European Post-Approval Safety Study (PASS) of Relapsed/Refractory Multiple Myeloma (RRMM): Safety, Including SPM, in a Large Cohort of Patients Treated with Lenalidomide, Thalidomide, and Bortezomib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3331-3331
Author(s):  
Barbara Gamberi ◽  
Miguel Hernandez ◽  
Christian Berthou ◽  
Eleni Tholouli ◽  
Elena Zamagni ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Treatment Discontinuation ◽  
Second Primary ◽  
Advisory Committees ◽  
Grade 3 ◽  
Noninterventional Study ◽  
Dose Reductions

Abstract Background: EU PASS is an observational, noninterventional study designed to investigate the safety of lenalidomide (LEN) and other agents in the treatment of RRMM in a real-world setting. Aims:To assess the incidence of adverse events (AEs) of special interest, including neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN), and second primary malignancies (SPMs) in RRMM patients (pts) treated with LEN and other antimyeloma therapies according to current clinical practice. Methods: Pts with RRMM who were commencing LEN treatment were enrolled at the investigator's discretion into a LEN cohort (LEN + dexamethasone, the approved combination for the treatment of RRMM); pts who received ≥ 1 prior therapy and were commencing a non-LEN-based therapy were enrolled into a background cohort (all other treatments, including novel agents). Thromboprophylaxis was per local standard practice. AEs were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (version 3). SPMs were defined using Medical Dictionary for Regulatory Activities (MedDRA) terms under the category Neoplasms SOC. Following protocol amendment in 2011, assessments for SPMs were to be conducted up to 36 mos after treatment discontinuation. Results: As of June 2016, 3632 pts across 269 institutions in 17 European countries were included in the safety population. Of those, 59.2% received LEN (n = 2151), 32.7% received bortezomib (BORT; n = 1188), 3.8% received thalidomide (THAL; n = 137), and 4.3% received other therapies (n = 156). The majority of pts had discontinued from treatment (97.9%; n = 3556); of the 2.1% (n = 76) ongoing pts, 66 are treated with LEN, 6 with BORT, 0 with THAL, and 4 with other substances. Baseline characteristics were similar across the cohorts. Median age was 70 yrs (range, 25-95 yrs) and 54.0% were male. Of 2985 pts with available ECOG data, 2865 (96.0%) had good performance status (ECOG score 0-2), and the remaining 4.0% had an ECOG score of 3/4. The median number of prior therapies was 1 (range, 1-6) but was higher in the LEN cohort (2; range, 1-6) than in the BORT (1; range, 1-6) and THAL (1; range, 1-5) cohorts; the proportion of pts with only 1 prior treatment was also lower in the LEN cohort (44.3%), whereas BORT was 70.8% and THAL 56.2%. Overall, 50.7% of pts (n = 1842) had grade 3/4 AEs. Grade 3/4 neutropenia occurred in 17.1%, 3.5%, and 4.4% of pts in the LEN, BORT, and THAL cohorts, respectively, and grade 3/4 thrombocytopenia in 9.2%, 7.3%, and 3.6%. The incidence rate of SPM was 3.63 per 100 pt-yrs, with 3.18 per 100 pt-yrs in the LEN cohort, 5.23 per 100 pt-yrs in the BORT cohort, 2.73 per 100 pt-yrs in THAL, and 6.48 per 100 pt-yrs in others. AEs of interest of all grades are listed in Table 1. The median duration on study treatment was 6.6 mos (range, 0.1-81.6 mos) for LEN, 4.1 mos (range, 0-63.6 mos) for BORT, and 4.6 mos (range, 0.2-36.9 mos) for THAL. Treatment discontinuation rate due to AEs was similar in each cohort (22.1% in the LEN, 20.0% in the BORT, and 21.2% in the THAL cohorts). In the LEN cohort, dose reductions occurred in 38.1% of pts, with a median time to first dose reduction due to AEs of 12.4 weeks. Treatment-emergent adverse events leading to dose reductions were similar across cohorts, with 23.7% in the LEN cohort, 21.4% in the BORT cohort, and 17.5% in the THAL cohort. Conclusions: Results of this noninterventional study in RRMM show that AEs were similar across cohorts except for higher rates of neutropenia and lower rates of PN with LEN compared with THAL or BORT. Higher rates of neutropenia did not translate into increased febrile neutropenia. Infections, independent from neutrophil counts, occurred in all cohorts, but few pts developed serious infections such as pneumonia. VTEs as well as myocardial infarctions were low throughout all cohorts. The occurrence of SPMs was generally low and comparable between cohorts. LEN was generally well tolerated. Disclosures Tholouli: Johnson and Johnson: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria; MSD: Speakers Bureau; Giles: Speakers Bureau. Hájek:Janssen: Honoraria; Takeda: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Frost Andersen:Celgene: Research Funding. Waage:Amgen: Speakers Bureau; Celgene: Consultancy, Honoraria; Novartis, Amgen, Celgene: Membership on an entity's Board of Directors or advisory committees. Crotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Di Micco:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership.

