scholarly journals Comparison of Efficacy and Safety of Biosimilar CT-P10 to Rituximab in Patients with Previously Untreated Low Tumor Burden Follicular Lymphoma (LTBFL): A Randomized Phase III Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1596-1596
Author(s):  
Michinori Ogura ◽  
Juan Manuel Sancho ◽  
Seok-Goo Cho ◽  
Hideyuki Nakazawa ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Adverse Events ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Tumor Burden ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Advisory Committees

Abstract Background: CT-P10 is the first biosimilar to innovator rituximab (RTX) approved for all indications by the European Medicines Agency. The pharmacokinetics (PK) equivalence and non-inferior efficacy of CT-P10 compared with RTX in patients with newly diagnosed advanced follicular lymphoma (FL) was previously demonstrated when used with combination chemotherapy of cyclophosphamide, vincristine and prednisone (CVP) (Kim WS et al,. 2017). Objectives: This is an ongoing, phase 3, randomized, double blind, active controlled study to demonstrate similarity of efficacy and safety between CT-P10 and RTX as monotherapy in patients with newly diagnosed FL with low tumor burden (NCT02260804). The results of efficacy as determined by overall response rate (ORR), PK, pharmacodynamic, safety and immunogenicity up to 7 months (prior to Maintenance Cycle 3) are presented here. Methods: Patients with FL with stage II-IV, Grade 1-3a and low tumor burden as assessed by GELF criteria were randomized in a 1:1 ratio to receive either CT-P10 or RTX (375mg/m2 i.v.) monotherapy weekly for 4 weeks as induction therapy, followed by maintenance therapy every 2 months for 2 years. Patients who had complete response (CR), unconfirmed CR, partial response or stable disease after the induction therapy were eligible for maintenance therapy. The primary endpoint was ORR over 7 months according to the IWG criteria and was assessed by the independent review committee as central review and by the site investigator as local review. Results: In total, 258 patients were randomized to either the CT-P10 (n=130) or RTX (n=128) group with well-balanced baseline characteristics. Overall, 231 patients (n=119/130 [92%] and n=112/128 [88%] in the CT-P10 and rituximab groups, respectively) completed up to 7 months. Therapeutic similarity between CT-P10 and RTX was established by meeting the predefined margin of ±17% for the primary efficacy endpoint of ORR in the intent-to-treat (ITT) and per-protocol (PP) population (Figure 1). An ORR of 83.1% and 81.3% for CT-P10 and RTX, respectively, was observed over 7 months. The ORR difference was 1.8% and 90% confidence interval (CI) of the treatment difference estimate was entirely within the equivalence margin; 90% CI (-6.43, 10.20). Similar PK profiles were shown in the CT-P10 and RTX. Maximum and trough concentration of CT-P10 or RTX at each cycle were similar between the two groups. Median number of B-cells decreased to the lower limit of quantification (<20cells/μL) after the 1st infusion and remained as depleted over 7 months in both groups. CT-P10 was well tolerated and the safety profile of CT-P10 over 7 months was consistent with that of RTX, with no new, unexpected safety findings. Treatment-emergent adverse events (TEAEs) were reported in 71% and 67% patients in the CT-P10 and RTX, respectively. Adverse events of special interest included infections and infusion-related reactions occurred in a similar proportion of patients in each treatment group (Table 1). Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in either group. The proportion of patients with positive anti-drug antibody were similar between 2 groups (0.8% vs. 2.3%) over 7 months. Among them, neutralizing antibody were detected in one patient in the CT-P10 group. Conclusions: This study demonstrates therapeutic equivalence of CT-P10 to RTX in previously untreated LTBFL. CT-P10 was well-tolerated and the safety profile including immunogenicity of CT P10 was comparable to that of RTX over 7 months. Disclosures Ogura: SymBio: Research Funding; Mundi Pharma: Consultancy; Celltrion: Consultancy, Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Sancho:SERVIER: Honoraria; SANOFI: Honoraria; CELGENE: Honoraria; KERN FHARMA: Honoraria, Speakers Bureau; GILEAD: Honoraria, Research Funding; JANSSEN: Honoraria, Speakers Bureau; ROCHE: Honoraria, Speakers Bureau; MUNDIPHARMA: Honoraria. Lennard:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Buske:Roche: Honoraria, Research Funding; Bayer: Research Funding; Janssen: Honoraria, Research Funding. Lee:Celltrion, Inc: Employment.

