pts completed 24 wks. Relative consumed tablet count was high, but lower with DT (85.3%) than FCT (92.9%). Absolute median (range) change in SF at end of treatment was -85.5 (-2146 to 8250) ng/mL (from 2485 [915-8250] ng/mL at BL) with DT, and -350 (-4440 to 3572) ng/mL (from 2983 [939-8250] ng/mL at BL) with FCT, corresponding to a median relative change of -4.1% (DT) and -14.0% (FCT) at end of treatment. AEs regardless of causality were reported in similar proportions of pts for each formulation (Table 2). Fewer severe AEs were observed in FCT pts. The most common AEs with either formulation were consistent with the known DFX safety profile. Notable laboratory evaluation frequencies were similar with both formulations (Table 3). 61.6% (95% CI, 50.5-71.9%) of DT pts and 58.6% (95% CI, 47.6-69.1%) of FCT pts reported ≥1 GI AEs. Similar proportions of pts had diarrhea, nausea, and abdominal pain. Fewer FCT pts had constipation and vomiting than pts receiving DT. Fewer pts had severe GI AEs with FCT than with DT. In pts receiving DT prior to study entry, fewer FCT pts had GI AEs (53.5%, FCT; 60.3%, DT), particularly diarrhea, vomiting and constipation. Increased UPCR was reported in more FCT pts (12.8%, DT; 20.7%, FCT), which could be attributed to more FCT pts receiving a higher than recommended starting dose. Renal event frequency was similar when patients were started on a correct starting dose (30.9%, DT; 33.3%, FCT). 23 pts discontinued, 10 because of AEs (n=6, DT; n=4, FCT). Conclusions: These results in pts with TDT or very low-, low- or int-risk MDS demonstrate comparable FCT and DT safety profiles, consistent with the known DFX profile. In patients with prior DT exposure, fewer GI AEs were seen with FCT than DT. Pts receiving FCT had better compliance, continued longer on treatment and experienced greater SF reduction. DFX FCT may improve pt experience with ICT resulting in greater compliance and reduced frequency and severity of iron overload-related complications. Disclosures Taher: Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Gilead: Consultancy; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Bluebird Bio: Consultancy.

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

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

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

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Symptom Burden Among PV and ET Patients Receiving A Novel Histone Deacetylase Inhibitor: Findings From a Open-Label Phase II Study

Blood ◽

10.1182/blood.v120.21.1736.1736 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1736-1736

Author(s):

Christen Lykkegaard Andersen ◽

Mary Frances McMullin ◽

Robyn M. Emanuel ◽

Amylou C. Dueck ◽

David Bareford ◽

...

Keyword(s):

Histone Deacetylase ◽

Phase Ii ◽

Symptom Severity ◽

Research Funding ◽

Symptom Burden ◽

Open Label ◽

Hematologic Response ◽

Open Label Phase ◽

Maximum Improvement ◽

Sad Mood

Abstract Abstract 1736 Background: Histone deacetylase inhibition (HDACi) has shown a potent inhibitory activity on the autonomous proliferation of hematopoietic cells of PV and ET patients carrying the JAK2V617F mutation (Leukemia. 2008;22(4):740–7). Hematological responses have been recorded during treatment with the HDACi givinostat in patients with PV and myelofibrosis (Blood. 2011; 118:a1748). Additionally, combinational use of givinostat and hydroxyurea (HU) have shown encouraging clinical response in PV (Br J Haematol. 2010;150:446–55). Recent laboratory studies of vorinstat-treated JAK2V617F knock-in mice have observed normalization of peripheral blood counts, markedly reduced splenomegaly and decreased mutant allele burden (Blood 2012; 119, 3779–89). Despite this evidence of hematologic response, to date no studies have evaluated specific changes in symptom burden among PV and ET patients treated with HDACi. METHODS ET and PV patients from the UK were enrolled in a non-randomized, open-label phase II multicenter study of the HDACi vorinostat (Haematologica 2011;96(s2):a1023). Patients were asked to complete the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408), 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) and 30 item EORTC QLQ-C30 (J Natl Cancer Inst 1993; 85(5):365-76) at enrollment, week 12, week 24, and week 36. From weeks 1 through 24, participants were given 400mg of vorinostat daily and were observed from weeks 24 to 36. RESULTS Participant Demographics and Mutational Status: 15 PV and 10 ET patients were enrolled in the study. Median age of participants was 65 and 48% of participants were female. JAK2 mutations were present in 5/10 (50%) of ET and 14/15 (93%) of PV patients. Change in Symptom Severity with Vorinostat: Although most symptom severity changes did not reach statistical significance likely due to the small sample size, individual symptoms of headache (mean 1.6 baseline to 0.5 wk 36, mean maximum improvement 0.5 from baseline), dizziness (mean 1.6 baseline to 0.9 wk 36, mean maximum improvement 0.6 from baseline), sad mood (mean 2.6 baseline to 1.9 wk 36, mean max improvement 0.2 from baseline), and bone pain (mean 2.7 baseline to 0.8 wk 36, mean max improvement 0.7 from baseline) indicated consistent reductions in severity. Change in Symptom Incidence with Vorinostat: Non-sustained reductions in symptom incidence were seen with initiation of therapy for items of dizziness (50% baseline, 43% wk12, 55% wk 24, and 38% wk 36), numbness (65% baseline, 38% wk 12, 36% wk 24, 63% wk 36), sad mood (55% baseline, 47% wk 12, 40% wk 24, 50% wk 36), and itching (65% baseline, 50% wk 12, 40% wk 24, 75% wk 36). Change in MPN-SAF TSS Score with Vorinostat: Overall, MPN-SAF TSS did not vary significantly for the cohort over the course of the study (score change −.4 week 12, −0.5 week 24, −1.2 week 36, Figure 1). However, 9/17 participants who had a TSS of at least 6 at baseline had an overall improvement of at least 6 points (a moderate improvement) on at least one assessment after baseline. Of these, 5 of those 9 participants had an improvement of at least 10 points, which constitutes a large improvement in symptom burden based on a distributional definition of clinical significance using the standard deviation from a previous cohort. CONCLUSION This study represents the first analysis of symptom burden among PV and ET patients receiving vorinostat to date. In addition to previously identified changes in clinical and hematologic response, reductions in symptom burden including QOL and fatigue were observed in patients receiving vorinostat therapy which was most noticeable in patients with high baseline burden. The toxicity profile of vorinostat also suggests that better results might have observed if individualized assessment of clinicohematological responses including an integrated a marker for response into daily clinical practice and tailoring pharmacotherapy based on side effect profile (Leukemia. 2012;26(5):1148–9). Although further investigation among larger cohorts is needed, preliminary data is encouraging for successful therapeutic use of vorinostat in a clinical setting and with possible combinational therapy to reduce symptom burden among PV and ET patients. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

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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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