Post-Approval Safety Study (PASS) of Lenalidomide Compared with Other Treatments in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1867-1867
Author(s):  
Michele Cavo ◽  
Luciano Masini ◽  
Igor W. Blau ◽  
Miguel T. Hernandez ◽  
Renato Zambello ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Second Primary ◽  
Safety Study ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Prior Therapy ◽  
Non Invasive ◽  
Grade 3

Abstract Abstract 1867 Background: In recent years, there have been major advances in the treatment of multiple myeloma (MM) as patients now have treatment options that greatly improve clinical outcomes. Many publications have described the safety of anti-myeloma drugs in the clinical trial setting. However, very few have addressed the issue of tolerability of these agents in a real-world clinical setting. Lenalidomide is an effective treatment option for MM and is currently approved by the EMA and US FDA for the treatment of MM patients who have received at least 1 prior therapy. Here we analyze the tolerability of 3 common novel agent-based anti-myeloma therapies in daily clinical practice. Methods: This observational post-authorization safety study was designed to characterize the safety profile of lenalidomide and to compare the incidence of adverse events (AE) with those occurring in patients receiving other anti-myeloma treatments. Patients entering the study had previously received at least 1 prior therapy and were commencing a new treatment for their relapsed/refractory MM (RRMM). Patients were enrolled into the Lenalidomide Cohort (lenalidomide plus dexamethasone) or the Background Cohort (all other treatments) based on investigator's discretion. Thromboprophylaxis was allowed, but not required. Results: As of July 2011, 2201 RRMM patients in 265 institutions in 17 European countries were enrolled. 1500 received lenalidomide, 538 bortezomib, 90 thalidomide, and 73 received other therapies or had missing data. 75 patients from the Background Cohort crossed over to receive lenalidomide. Median follow-up was 20.7 weeks (range, 0.1–125.7 weeks). Overall, the median age was 69 years (range, 29–92) and 55% were male. Most patients had a good performance status (ECOG 0–1) but 18% had an ECOG score of 2–4. The median number of previous treatment lines was 2 (1–6), 51.5% had 2 previous lines and 24% had 3 or more. Baseline characteristics across treatment groups were similar. Patients receiving lenalidomide had a median treatment duration of 4.4 months; patients receiving bortezomib and thalidomide had 3.4 months and 3.7 months, respectively. NCI grade 3/4, serious and life threatening AEs are presented in the table. Venous thromboembolism was experienced in 5% of lenalidomide-treated patients (3% had grade 3/4); 0.7% of bortezomib-treated patients (0.6% had grade 3/4); 1 (1%) thalidomide-treated patient had grade 3/4. Peripheral neuropathy was observed in 10% of lenalidomide-treated patients (1% had grade 3/4); 28% of bortezomib-treated patients (4% had grade 3/4); and 21% of thalidomide-treated patients (2% had grade 3/4). Ten (0.5%) invasive second primary malignancies (SPM) were reported across all treatment groups; 5/1500 (0.3%) patients treated with lenalidomide, 4/538 (0.7%) with bortezomib, and 1/90 (1%) with thalidomide. Three cases of second primary hematologic malignancies (lenalidomide, 2; bortezomib, 1; thalidomide, none) and 7 cases of second primary solid tumors (lenalidomide, 3; bortezomib, 3; thalidomide, 1) were observed. Additionally in the lenalidomide group, 1 patient each developed a non-invasive basal cell carcinoma and a non-invasive fibrous histiocytoma. All of these patients were heavily pre-treated and most had received autologous stem cell transplantation to support high-dose melphalan during the course of their disease. 51% of patients in the lenalidomide group discontinued therapy while 65% and 71% discontinued bortezomib and thalidomide treatments, respectively. Primary reasons for discontinuation were adverse events (lenalidomide, 13%; bortezomib, 14%; thalidomide, 18%) and disease progression (lenalidomide, 15%; bortezomib, 13%; thalidomide, 17%). Overall, 1% of patients died due to an adverse event suspected to be related to drug (lenalidomide, 1%; bortezomib, 0%; thalidomide, 1%). Conclusion: Consistent with previous reports, lenalidomide is generally well tolerated. With the exception of peripheral neuropathy, adverse events in this group of patients treated in daily clinical practice appeared similar across treatment groups. Disclosures: Cavo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Symeonidis:Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Genzyme: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding. Bird:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Genzyme: Membership on an entity's Board of Directors or advisory committees. Bacon:Celgene Corporation: Employment. Rosettani:Celgene Corporation: Employment. Kueenburg:Celgene Corporation: Employment. Minton:Celgene Corporation: Employment, Equity Ownership.

