Interim Results of A Randomized Phase II Trial of Azacitidine (AZA) +/− Epo In Lower Risk Myelodysplastic Syndrome (MDS) Resistant to An Erythropoietic Stimulating Agent (ESA) Alone

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1880-1880 ◽  
Author(s):  
Simone Boehrer ◽  
Odile Beyne-Rauzy ◽  
Thomas Prebet ◽  
Sophie Park ◽  
Agnès Guerci ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Lower Risk ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Response Duration ◽  
Prolonged Treatment ◽  
Median Response ◽  
Randomized Phase Ii

Abstract Abstract 1880 Background: Red blood cell (RBC) cell transfusion dependency (TD) is an indicator of poor prognosis in IPSS low and int-1 (lower risk) MDS. In addition, median response duration to ESAs is only about 2 years (Park, Blood, 2008). AZA can lead to RBC transfusion independence (RBC-TI) in 30–40% of lower risk MDS (Lyons, JCO, 2009), but it has not been systematically evaluated in ESA-resistant lower risk MDS and it remains unknown if the combination of AZA and ESA would be useful in such patients (pts). Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), we compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus epoetin beta 60000 U/week (AZA+EPO arm) in lower risk MDS. Inclusion criteria were: IPSS low or int-1 MDS resistant to ESA (i.e having received at least 12 weeks of EPO ≥60000 U/w or darbepoetin ≥250 μg/w or having relapsed after response to ESA), and with RBC-TD of at least 4 RBC units in the 8 weeks prior to enrollment. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was major erythroid responses (HI-E major) after 6 courses, according to IWG 2000 criteria. Secondary endpoints included overall IWG 2000 HI-E, including major and minor, after 4 and 6 courses, response duration, IPSS progression, survival and toxicity. An interim analysis was planned after 49 of 98 planned patients were evaluable for response after 6 courses. Results: From Feb 09 to first of Jul 10, 96 pts were included (M/F=2:1); median age 72y (45-85); 3 pts did not receive any study drug and were excluded from the analysis (one consent withdrawal, one pancreatic cancer and one fatal cardiac event); 93 pts are the subject of this analysis (RARS=40, RCMD-RS=16, RCMD=12, RA=5, RAEB1=12, CMML=7, Unclassified=1). IPSS cytogenetics was favorable in 73, intermediate in 18, adverse in 1 (this pt was not excluded from the present analysis) and failed in 1 cases, with no imbalance for all these characteristics between arms. Overall, 68% of the pts were resistant to ESAs and 32% had lost response to ESA (after a median response duration of 32 weeks, range: 4–120). Median RBC-TD was 6 units (range: 4–16) in the 8 weeks prior to enrollment. Fifteen pts were too early for evaluation of response, 78 were evaluable for toxicity and 72 and 52 pts were evaluable for response after 4 and 6 courses, respectively, as 6 and 22 patients went off-study before 4 and 6 courses, respectively, due to toxicity or progression. Although overall HI-E rates were similar in the AZA and AZA+EPO arms, (40 and 36.5 % respectively, P=0.51), there was a trend for more frequent HI-E major after 6 courses (ie the primary endpoint of the study), in the AZA+EPO arm (7/22,32%), compared to the AZA arm (4/30,13%, P=0.17). Furthermore, in responding patients, the proportion of HI-E major was significantly greater in the AZA+EPO arm (87.5%) compared to the AZA arm (30%, P=0.03). Finally, a significant increase in HI-E major between 4 and 6 cycles was noted only in the AZA+EPO arm (P=0.016). Seventeen responding patients entered the maintenance phase. Of the 78 pts evaluable for toxicity, 22 (28%) had to be hospitalized at least once for an anemia-related event (N=6) and/or a clinical infection/febrile neutropenia (N= 16). Interestingly, only 6 pts had to be hospitalized in the AZA+EPO arm, compared to 16 in the AZA arm, (P=0.o4). Conclusions: In this first randomized study comparing AZA and AZA+ EPO in highly transfusion-dependent lower-risk MDS, this planned interim analysis shows a promising trend for more major HI-E in the AZA+EPO arm, suggesting that addition of EPO to AZA increases the frequency of major erythroid responses in those patients, and may also significantly decrease the hospitalization rate due to infectious and non-infectious complications, allowing more patients to receive prolonged treatment with azacitidine. Updated results will be presented at the meeting. Disclosures: Récher: Celgene: Consultancy, Honoraria, Research Funding. Vey:Celgene: Consultancy, Honoraria, Research Funding. Fenaux:Celgene: Consultancy, Honoraria, Research Funding. Gardin:Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Muktwelve: A Randomized Phase II Trial of Selinexor, Cyclophosphamide and Prednisolone Vs Cyclophosphamide and Prednisolone in Relapsed or Refractory Multiple Myeloma (RRMM) Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5552-5552
Author(s):  
Sarah R Brown ◽  
Andrew Hall ◽  
Jessica Kendall ◽  
Emma Ingleson ◽  
Louise Flanagan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Efficacy ◽  
Primary Endpoint ◽  
Patient Population ◽  
Research Funding ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
Triplet Regimen