scholarly journals Survival Analysis from the CALGB Study of Lenalidomide Maintenance Therapy in Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation Adjusted for Crossover (Alliance 100104)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4737-4737 ◽  
Author(s):  
Philip L. McCarthy ◽  
Paul Richardson ◽  
Vera Suman ◽  
Miranda Cooper ◽  
Owain Saunders ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Active Treatment ◽  
Treatment Effect ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: The phase 3 double-blind, CALGB/Alliance 100104 study assessed the efficacy and safety of lenalidomide (LEN) or placebo maintenance therapy until relapse in post-autologous stem cell transplantation (ASCT) patients with newly-diagnosed multiple myeloma (NDMM). Interim analyses demonstrated superiority for LEN versus placebo for time to progression (TTP), thus meeting the primary TTP endpoint of the trial. The study was unblinded in December 2009 and, based on the TTP and overall survival (OS) benefit observed with LEN, patients in the placebo arm (who had not yet progressed) at the time of unblinding were given the option of crossing over to receive LEN. Data have been reported for a follow-up of 91 months based on the planned intention to treat (ITT) analysis, yielding a TTP hazard ratio (HR) 0.57 and an OS difference of HR 0.61 (Holstein SA, et al. Lancet Haematol. 2017;4:e431-42). Crossover to active treatment enabled patients to benefit from LEN maintenance and collection of additional efficacy and safety data; however, crossover can confound the estimates of OS for longer follow-up. We report the results of an analysis adjusted for crossover, thus aiming to provide a more accurate estimate of the survival benefit achieved with LEN maintenance therapy. Methods: Results are reported for an analysis based on an updated data cutoff, post-October 2016. The rank-preserving structural failure time model (RPSFTM) was considered the most appropriate method to adjust for crossover (Robins JM, Tsiatis AA. Commun Stat Theory Methods. 1991;20:2609-31). This method requires that the assumption that the treatment effect is the same for patients who receive LEN at randomization as those who receive LEN as crossover treatment is not violated; a landmark analysis was performed to explore this. The iterative parameter estimation (IPE; Branson M, Whitehead J. Stat Med. 2002;21:2449-63) algorithm was used as validation. Both the RPSFTM and IPE analyses assume a residual LEN effect after discontinuation (base case). Results: A total of 76 NDMM patients who had not progressed, as determined by central adjudication, crossed over from placebo to LEN and were included in the analysis. The landmark analysis of OS from the date of unblinding indicated that the treatment effect for the crossover versus the non-crossover placebo group was HR 0.57 (95% confidence interval [CI] 0.29-1.15) (Figure). This also provided a measure of the benefit of LEN maintenance in patients who started maintenance therapy after the trial-specified 90-100 day window post-ASCT (median 11.5 months post-randomization; range 3.2-51.0 months). Adjustment for crossover using the RPSFTM or IPE resulted in an increase in the relative treatment effect of LEN maintenance (vs placebo) on OS from 30.8 months for the ITT analysis (HR 0.61; 95% CI 0.47-0.81) to 40.1 months (HR 0.52; 95% CI 0.36-0.73) for the RPSFTM analysis and 38.8 months (HR 0.52; 95% CI 0.37-0.74) for the IPE analysis (Table). Results were consistent across the two methods. Discussion: This analysis was performed on an updated version of the data set reported in the Holstein article. Once we adjusted for crossover, depending on the methodology used, there was an additional gain of ~40 months of OS. Previously, a pre-planned, pooled meta-analysis of 3 studies that included CALGB/Alliance (McCarthy PL, et al J Clin Oncol. 2017;35:3279-89) indicated that the OS gain was 2.5 years; however, our analysis from the CALGB study alone shows that LEN maintenance may provide a survival benefit of > 3 years. In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of LEN maintenance therapy post-ASCT and support guideline recommendations to offer LEN maintenance therapy to all patients post-ASCT. Support: U10CA180821, U10CA180882, U10CA180820; ClinicalTrials.gov Identifier: NCT00114101. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cooper:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Saunders:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Dhanasiri:Celgene: Employment, Equity Ownership. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1956-1956
Author(s):  
Amy Wang ◽  
Justin Kline ◽  
Wendy Stock ◽  
Satyajit Kosuri ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Stem Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Advisory Committees ◽  
Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