scholarly journals 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 ◽  
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.

ENESTxtnd: Impact Of Nilotinib Dose Re-Escalation In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4009-4009
Author(s):  
Jeff H. Lipton ◽  
Luis Meillon ◽  
Vernon Louw ◽  
Carolina Pavlovsky ◽  
Lee-Yung Shih ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Dose Intensity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Study Dose ◽  
Dose Reductions

Abstract Background Frontline nilotinib 300 mg twice daily (BID) provides superior efficacy vs imatinib in pts with CML-CP, with good tolerability. Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd) is evaluating the kinetics of molecular response to frontline nilotinib 300 mg BID in pts with newly diagnosed CML-CP, as assessed in national and local laboratories, and is also the first study to evaluate the safety and efficacy of nilotinib dose optimization (including dose re-escalation in pts who require dose reductions due to adverse events [AEs] and dose increase in pts with less than optimal response). Here, we present results of a preplanned, interim analysis (IA) based on the first 20% of pts who completed 12 mo of treatment or discontinued early. Methods ENESTxtnd (NCT01254188) is an open-label, multicenter, phase 3b clinical trial of nilotinib 300 mg BID in adults with CML-CP newly diagnosed within 6 mo of study entry. The primary endpoint is rate of MMR by 12 mo. Molecular responses were monitored by real-time quantitative polymerase chain reaction (RQ-PCR) at local laboratories at baseline, at 1, 2, and 3 mo, and every 3 mo thereafter. Bone marrow cytogenetic analyses were performed locally at baseline, 6 mo, and end of study. Dose reductions were allowed for grade ≥ 2 nonhematologic AEs and grade 3/4 hematologic AEs. Pts with dose reductions could attempt to re-escalate (successful re-escalation defined as ≥ 4 wk on nilotinib 300 mg BID with no dose adjustments for any AE) and remain on study. Dose increase to nilotinib 400 mg BID was allowed in cases of BCR-ABL > 10% on the International Scale (BCR-ABLIS) at 3 mo or later, no major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo, loss of MMR, or treatment failure. Results This IA includes 85 pts treated in 12 countries (Argentina, Australia, Brazil, Canada, Israel, Lebanon, Mexico, Malaysia, Saudi Arabia, Thailand, Taiwan, and South Africa). Median age was 49 y (range, 19-85 y), and 58% of pts were male. Median time since diagnosis was 35 days (range, 2-157 days). Prior to study entry, 64 pts (75%) received hydroxyurea, and 3 pts (4%) received imatinib (all for ≤ 2 wk). At the data cutoff, 68 pts (80%) had treatment ongoing, and the remaining 17 had discontinued due to AEs/laboratory abnormalities (n = 8; nonhematologic AEs [n = 5], biochemical abnormalities [n = 2], and hematologic abnormalities [n = 1]), loss to follow-up (n = 2), administrative problems (n = 2), intolerance to the protocol-proposed dose (n = 2), suboptimal response (n = 1), withdrawal of consent (n = 1), or protocol deviation (n = 1). Median time on treatment was 13.8 mo (range, 1 day-18 mo). Median actual dose intensity of nilotinib was 597 mg/day (range, 165-756 mg/day), and 85% of pts had an actual dose intensity of > 400 mg/day to ≤ 600 mg/day. Of 30 pts with dose reductions due to AEs, 19 (63%) successfully re-escalated to nilotinib 300 mg BID. Nine pts (11%) dose escalated to nilotinib 400 mg BID due to lack of efficacy. The primary endpoint of MMR by 12 mo was achieved by 57 pts (67%; 99.89% CI, 49%-82%). Complete cytogenetic response by 6 mo was achieved by 48 pts (56%). Median BCR-ABLIS decreased over time, with a median value of 0.05% (range, 0.00%-41.36%) at 12 mo (Figure). Most pts (91%) achieved early molecular response (BCR-ABLIS ≤ 10% at 3 mo). Of the 8 pts (9%) with BCR-ABLIS > 10% at 3 mo (4 of whom were then dose escalated), 3 achieved MMR by 12 mo (1 of whom had been dose escalated). By the data cutoff, no pt had progressed to accelerated phase/blast crisis (AP/BC), and there had been no deaths on study. Nilotinib was well tolerated, with a safety profile similar to that seen in other frontline studies. Drug-related nonhematologic AEs (≥ 10% of pts) were rash (31%), constipation (13%), and headache (13%). Newly occurring or worsening grade 3/4 hematologic or biochemical abnormalities (≥ 10% of pts) were neutropenia (17%), thrombocytopenia (17%), increased lipase (13%), and increased bilirubin (12%). Conclusions These results demonstrate that dose-optimized nilotinib affords high rates of molecular response in pts with newly diagnosed CML-CP. Further, they support the feasibility of nilotinib dose re-escalation in pts who require temporary dose reductions due to AEs, with 63% of dose-reduced pts able to successfully re-escalate to nilotinib 300 mg BID and safely continue therapy. Disclosures: Lipton: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Meillon:Bayer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Louw:Novartis: Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Congress attendance support, Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Pavlovsky:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Jin:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Woodman:Novartis: Employment, Equity Ownership. Hughes:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