Background Triplet combination therapies are the preferred treatment choice for RRMM, however, high-cost-high-cost drug combinations pose significant barriers for health technology assessments (HTA) and access in many public healthcare systems, including the UK. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1), thereby forcing the nuclear retention of key tumour suppressor proteins (TSPs), leading to MM cell death. Recently, the FDA has granted accelerated approval to selinexor for MM on the basis of results from the STORM trial, which tested selinexor in doublet combination with dexamethasone in RRMM. Several trials exploring triplet combinations are ongoing, but most are with high-cost combination partners. In the Myeloma UK Twelve (MUKTwelve) trial Selinexor is combined with low-dose cyclophosphamide and prednisolone in a randomized phase II design, exploring a triplet regimen that could potentially be more accessible for wider patient population. Study design and methods MUKtwelve is a randomized, controlled, open, parallel group, multi-centre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with RRMM (ISRCTN15028850). The primary objective is to determine whether the addition of selinexor to cyclophosphamide and prednisolone (CP) may lead to increased progression free survival (PFS) compared to historic CP data. A calibration arm of patients will receive CP alone, and will be used to evaluate the validity of the outcome in the experimental arm in comparison to historical control data. Participants who experience disease progression on the CP arm may, if deemed eligible receive SCP. Eligible participants are those with RRMM who have received ≥ 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide. Entry criteria are inclusive to allow for a real-world RRMM population, including GFR >=20, no limitation regarding pre-existing polyneuropathy and allowance of growth factor and transfusion support. A maximum of 60 participants will be recruited (45 participants in the SCP arm, and 15 in the CP arm) from 10 UK NHS hospitals. Participants are randomized on a 3:1 basis to receive either SCP or CP. The trial opened on 20th July 2018 and as of 23rd July 2019 16 patients have been randomized. Trial treatment is as shown in Table 1 (28 day cycle). Metronomic, continuous doses of cyclophosphamide and intermittent doses of prednisolone in conjuncture with proactive, prophylactic side effect management, in particular nausea and kachexia, have been chosen to make the trial more accessible for a wider RRMM population. The primary endpoint is proportion of patients alive and progression-free at 6 months (PFS6m). Secondary endpoints include response, response duration, safety and toxicity, PFS and treatment compliance. A three outcome statistical design is used based on the SCP arm only. The trial is designed to test the hypothesis PFS 6m ≤0.28 vs. PFS 6m ≥0.44 (equivalent to median PFS 3.3 vs. 5.1 months). With 90% power, 1-sided 10% significance level, a total of 45 patients are required in the SCP arm. Cut-off values and conclusions for the three outcome design: ≤14/45 patients PFS6m, SCP does not warrant further study≥17/45 patients PFS6m, sufficient evidence for further study of SCP15 or 16/45 patients PFS6m, decision uncertain and can be based upon other secondary endpoints. This approach provides more realistic decision-making compared to those where success of failure is hinged on a difference of a single primary endpoint event. Discussion The MUKtwelve trial is the first trial to assess the clinical efficacy of selinexor with low-dose cyclophosphamide and prednisolone in RRMM, a triplet regimen that, if found to be effective, is likely to be accessible to a wider patient population. Disclosures Brown: Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Kendall:Karyopharm: Other: Research funding to Institution. Ingleson:Karyopharm: Other: Research funding to Institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Auner:Karyopharm: Consultancy; Takeda: Consultancy; Amgen: Other: Consultancy and Research Funding. Boyd:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garg:Janssen: Honoraria; Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding. Kaiser:Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 908-908 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Megan Othus ◽  
Alan F. List ◽  
Olatoyosi Odenike ◽  
Richard M. Stone ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Response Duration ◽  
High Volume ◽  
Centers Of Excellence ◽  
Advisory Committees ◽  
Data Safety ◽  
Randomized Phase Ii