scholarly journals Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2831-2831 ◽  
Author(s):  
Swaminathan P. Iyer ◽  
Brad M. Haverkos ◽  
Jasmine Zain ◽  
Radhakrishnan Ramchandren ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: 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; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 613-613 ◽  
Author(s):  
Antonio Palumbo ◽  
Meletios A. Dimopoulos ◽  
Michel Delforge ◽  
Martin Kropff ◽  
Robin Foa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Time To Progression ◽  
First Line ◽  
Advisory Committees

Abstract Abstract 613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free survival (PFS). The secondary endpoints are OS, time-to-progression, response rate, time to response, response duration, time-to-next anti-myeloma therapy, safety, quality of life and exploratory assessment of cytogenetic abnormalities. Primary comparison is based on the intent-to-treat population comparing PFS between MPR followed by lenalidomide with MP followed by placebo; secondary comparisons are between MPR followed by lenalidomide and MPR followed by placebo, and between MPR followed by placebo and MP followed by placebo. Results: The first patient was enrolled in February 2007. A pre-planned interim analysis to evaluate the efficacy and safety was performed at 50% information. An independent central adjudication committee determined the assessment and timing of progressive disease prior to the interim analysis. At the interim analysis, it was determined by the Data Monitoring Committee (DMC) that the study had crossed the O'Brien Fleming superiority boundary for the primary endpoint, demonstrating a highly statistically significant improvement in PFS for patients treated with MPR compared with MP as first-line treatment for MM patients. The topline results will be availabel at the time of the meeting. Conclusions: MPR is an effective and safe regimen for front-line use in MM. PFS was significantly improved in patients who received MPR followed by lenalidomide maintenance compared with those who received MP followed by placebo maintenance. MPR followed by lenalidomide maintenance is a new therapeutic option and can be considered a new standard for patients older than 65 years old. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Dimopoulos:Celgene: Honoraria. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Kropff:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:Celgene: Membership on an entity's Board of Directors or advisory committees. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Catalano:Celgene: Research Funding.

A Multicenter, Phase IV Observational Study Of Ofatumumab In Chronic Lymphocytic Leukemia (CLL): A European Research Initiative On CLL (ERIC) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1645-1645 ◽  
Author(s):  
Carol Moreno ◽  
Marco Montillo ◽  
Panayiotidis Panayiotis ◽  
Adrian Bloor ◽  
Jehan Dupuis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Advisory Committees