scholarly journals A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 348-348 ◽  
Author(s):  
Nathan H Fowler ◽  
Loretta J. Nastoupil ◽  
Collin Chin ◽  
Paolo Strati ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Advisory Board ◽  
Indolent Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

scholarly journals A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3411-3411
Author(s):  
Maro Ohanian ◽  
Martha L. Arellano ◽  
Moshe Y. Levy ◽  
Kristen O'Dwyer ◽  
Hani Babiker ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Grade 3 ◽  
Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

scholarly journals Efficacy and Safety of Once Weekly Bortezomib In Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3029-3029 ◽  
Author(s):  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Davide Rossi ◽  
Alessandra Romano ◽  
Mariella Genuardi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Severe Thrombocytopenia ◽  
Weekly Schedule ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3 ◽  
The Impact ◽  
Weekly Group ◽  
Dose Reductions

Abstract Abstract 3029 Background. In a recent phase 3 trial, bortezomib–melphalan – prednisone–thalidomide followed by maintenance treatment with bortezomib–thalidomide (VMPT-VT) demonstrated superior efficacy compared with VMP. Peripheral neuropathy (PN) was the most important dose limiting toxicity. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions. This post-hoc analysis assessed the impact of bortezomib dose-modification schedule on clinical outcomes and safety. Methods. Patients (N=511) older than 65 years were randomized to receive nine 6-week cycles of VMPT-VT (N=254; induction:V 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; M 9 mg/m2 d 1–4, P 60 mg/m2, d 1–4, T 50 mg d 1–42; maintenance: V 1.3 mg/m2 every 14 days and T 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). Patients receiving VMPT-VT and VMP were pooled together and stratified according to the once-weekly or twice-weekly infusion modality; analyses were also conducted for patients receiving VMP only, to eliminate the influence of thalidomide and of maintenance on efficacy and safety. Results. Patients were evaluated in intention-to-treat: 372 patients received once-weekly and 139 twice-weekly bortezomib infusion. Patient characteristics were similar in the two groups, median age was 71 years. The efficacy data did not appear to be affected by the bortezomib schedule. Overall response rates were 85% with once weekly and 86% with twice- weekly schedule (P = .78), including CR rates of 30% and 35% (P = .27).Three-year PFS was 50% in the once-weekly and 47% in the twice-weekly group (P = 1.00), and 3-year OS was 88% and 89%, respectively (P = .54). Similar outcome was seen in the analyses restricted to VMP patients: CR rates were 23% with once-weekly and 27% with twice-weekly schedule (P = .54), 3-years PFS was 46% in once-weekly and 39% (P = .86) in twice-weekly group and 3-years OS was 87% and 89% (P = .47), respectively. The incidence of grade 3/4 hematologic toxicity was similar in the two groups (44% vs 45%, P = .83), but severe thrombocytopenia was slightly less common in the once-weekly patients (19% vs 26%, P = .08).The incidence of non-hematologic grade 3/4 adverse events was significantly reduced in the once-weekly: 35% vs 51% (P = .003). Grade 3/4 gastrointestinal events (6% vs 11%, P = .08), severe systemic events (4% vs 7%, P = .09) and grade 3/4 dermatologic events (2% vs 7%, P = .006) were less frequent in patients receiving once-weekly bortezomib. There was a significantly reduced overall incidence of grade 3/4 PN (8% vs 28%, P < .001) in the once-weekly group. The median time to onset of grade 3/4 sensory PN was 4.3 months in the once-weekly group and 3.2 months in the twice-weekly group (P = .10). The cumulative incidence of sensory PN appeared to plateau after 12 months of therapy in both groups. Rates of discontinuations (5% versus 15%) and dose reductions (15% versus 41%) due to PN were also significantly lower in the once-weekly group (P < .001). These results were reflected in analysis restricted to VMP patients, in which the incidence of grade 3/4 PN (7% vs 29%, P < .001), the discontinuation rate (4% vs 16%, P = 0.002), and the dose reductions rate (15% vs 41% P < 0.001) were significantly lower in once-weekly group. Despite the cumulative planned dose being lower in the once-weekly group (46.8 vs 67.6 mg/m2), the delivered cumulative dose of bortezomib was similar in the two groups (39.4 mg/m2 vs 40.1 mg/m2). No association of