Abstract Background: The few therapies available to treat higher-risk MDS and CMML have limited impact on outcome. We previously reported initial results of S1117, which compared overall response rates (ORRs) of azacitidine (AZA) monotherapy to AZA combined with the histone deacetylase inhibitor vorinostat (VOR), or the immunomodulator lenalidomide (LEN)( ASH 2014 LBA-5). We now report updated response data and overall survival (OS), subgroup analyses, impact of cytogenetics, and effect of treatment center volume/centers of excellence on outcome. Methods: This randomized, Phase II study (ClinTrials.gov # NCT01522976) enrolled higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts ≥5%) and CMML adult patients (pts) with <20% blasts from 3/12-6/14 to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Pts continued treatment until treatment failure, defined as disease progression, relapse, significant or unresolved toxicity, or lack of response. Dose reductions occurred for grade ≥3 adverse events (per NCI CTCAE) or delayed count recovery. Cytogenetic risk groups were defined per IPSS-R. The primary endpoint was improvement in ORR, by intention to treat and reviewed centrally, of one of the combination arms vs. AZA per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). OS was from study entry. MDS Centers of Excellence (MCE) were defined per MDS Foundation; center volume was defined as low (1-4 pts enrolled) or high (5-17 pts). Results: Of 277 pts, 92 received AZA, 93 AZA+LEN, and 92 AZA+VOR. Baseline characteristics, previously reported, were similar across arms. Pts received a median of 22 weeks of therapy and were followed for a median of 10 months (range: 0-30). Non-protocol defined dose modification and protocol discontinuation due to toxicity occurred more frequently in combination arms vs. AZA (p=.0014 and p=.018, respectively). Responses are now assessable in all pts (Table 1). ORR was statistically similar for combination arms vs. AZA, with a trend for longer response duration (p=.083) for combinations. Within HI, AZA+LEN pts had higher HI-n than AZA pts (16% vs. 5%, p=.031). ORR for CMML pts was significantly higher for LEN+AZA vs. AZA (63% vs. 29%, p=.04), with a trend for longer response duration for combinations (p=.06); no differences in ORR were seen for therapy-related MDS, IPSS subgroups, or transfusion-dependent pts. Allogeneic transplantation rates were similar. Median OS (Figure) for AZA:AZA+LEN:AZA+VOR was 15:18 (p=.38):17 (p=.17) months; p=.19 for combination arms vs. AZA. Median OS after failure was 7:9 (p=.6):9 (p=.05) months; p=.15 for combination arms after failure vs. AZA. For pts on therapy >6 months, there was a trend (p=.08) for higher ORR for AZA+LEN vs. AZA, though response duration was similar; median OS was 18:21 (p=.44 vs. AZA):21 months (p=.45 vs. AZA). Cytogenetic risk category distribution and ORR was similar across arms. OS (compared to Very Good/Good) was worse for Poor (HR 2.07, p=.022) and Very poor (HR 4.41, p<.001), without significant modification by treatment arm (Table 2). Compared to pts without identified cytogenetic abnormalities (abn), ORR across arms was better for pts with Chr 5 abn (OR 2.38, p=.004); OS was better for normal (HR .42, p<.001) and worse for Chr 5 abn (HR 3.1, p<.001), -7 (HR 2.69, p<.001), and 17p (HR 2.61, p<.001). While small numbers prevented definitive conclusions for treatment arm effect, combinations trended towards improving OS in Normal and Chr 5 abn only. The outcome of all pts and pts on discrete study arms treated at MCE (n=75) or high volume (n=138) sites were similar to non-MCE or low-volume sites for ORR, non-protocol defined dose modifications, dose adjustment in first 4 cycles, time to off-protocol (HR 1.2, p=.21 and HR .94, p=.64), and OS (HR .81, p=.3 and HR .77, p=.12). Conclusions: In higher-risk MDS pts, ORR and OS was similar for AZA monotherapy compared to combination arms, while for CMML pts, ORR was significantly higher with AZA+LEN. For cytogenetic subgroups, OS was worse for Chr 5 abn, -7, and 17p, and may be improved by combinations in normal or Chr 5 abn. MCE or treatment at a high volume site did not impact these effects or outcomes. Figure 1. Responses Figure 1. Responses Figure 2. Cytogenetics Figure 2. Cytogenetics Figure 3. Figure 3. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Honoraria, Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Merck: Consultancy; Celgene: Consultancy. Gore:Celgene: Consultancy, Honoraria, Research Funding. Buckstein:Celgene: Honoraria, Research Funding. Fang:Affymetrix: Research Funding. Attar:Agios Pharmaceuticals: Employment. Erba:Ariad: Consultancy; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Celator: Research Funding; Celator: Research Funding; Astellas: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees.

Gemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: Final analysis of a randomized phase II trial (BINGO).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4032-4032 ◽  
Author(s):  
David Malka ◽  
Laetitia Fartoux ◽  
Vanessa Rousseau ◽  
Tanja Trarbach ◽  
Eveline Boucher ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Mutational Analysis ◽  
Metabolic Response ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Objective Response ◽  
First Line ◽  
Open Label ◽  
Randomized Phase Ii

4032 Background: Gemcitabine-platinum chemotherapy (CTx) regimens are widely accepted as first-line standard of care for patients (pts) with advanced biliary cancers (ABC). EGFR overexpression has been observed in ABC, suggesting that the combination with anti-EGFR monoclonal antibodies may be appropriate. Methods: Patients with ABC, WHO performance status (PS) 0-1, and without prior palliative CTx were eligible for this international, open-label, two-stage, non-comparative, randomized phase II trial. Patients received GEMOX (gemcitabine, 1 g/m² [10 mg/m²/min] at day [D]1 + oxaliplatin, 100 mg/m² at D2, arm A) or GEMOX + cetuximab (500 mg/m² at D1 or 2, arm B), every 2 weeks. The primary endpoint was crude 4-month progression-free survival (PFS) rate (H0, <40%; H1, ≥60%; planned sample size, 100 pts, increased to 150 pts by amendment to allow subgroup analyses). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and toxicity (NCI-CTC v3.0). Exploratory endpoints included early metabolic response as assessed by PET at 1 month, and tumor KRAS mutational analysis. Results: From Oct. 2007 to Dec. 2009, we enrolled 150 pts (median age, 62 years; male, 57%; metastatic, 79%; cholangiocarcinoma, 84%; median follow-up, 30 months) (Table). Conclusions: GEMOX-cetuximab regimen was well tolerated and met its primary endpoint (4-month PFS ≥60%). However, median PFS and OS were similar in both arms. Exploratory analyses (e.g., KRAS tumor status) are underway to identify pt subgroups deriving benefit from the addition of cetuximab to CTx. [Table: see text]

scholarly journals Randomized Phase II Trial of Combination Idiotype Vaccine and Anti-CD3/Anti-CD28 Costimulated Autologous T Cells in Patients with Multiple Myeloma Post-Autotransplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4548-4548 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Edward A Stadtmauer ◽  
Veera Baladandayuthapani ◽  
Heather Lin ◽  
Beryl M. Tross ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Hematopoietic Stem ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Equity Ownership ◽  
To Receive