Abstract Background Ofatumumab was given a conditional approval in the EU on April 2010 for the treatment of CLL refractory to fludarabine (F-ref) and alemtuzumab (A-ref), encouraging the retrieval of further data in patients treated in a “daily life” setting and to investigate treatment safety. Aims The main objective of this study was to obtain information on the safety profile of ofatumumab given outside clinical trials in patients with previously treated CLL. The secondary endpoints were efficacy, progression-free-survival (PFS), and overall survival (OS). Methods This was an observational, retrospective study. Patients were eligible regardless of prior treatments or disease status and provided they had not been included in ofatumumab clinical trials. Data on patients’ characteristics at diagnosis, prior treatment, adverse events response rate, PFS and OS were recorded. Results One-hundred and twenty patients were screened of which 103 from 25 centers in 10 European countries were eventually eligible for the study. There were 71 males; median age at initiation of ofatumumab was 64 years (range, 38-84); 66% patients were in advanced clinical stage (Rai III-IV/Binet C) and 33 patients presented bulky lymphadenopathy. Number of prior lines of therapy was 4 (range, 1-13). 94% had received prior F-based therapy, 54% received A-based therapy and 51% received both. Eighty-one percent had been previously exposed to rituximab-combination regimens. Fifty-four percent were F-ref, 70% A-ref and 41% were both F- and A-refractory. Cytogenetics within 3 months prior therapy was available in 52 patients of which 34 presented abnormalities (11 patients: 17p-; 9 patients: 11q-; 2 patients: 13q-; 1 patient: trisomy 12; 11 patients: two or more abnormalities including 17p- or 11q-). Forty-two of 50 patients showed unmutated IGHV genes. The median number of cycles of ofatumumab given was 9 (range, 0-16) and the median percentage of given/planned cycles was 83.3% (range, 0-133). In most patients the treatment dose and schedule were as follows: 300 mg 1st infusion followed by 2000 mg for subsequent infusions (8 weekly followed by 4 doses monthly). One hundred and sixty-one adverse events were reported in 68 patients, with 28 (17%) of them being considered as ofatumumab-related. Infusion related-reactions occurred in 19 (28%) patients (III-IV: 6%). Neutropenia was reported in 26% (III-IV: 19%), thrombocytopenia in 15% (III-IV: 12%) and anemia in 15% (III-IV: 7%). The non-hematological adverse events, included infection 44% (III-IV: 36%), fatigue 10% (III-IV: 4%), fever 10% (III-IV: 6%), rash 10% (III-IV: 3%), cough 7% (III-IV: 1%), diarrhea 6% (grade III-IV: 0%) and nausea 1% (III-IV: 0%). Hematologic toxicity correlated with the number of prior lines of therapy. Autoimmune hemolytic anemia and Richter syndrome were reported in one patient each. Two heavily pre-treated patients (5 and 6 prior lines of therapy, respectively) developed progressive multifocal leukoencephalopathy. The overall response rate (ORR) was 23% and the median PFS and OS were 5 and 12 months, respectively. The main causes of death were disease progression (61%) and infection (28%). Conclusions The safety profile of ofatumumab given outside clinical trials to patients with poor-prognosis and heavily pre-treated CLL was consistent with that observed in clinical trials. Although not unexpectedly the ORR was lower in this study, PFS and OS were in line with those reported in phase II trials. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bloor:GSK: Consultancy, Honoraria, Paid speaker Other. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Geisler:Roche: Consultancy; GSK: Consultancy. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Stilgenbauer:GSK: Honoraria, support Other. Smolej:GSK: Consultancy, Honoraria, travel grants Other. Jaeger:GSK: Honoraria, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kimby:Roche: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Emergent BioSolutions: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

Intervention Versus Observation: What Is the Appropriate Endpoint? Assessment of Endpoints in Patients with Advanced Stage Follicular Lymphoma Who Are Initially Observed

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1777-1777 ◽  
Author(s):  
Jacob D Soumerai ◽  
Kurt S Bantilan ◽  
Ai Ni ◽  
Connie Batlevi ◽  
Anna Alperovich ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Burden ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Kendall’S Tau ◽  
Kendall's Tau ◽  
Genetics Research ◽  
Asymptomatic Patients