PN with age or other baseline characteristics was outlined. The only significant factor influencing the incidence of PN was the reduction of bortezomib infusion from twice- to once-weekly (p<0.001). Low dose thalidomide did not affect grade 3/4 PN rate (p=0.16). Conclusion. These results demonstrate that 1. both once-weekly and twice-weekly schedules in combination with MP ± thalidomide are highly effective in patients ≥ 65 years; 2. once-weekly schedule significantly reduced the incidence of PN and decreased the rate of discontinuation, resulting in similar cumulative bortezomib doses in the two groups; 3. the improvement in the safety profile was not associated with any reduction in the efficacy. Disclosures: Bringhen: Celgene: Honoraria; Janssen Cilag: Honoraria. Leoni: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. Elice:Celgene: Honoraria; Novatis: 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. 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.

scholarly journals Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5392-5392 ◽  
Author(s):  
Georg Hess ◽  
Andreas Hüttmann ◽  
Reinhard Marks ◽  
Mathias Witzens-Harig ◽  
Martin H. Dreyling ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody. Superiority of Obinutuzumab could be demonstrated in xenograft models of mantle cell lymphoma and DLBCL. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclins from higher treatment lines. With Pixantrone, a drug structurally related to anthracyclines and especially anthracenediones, a re-exposition against this drug class has been shown to be feasible. In 70 heavily pre-treated patients, a best ORR of 40% (20% CR/CRu) was observed (Pettengell et al). Experiences from further antibody drug combinations lead to the assumption that the effects of Pixantrone will be augmented by a monoclonal antibody without increasing toxicity. We thus initiated a trial combining both agents for the first time. The trial has opened in Q4/2015 and recruitment is ongoing. Overall, a total of up 70 patients will be enrolled for a number of 64 evaluable patients. Primary endpoint will be the objective overall response rate, with secondary endpoints being safety, PFS and OS. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven DLBCL, FL grade IIIb or transformed indolent lymphoma, CD20 positive disease, no curative option available, relapsed disease, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. There was no upper limit or prior treatment lines. Treatment consisted of Pixantrone 50mg/m² day 1, 8 and 15 of each cycle, Obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. A total of 6 cycles was planned with interim staging after 3 cycles. Results: 24 patients (pts) have been included until now. Concerning clinical characteristics, all were caucasian, 12 were female and the other 12 male and median age was 75 years. Most of the patients suffered from DLBCL (18 pts, 82%). Median number of prior therapies was 2 (1 to 6). Until now 55 evaluable cycles of chemotherapy (median 2 cycles (0 to 6)) have been performed. At this time, the treatment seems to be well tolerated, with no unforeseen side effects. Observed toxicity was predominantly hematologic. The following hematologic adverse events of grade 3/4 were noted: leukopenia (4 pts, 17%), neutropenia (6 pts, 25%), granulocytopenia (1 pts, 4%), as well as thrombocytopenia (2 pts). Non-hematologic grade 3/4 adverse events were observed in at least two patients: hypertension (2 pts) and pelvic pain (2 pts). Response: currently, best responses were 4 PR, 1 SD, and 8 PD in 13 patients evaluable so far. Four patients died, all after progression of lymphoma. Summary: the combination of Obinutuzumab and Pixantrone seems to be feasible and safe with early signs of efficacy. Updated results of this trial in progress with a focus on safety will be presented. Disclosures Hess: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria. Marks:Pfizer: Honoraria. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Viardot:Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 536-536 ◽  
Author(s):  
Antonio Palumbo ◽  
Valeria Magarotto ◽  
Sara Bringhen ◽  
Massimo Offidani ◽  
Giuseppe Pietrantuono ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference ◽  
Grade 3 ◽  
To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 25-25 ◽  
Author(s):  
Brian Durie ◽  
Antje Hoering ◽  
S. Vincent Rajkumar ◽  
Muneer H. Abidi ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Rank Test ◽  
P Value ◽  
Advisory Committees ◽  
Significance Level ◽  
Grade 3