Abstract Background: Despite major advances in the treatment of multiple myeloma (MM) only a minority of patients achieve long-term disease control. Immunotherapy combined with autologous hematopoietic stem cell transplantation (auto-HCT) may reduce relapse rates. Immunoglobulin idiotype (Id) conjugated with a carrier protein, Keyhole limpet hemocyanin (KLH), is a tumor-specific antigen in MM. Vaccine-primed, anti-CD3/anti-CD28 costimulated adoptive T-cell transfer can augment humoral and cellular immune responses to vaccination despite cytotoxic therapy. We hypothesized that Id-KLH vaccine + the vaccine-primed costimulated T cells will result in a robust Id-specific humoral and cellular response, compared to a control vaccine (KLH only). Methods: In this randomized, phase II trial, the primary objective was to determine if Id-KLH primed, costimulated T cells will induce a more robust Id-specific immunity than KLH-primed T cells. Eligible patients had IgG monoclonal protein. Patients were randomized 1:1 to receive either Id-KLH vaccine or KLH-only vaccine, followed by auto-HCT, and then vaccine- primed costimulated T cells followed by two booster doses of the vaccine to which they were randomized. This study was supported by The MD Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 36 patients were enrolled between 1/2013 and 5/2015. Sixteen (44%) were randomized to Id-KLH and 20 (55%) to KLH-only. The Table below summarizes the patient characteristics. There was no significant difference between the two groups in terms of age, risk status or induction therapy. No treatment-related mortality, infusion reactions or dose-limiting toxicity was seen in either arm. Five (31%) and 3 (15%) patients achieved complete remission (CR) by day+180 in the Id-KLH and KLH arms, respectively (p=0.42). Initial analysis of a subgroup of patients revealed a significantly higher mRNA expression of immune activation genes IL-2, CCR6 and CD40 by NanoString nCounter in the Id-KLH group compared with the KLH only group (Figure). Eleven (68%) and 17 (85%) went on to receive maintenance therapy with lenalidomide or lenalidomide + ixazomib in the Id-KLH and KLH arms, respectively (p=0.42). After a median follow up of 26 months, 2-year PFS was 81% and 83% in Id-KLH and KLH arms, respectively (p=0.35). Conclusion: Id-KLH vaccine and vaccine-primed costimulated T cells can be safely administered in the setting of auto-HCT.There was a more robust immune response and a trend towards higher CR rate in the Id-KLH group. Disclosures Stadtmauer: Teva: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Cohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. June:Johnson & Johnson: Research Funding; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Celldex: Consultancy, Equity Ownership; Tmunity: Equity Ownership, Other: Founder, stockholder ; Pfizer: Honoraria.

Final report of a randomized phase II study of docetaxel/oxaliplatin (DO) and docetaxel (D) in previously treated non-small cell lung cancer (NSCLC) patients (pts). A novel design, Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 019)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19010-e19010
Author(s):  
O. Belvedere ◽  
A. Follador ◽  
C. Rossetto ◽  
A. M. Sibau ◽  
C. Defferrari ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Trial Design ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Cross Resistance ◽  
Line Therapy ◽  
Randomized Phase Ii ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