Abstract BACKGROUND: Treatment may be safely deferred in asymptomatic patients with advanced stage, low tumor burden follicular lymphoma (FL) until onset of symptoms or organ failure without compromising overall survival (OS). A randomized trial comparing immediate rituximab vs. observation in this setting reported a Time to New Treatment benefit without a corresponding OS benefit (Ardeshna et al, Lancet Oncol 2014). This is a comparison of Time to 1st Treatment (TT1T, observation arm) vs. Time to 2nd Treatment (TT2T, rituximab arm) and thus biased to immediate intervention. TT2T might be a less biased primary endpoint for trials evaluating immediate intervention vs. observation. Time to Treatment n (TT(n)T) is a function of cumulative time spent from diagnosis in periods of observation, treatment, and remission, and TT(n)T approaches OS as n approaches the maximum number of therapies received, thus we also hypothesize that TT2T might be a surrogate for OS. We have therefore performed a comprehensive evaluation of standard endpoints (TT1T, OS, and EFS12), described TT2T as a novel endpoint for trials evaluating intervention vs. observation in asymptomatic patients with advanced stage, low tumor burden FL, and aimed to determine if TT2T is a reliable surrogate for OS. METHODS: We identified 246 consecutive patients at our institution, diagnosed from 1998 to 2007 with advanced stage, low tumor burden follicular lymphoma grade 1-3A, for whom physician intention at diagnosis was observation. Median time to event was calculated using the Kaplan-Meier method for each event: TT1T, TT2T, and OS. Modified Kendall's tau was used to assess the correlation between TT1T, TT2T, and OS, accounting for censoring in these quantities. Tests of modified Kendall's tau against 0 (i.e. no correlation) were performed. EFS12 was defined as non-death event within 12 months of initiation of first treatment, and median OS for EFS12 analysis was calculated from end of first treatment. Of 69 patients who received chemoimmunotherapy as first therapy following initial observation, the log-rank test was used to compare survival distributions by EFS12. RESULTS: Of 246 patients with advanced stage, follicular lymphoma grade 1-3A for whom physician intention at diagnosis was observation, there was a slight female predominance (1.16:1), 34.6% were above age 60 with a median age of 56.1 years (range 25-88), and 11.8% (29/246) developed histologic transformation prior to 1st/2nd therapy, including 7.7% (19/246) prior to 1st treatment. At a median follow-up of 10.9 years: median TT1T was 43.5 months (3.5-217.4+, 179 events), median TT2T was 151.8 months (range 5.2-219.6+, 101 events), and median OS was not reached (range 5.2-219.6+, 48 events). The modified Kendall's tau measuring correlation between TT1T and OS was 0.012 (p = 0.537), and was 0.078 (p < 0.001) between TT2T and OS, suggesting that TT2T is strongly correlated with OS while TT1T is not. Failure to achieve EFS12 was observed in 10.3% (7/68) and associated with inferior OS (p=0.001). Of 7 patients who failed to achieve EFS12, 3 had histologic transformation. CONCLUSIONS: TT2T is a preferred primary endpoint for clinical trials evaluating intervention vs. observation. In patients with advanced stage, low tumor burden FL who are initially observed, the median time from diagnosis to 2nd treatment is 12.7 years. Future trials evaluating the role of immediate therapy in low tumor burden FL might restrict eligibility to high risk patients expected to have inferior TT2T. Efforts are ongoing to develop biomarkers (e.g. m7-FLIPI) that identify a population enriched with high risk patients. Our data also suggest that TT2T might be a better surrogate for OS than TT1T, and analyses are ongoing to validate this finding. Figure 1 Figure 1. Disclosures Hamlin: Molecular Templates: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Palomba:Pharmacyclics: Consultancy. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Kumar:Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board. Zelenetz:Amgen: Consultancy; Takeda Pharma: Consultancy; Novartis: Consultancy; Nanostring Tech: Consultancy; Portola Pharmaceuticals: Consultancy; Adaptive Biotechnology: Consultancy; Bristol Myers: Research Funding; Boehringer Ingelheim: Other: DMC Membership; Janssen: Consultancy, Research Funding; Hospira: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding.