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski: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; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: Travel Stipend.

scholarly journals Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1678-1678 ◽  
Author(s):  
Georg Hess ◽  
Andreas Hüttmann ◽  
Julia Meissner ◽  
Reinhard Marks ◽  
Martin Dreyling ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Phase Iii ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Grade 3 ◽  
One Year

Abstract Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefit in patients with untreated DLBCL, although a subset analysis showed a potential benefit in a subset GCB DLBCL of patients, its value in relapsed disease is not yet finally determined. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclines from relapse treatments. With pixantrone, a drug related to anthracyclines, a re-exposition against this drug class has been shown to be feasible, a best EOT-ORR of 37% (20% CR/CRu) was observed in a phase III trial. We thus initiated a trial combining both agents for the first time. The trial has opened in Q3/2015 and recruitment of 70 patients is completed as of 7/2018. Primary endpoint is the ORR, secondary endpoints being safety, PFS and OS. We report about available data after enrollment of the last patient. Methods: this is a multicenter, national, prospective trial. Main inclusion criteria: histologically proven DLBCL, FL grade IIIb or transformed iNHL (20% Quorum), no curative option available, relapsed and measurable disease, ECOG < 3, sufficient BM reserve, no severe concomitant diseases and given informed consent. There was no upper limit of prior treatment lines. Treatment consisted of up to 6 cycles of pixantrone 50mg/m² day 1, 8 and 15 of each cycle, obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. Interim staging was scheduled after 3 cycles. Results: Basic data are available of 67 patients, all were caucasian, 37 were female the other 30 male and median age was 75 years. Most of the patients suffered from DLBCL (49 pts, 68%), 68% had advanced stage at diagnosis and the median secondary IPI was 3. Data collection is ongoing, until now data of 32 patients are fully available and updated results will be presented. Median number of prior therapies was 2 (1 to 6). Treatment seemed to be well tolerated, median number of cycles applied was 3, pre-mature stop of treatment was primarily based on progression. Response evaluation: at this time 13/32 (40.6%) evaluable patients responded with 5 patients achieving CR/CRu (15.6%) and 8 a PR. One year after initiation of treatment 54% of patients remained alive. Median follow up is 8.2 months. Median PFS and OS is 82 day and not reached, 1 year PFS and OS are 37% and 54%, respectively, no patient experienced relapse if the patient remained free from relapse at one year. Observed toxicity was predominantly hematologic. The following hematologic grade 3/4 adverse events were observed: leukopenia (9.4%) neutropenia (75%), thrombocytopenia (12.5%). The febrile neutropenia rate was 6.3%. Non-hematologic grade 3/4 adverse events were very rare, no single side effect was observed with a frequency of 5% or more. Summary: the combination of Obinutuzumab and Pixantrone is feasible and safe. Early response rates are interesting. Importantly, although some patients experience progress early, a promising proportion shows long lasting remissions. Molecular analyses are ongoing, as well as a detailed analysis on the impact of factors such as of number of prior treatments, status at inclusion. Figure. Figure. Disclosures Hess: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Marks:BMS: Honoraria; Merck: Honoraria; Servier: Honoraria. Dreyling:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Keller:Takeda: Consultancy, Research Funding; MSD: Consultancy; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; BMS: Consultancy; Celgene: Research Funding. Ernst:Novartis: Research Funding. Viardot:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria. Lenz:Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria.

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