e19010 Background: No combination regimen has proven superior to single agent chemotherapy as 2nd-line treatment for NSCLC. The absence of cross-resistance with cisplatin/carboplatin, favorable toxicity profile, along with both pre-clinical and clinical evidence of activity make O a good candidate for combination with D as 2nd-line therapy of NSCLC. We evaluated the activity of DO in this setting using a novel phase II trial design. Methods: This multicenter, non-comparative randomized phase II trial evaluated the activity of D (75 mg/m2 d1) and O (70 mg/m2 d2) every 3 weeks in previously treated NSCLC pts; the comparator arm was D (75 mg/m2 d1 every 3 weeks). This one-stage, three-outcome phase II trial design (Sargent, Control Clin Trials 2001) had 21 evaluable pts/arm. All had histologically confirmed NSCLC that progressed during/after platinum-based chemotherapy. Primary endpoint was response rate; secondary endpoints were toxicity, time to progression (TTP), 1-yr survival. Results: Fifty pts were enrolled. Pts characteristics: M/F, 76/24%; median age 62 yrs (range 43–69); ECOG PS 0/1, 36/64%; adenocarcinoma/other, 36/64%. With 48 pts evaluable, partial response was seen in 20% and 8% of pts; stable disease in 52% and 32% and progressive disease in 24% and 56% for DO and D, respectively; 1 pt was inevaluable due to early death (D arm). Main grade 3–4 toxicities were: neutropenia 56% and 64%; febrile neutropenia 4% and 8%; diarrhea 12% and 4% for DO and D, respectively. Median TTP was 4.9 and 1.8 months, median survival 10.9 and 6.9 months, and 1-yr survival 41% and 16% for DO and D, respectively. Conclusions: This study shows how novel phase II trial designs enrolling a limited number of pts may help identify promising regimens for subsequent study in phase III trials. The level of activity for DO we observed satisfied the pre-defined study primary endpoint and warrants further evaluation of this combination as 2nd-line therapy for NSCLC. Protocol developed at the 6th FECS/AACR/ASCO Workshop on Methods in Clinical Cancer Research, Flims 2004, with Professors Marc Buyse and Chris Twelves. [Table: see text]

Bendamustine, Ofatumumab and High-Dose Methylprednisolone (BOMP) in Relapsed/Refractory CLL: Results of a Planned Interim Analysis of the French CLL Intergroup ICLL01 Phase II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3341-3341 ◽  
Author(s):  
Sophie de Guibert ◽  
Marie-Sarah Dilhuydy ◽  
Loic Ysebaert ◽  
Laurence Sanhès ◽  
Sylvain Choquet ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Interim Analysis ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase Ii Trial ◽  
Risk Group ◽  
High Dose ◽  
Color Flow ◽  
High Dose Methylprednisolone