Contempo: Preliminary Results in First-Line Treatment of Follicular Lymphoma with the Oral Dual PI3K-δ,γ Inhibitor, Duvelisib, in Combination with Rituximab or Obinutuzumab

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2979-2979 ◽  
Author(s):  
Carla Casulo ◽  
Juan-Manuel Sancho ◽  
Koen Van Eygen ◽  
Sven de Vos ◽  
Santiago Mercadal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Safety Profile ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Dose Modification

Abstract Background: Duvelisib is an oral, dual inhibitor of PI3K-d,γ, in development for the treatment of hematologic malignancies, including follicular lymphoma (FL). Duvelisib disrupts PI3K-d,γ-mediated signaling within tumor cells and their interactions with the tumor microenvironment, hindering hematologic tumor cell survival. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for FL, with an acceptable safety profile. CONTEMPO (NCT02391545), is designed to evaluate the safety and clinical activity of duvelisib in combination with rituximab (DR) or obinutuzumab (DO) in patients (pts) with previously-untreated CD20+ FL. Methods: In CONTEMPO, duvelisib is administered at 25 mg BID continuously in 28-day treatment cycles, combined either with rituximab (375 mg/m2 for 4 weekly doses, then 1 dose every 2 cycles) or obinutuzumab (1000 mg for 4 weekly doses, then 1 dose every 2 cycles). Pts are assigned 1:1 into the two parallel treatment arms. Key inclusion criteria include: diagnosis of previously-untreated CD20+ FL, Stage II with bulky disease (≥ 7 cm lesion), or Stage III-IV disease, at least 1 measurable disease lesion > 1.5 cm, adequate liver and renal function, and no clinical evidence of transformation to a more aggressive subtype of lymphoma or Grade 3B FL. Prophylaxis for herpes (HSV/VZV) is recommended. For pts with a history of CMV infection requiring treatment, prophylaxis and monitoring of reactivation is recommended. The original protocol mandated PJP prophylaxis when CD4 counts were ≤ 200 cells/mm3, and was subsequently amended to include all pts. Disease response assessments (CT scans and physical exams) occur on Day 1 of Cycle 4 (C4), C8, C12, C16, C20, and C26. Results: As of 19 July 2016 (data cut-off), 28 pts received DR and 27 received DO. For DR pts, the median age was 58 years, most were male (64%), 21% had Gr 1 and 64% Gr 2 disease at baseline, and 54% had bone marrow involvement. Median time from diagnosis was 2.3 months. For DO pts, the median age was 58 years, most were female (59%), 48% had Gr 1 and 30% Gr 2 disease at baseline, and 59% had bone marrow involvement. Median time from diagnosis was 2.6 months. DR pts were on treatment for a median of 3.9 months, DO pts for 4.5 months. The overall response rate (ORR) per IWG criteria for DR was 87% and for DO was 91% (see table) The rate of AEs for DR pts was 93%, with 50% having a ≥ Gr 3 AE. 64% of DR pts had an AE leading to duvelisib dose modification (reduction or hold), while 14% discontinued duvelisib due to an AE. The most common ≥ Gr 3 AEs on DR (> 2 pts) were ALT increased (21%) and rash (14%). The rate of ≥ Gr 3 infections was 11%, including PJP (n=2; no prophylaxis, pre-amendment), followed by lung infection and pneumococcal pneumonia (1 pt, each). One PJP case resolved and the pt continued on study. The second PJP case resolved, however the pt had a subsequent fatal event of acute respiratory distress, the only fatal AE on study. The rate of AEs for DO pts was 89%, with 70% of pts having a ≥ Gr 3 AE. 63% of DO pts had an AE leading to duvelisib dose modification (reduction or hold), while 7% discontinued duvelisib due to an AE. Most common ≥ Gr 3 AEs (> 2pts) on DO were neutropenia (19%), ALT increased (15%), and AST increased (11%). The rate of ≥ Gr 3 infections was 15%, including conjunctivitis, RSV pneumonia, pyelonephritis, and septic shock (1 pt, each). No pts on DO died due to an AE. Conclusions: Preliminary clinical activity with DR (87% ORR, 22% CR) and DO (91% ORR, 18% CR) supports the potential role of duvelisib in combination with an anti-CD20 monoclonal antibody as initial treatment for pts with FL. The safety profile was manageable with appropriate risk mitigation measures, suggesting further investigation of these combinations may be warranted. Disclosures Casulo: Celgene: Research Funding; Infinity: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Speakers Bureau. Gyan:Amgen: Honoraria; Sanofi: Honoraria; Pierre Fabre: Honoraria; Novartis: Research Funding; Celgene: Research Funding; Fresenius Kabi: Honoraria; Gilead: Consultancy, Speakers Bureau; Mundipharma: Consultancy; Roche: Research Funding. Steelman:Infinity: Employment. Pearlberg:Infinity: Employment. Goy:Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Early Safety Data from an Ongoing Single Arm Phase-II Investigator-Initiated Clinical Trial (PRIME Study)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2752-2752
Author(s):  
Vivek S Radhakrishnan ◽  
Naveed Tamboli ◽  
Shreya Das ◽  
Jeevan Kumar Garg ◽  
Arijit Nag ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Safety Data ◽  
Bone Lesions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Tertiary Center