Abstract Introduction: For relapsed or refractory (R/R) CLL patients (pts), combination of bendamustine and rituximab appears safe and effective (Fischer 2011). Ofatumumab monotherapy gives 58% ORR in heavily pre-treated (median 4 prior lines) R/R CLL pts (Wierda JCO 2010). High doses (HD) steroids are also active in poor prognosis pts with bulky nodal involvement or p53 impairment (Castro 2008, Xu 2010). We report a planned interim analysis of the ICLL01-BOMP phase II trial evaluating the association of Bendamustine, Ofatumumab and high-dose MethylPrednisolone for fit R/R CLL pts after 1-3 previous lines (NCT01612988). Patients and Methods: Primary endpoint was CR rate after 6 cycles (cy) of the BOMP regimen [i.e. bendamustine (70 mg/m2 d1, d2), ofatumumab (1000 mg d1;15 on cy#1-2 and d1 on cy#3-6) and HD methylprednisolone (1 g/m2 d1-3)]. The c#1 was preceded by an ofatumumab (300 mg) prephase. Response evaluation (IWCLL 2008) was done 3 months (m) after the last cy along with blood and bone marrow 10-color flow MRD analysis. Results: Among the 55 pts of this analysis, median age was 64 years (44-76). CIRS-G comorbidity score was 2-6 in 61% and pts had received 2-3 lines in 37% of the cases. Prior FCR-like regimens (50 (91%) patients) had been followed by relapse within 2y in 22/55 and 5/55 pts were fludarabine-refractory (FR). IGVH was unmutated (UM) in (47/52) 90.4%. Karyotypes were complex in 18/46 (39%) cases. Distribution according to FISH hierarchical model was: del(17p) in 15 (27%), del(11q) in 14 (26%), trisomy 12 in 4 (7%), del(13q) in 17 (31%) and normal in 5 (9%). Mutations on the TP53, SF3B1 and NOTCH1 genes occurred in 17 (31%), 14 (26%) and 5 (9%) pts, respectively. According to published risk stratification (Zenz, 2012), 34/55 pts (62%) belonged to the “highest-risk” group with either TP53 disruption (deletion and/or mutation) (n=19) and/or early relapse within 2 years post-FCR (n=22). The remaining patients belonged to either the “high-risk” group (UM-IGVH and/or Highb2mic and/or del11q) accounting for 17 pts (31%) or to the “low-risk” group (or non evaluable) accounting for 4 (7%) pts. Overall, 292 BOMP cy (mean 5.3 cy/pts) were delivered. Safety analysis recorded 158 grade 3-4 adverse events (G3-4/AE) with according to cy: neutropenia: 20.8%, thrombocytopenia: 11.3%, anemia: 2.4%, infection: 5,8%, hyperglycemia: 7,5%, liver enzyme elevation: 1,4%, cutaneous reaction: 1,4%, ofatumumab infusion related reaction: 0,3% and other AE: 3,4%. Overall 43 out of 55 pts (78.2%) had at least one G3-4/AE. Twenty-eight severe adverse events were reported in 20 pts. Treatment interruption before planned 6 cy occurred for pts' decision (n=3), excessive toxicity (n=5) or early progressive disease (PD) (n = 4). Response in the ITT population was 76.4% ORR with 20% CR (n=11), 56.4% PR (n=31 including 5 nPR and 1 CRi), 9.1% stable disease (n=5), 10.9% PD (n=6) and 3.6% (n=3) non evaluable. Blood MRD obtained in 45 pts was negative (<10-4) in 13 (28.8%) cases. Following evaluation, 5 responding pts (9%) had RIC allogeneic (RIC-Allo) transplantation with a persistent remission. With median follow-up of 16.2 (5.1-23.6) months (m) we observed 9 deaths, related to PD (n=5), EBV-induced lymphoproliferation (n=1), PML encephalitis (n=1), sepsis/pancytopenia (n=1) or unknown origin (n=1). We recorded 22 relapses (including 4 Richter Syndromes) resulting in treatment in 17 cases, with a BTK inhibitor in 8 cases. The median OS has not been reached (estimation 84% at 18 m) (Fig 1B). The median PFS was 18.4 m (95%CI, 14.6-22.2) and the median time to next treatment 17.6 m (95%CI, 12.9-22.4). With 5 cases censored at time of RIC-Allo, the PFS (censored analysis) was 17.5 m (95%CI, 13.2-21.8). (Fig 1A) After univariate analysis, ORR was lower in the “highest-risk” (64,6%, p=0.01), del(17p) (40%, p=0.003), TP53 mutation (47.1%, p=0.01) and complex karyotype (61.2%, p=0.024) groups. PFS was shorter in the “highest-risk” (14 m, p=0.046), FR (4.96 m, p<0.001), del(17p) (9.5 m, p=0.017) and TP53 mutation (9.5 m, p=0.007) groups. Conclusion: Relapse treatment of CLL is a challenge especially after prior FCR-like treatments, accounting for >90% of this trial population. These results in terms of response and survival appear noteworthy considering that >60% are “highest-risk” pts. This study provides important information for forthcoming comparison with next emerging CLL therapies. Figure 1 Figure 1. Disclosures de Guibert: Roche: Honoraria. Feugier:Roche: Honoraria. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Leblond:Roche: Honoraria, Speakers Bureau. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding.

scholarly journals A randomized phase II trial of azacitidine +/- epoetin-  in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

Haematologica ◽  
2016 ◽  
Vol 101 (8) ◽  
pp. 918-925 ◽  
Author(s):  
S. Thepot ◽  
R. Ben Abdelali ◽  
S. Chevret ◽  
A. Renneville ◽  
O. Beyne-Rauzy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Phase Ii Trial ◽  
Randomized Phase Ii
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