Abstract Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing this combination in Newly Diagnosed Multiple Myeloma (NDMM) Aim: To determine safety of Pomalidomide in combination with Bortezomib and dexamethasone (VPD) in NDMM Study design: A prospective, single arm, phase II study from a tertiary center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years are being recruited in the study. Patients with Plasma cell leukemia, POEMS and amyloidosis were excluded. The regimen consists of weekly Bortezomib 1.3mg/sq.m (subcutaneous), Tab. Pomalidomide 2-4mg once daily for 21days, and Tab Dexamethasone 20mg twice weekly, with the cycle repeating every 28 days, 9-12 cycles. Here we report the adverse events (AE) by NCI CTCAE v5.0, upon recruiting 26 patients, as predetermined in the study. Results: Of the proposed 45-50 patients, 26 patients were enrolled in the study between April 2020 to May 2021 and 23 (88.4%) have completed 4 cycles of VPD. The median age is 55years (18-70), and gender ratio 1:1. At disease presentation, bone lesions were the commonest (96.2%, n=25), IMWG high risk cytogenetics were seen in 42.4% (n=11), RISS-2 in 69.3% (n=18), IgG kappa paraproteinemia in 54% (n=14) patients and ECOG performance score 2-3 in 57.6%(n=15). Ten (38.5%) patients have completed 9 cycles, and 3 underwent auto-transplant (between Cycle 4 & 6). Protocol adherence was 96.1% (25/26 patients). Table-1 shows drug-induced toxicity, hematological toxicities were the commonest. Two patients withdrew consent in view of bortezomib-induced peripheral neuropathy. Serious adverse events (SAE) were reported in 9 (34.6%) patients and were considered unrelated to the regimen by the safety committee (PSVT=1, Bony pain=2, dyspnea=1, pneumonia=1, constipation=1, diarrhea=1, hypotension=1) and one death due to SARS-CoV2 pneumonia. Treatment delays of 2 weeks in 4 patients (SARS-CoV2 = 3, Syncope = 1) After 4 cycles (n=23), 6 (26%) patients were in stringent Complete Response (sCR), 17(74%) in Very Good partial response (VGPR) and 13 (56.5%) are Measurable Residual Disease (MRD) negative. Of 10 patients who completed cycle 9, 9 were MRD negative and 1 showed disease progression. Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM. Early efficacy signals are encouraging, and recruitment continues. Figure 1 Figure 1. Disclosures Radhakrishnan: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emcure Pharmaceuticals: Research Funding; Intas Pharmaceuticals: Research Funding; Janssen India: Honoraria; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca India: Honoraria, Speakers Bureau; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cipla Pharmaceuticals India: Research Funding; Aurigene: Speakers Bureau. Garg: Dr Reddys Laboratories: Honoraria, Speakers Bureau. Nair: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intas pharmaceuticals: Honoraria, Speakers Bureau; Mylan pharmaceuticals: Honoraria; Novartis India: Honoraria; Fresenius Kabi India: Honoraria; Cipla Pharmaceuticals: Honoraria, Speakers Bureau; Janssen India: Honoraria, Speakers Bureau. Chandy: Janssen: Honoraria; Pfizer: Honoraria; Intas Pharmaceuticals: Research Funding.

scholarly journals Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 125-125 ◽  
Author(s):  
Loretta J. Nastoupil ◽  
Jason R. Westin ◽  
Fredrick B. Hagemeister ◽  
Hun Ju Lee ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Tumor Burden ◽  
Advisory Board ◽  
Advisory Committees ◽  
High Tumor Burden ◽  
Equity Ownership ◽  
Grade 3

Introduction: FL, the most common indolent non-Hodgkin lymphoma, is characterized by a defective immune microenvironment that suppresses normal T-cell and natural-killer (NK)-cell activity. The clinical course is often depicted by high initial response rates coupled with a prolonged natural history and repeated relapses with most patients (pts) succumbing to their disease. Effective, well tolerated therapies are desirable. Obinutuzumab (O) is a humanized, type II anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Lenalidomide (len) is an immunomodulatory agent that binds the cereblon E3 ubiquitin ligase complex resulting in recruitment, ubiquitination, and degradation of transcription factors Aiolos and Ikaros resulting in T-cell and NK-cell activation. Therefore, combining O with len is anticipated to be synergistic in augmenting the innate and adaptive immune response in FL. The combination has been shown to be well tolerated and effective in relapsed FL (Fowler ICML 2017). Therefore, we sought to explore the efficacy and safety of O-len in previously untreated, high tumor burden FL. Methods: We conducted as single-center, phase 2 study in previously untreated, stage II, III, or IV, high tumor burden (defined by GELF) FL (grade 1, 2 or 3A). Pts received 1000mg of O on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and day 1 of even numbered cycles, cycle 8-30. Cycle length was 28 days. Len was administered as 20mg on days 1-21 of cycles 1-6. Pts in a complete response (CR) after 6 cycles received reduced dose len (10mg on days 1-21) for cycles 7-18. Among pts in a partial response (PR) after 6 cycles, len was continued at 20mg for the next 3-6 cycles or until CR, whichever occurred first, len was then dose reduced to 10mg on days 1-21 for the remainder of 18 cycles. The primary endpoint was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria). Secondary endpoints included: safety, CR, PR, overall response (ORR), and overall survival (OS). Results: 90 pts with high tumor burden FL were enrolled. Median age was 58 years (range 33-84), 52% (N=47) were male, 67 (74%) had an ECOG performance status of 0, 9 (10%) had stage II, 23 (26%) stage III, and 58 (64%) had stage IV disease. The majority had grade 1/2 FL (80%). Twenty-one percent had low risk FLIPI scores, 37% intermediate risk, and 42% were high risk. With a median follow-up of 22 months (range 1-30 months), the 2-year PFS estimate is 96% (95% CI 92-100%) with only 2 pts experiencing progression to date. The ORR is 98% (85 CR, 1 PR), 92% achieved a CR at the first response assessment (cycle 4, day 1). Correlative studies are underway including serial circulating tumor DNA measurements. No deaths have been observed to date. Eleven pts (12%) discontinued therapy as a result of an adverse event (AE), upper respiratory infection was the most common reason (N=5). Other reasons included bradycardia with sick sinus syndrome, urinary tract infection, constipation, abdominal pain, fatigue, foot neuroma (N=1 for each instance). The most common grade 3 or higher AEs include neutropenia (16%, grade 3 N=5, grade 4 N= 9), rash (10%), lung infection (4%), neutropenic fever (1%). Conclusions: O-Len was associated with very high CR rates and 2-year PFS estimates in untreated, high tumor burden FL. The toxicity profile was manageable. Further study of this effective, immune therapy approach in untreated FL is warranted. Figure Disclosures Nastoupil: Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Poseida: Research Funding; Karus: Research Funding; Novartis: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding. Fowler:ABBVIE: 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; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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. OffLabel Disclosure: Lenalidomide in untreated follicular lymphoma

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 933-933 ◽  
Author(s):  
Nathan Fowler ◽  
Brad S Kahl ◽  
Peter Rosen ◽  
Jeffrey Matous ◽  
Amanda Cashen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Clin Oncol ◽  
Board Of Directors ◽  
Research Funding ◽  
High Risk Population ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document