Response Rates of Phase 2 and Phase 3 Trials of Decitabine (DAC) in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2515-2515 ◽  
Author(s):  
Hussain I. Saba ◽  
Michael Lübbert ◽  
P.W. Wijermans
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Duration ◽  
Response Rate ◽  
Response Rates ◽  
Median Number ◽  
Phase 2 ◽  
Phase 3 ◽  
Overall Response ◽  
Number Of Cycles

Abstract Background: MDS is characterized by ineffective hematopoiesis, resulting in cytopenias with dysplastic morphology of peripheral blood cells and bone marrow. Decitabine (Dacogen™ DAC) is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. Due to the requirement for DNA synthesis and subsequent demethylation, decitabine may require prolonged administration to achieve maximum benefit. Overall response rates (ORR) (CR+PR) from 1 pivotal Phase 3 (D-0007) and 3 supportive Phase 2 trials (91–01, 95–11 and 97–19) in patients with intermediate and high risk MDS receiving DAC are being presented. Methods: The Phase 2 trials were open-label and single-arm, with a minimum of 4 treatment cycles and a maximum of 8 cycles, while the D-0007 was a 1:1 randomized comparison of DAC plus supportive care (SC) vs. SC alone, with a maximum of 10 cycles of therapy. The D-0007 study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. Results: A total of 271 unique patients were exposed to DAC in the studies (n= 89 in D-0007, n=29 in 91–01, n = 66 in 95–11, n = 87 in 97–19). Patients receiving DAC had similar demographics and disease characteristics in all trials. Responses were observed in all IPSS and FAB subgroups. The percent of patients classified as intermediate-2 and high risk (according to the International Prognostic Scoring System) in the Phase 3 trial was 69% vs. 72% in the Phase 2 trials. By intent-to-treat analysis, the ORRs were 45%, 26%, and 26% respectively, for the Phase 2 trials. These results were corroborated in the Phase 3 trial, where the response rates were evaluated according to the more robust International Working Group MDS criteria, following a blinded, centralized bone marrow review. The D-0007 overall response rate was 17% for DAC (9% CR, 8% PR) vs. 0% for SC (p<0.001). Responses were durable, lasting a median of 266 days. The 95–11 and 97–19 response rates were also centrally reviewed, while 91–01 responses were investigator-assessed. In the 91–01 trial, the ORR was 45% (28% CR, 17% PR) with a median duration of response of 217 days, the 95–11 ORR was 26% (21% CR, 5% PR) with a median duration of 250 days, and the 97–19 ORR was 26% (22% CR, 5% PR) with a median duration of 146 days. Hematologic improvement (HI) was also evaluated according to varied criteria in conjunction with the response rates in all 4 studies; 12 patients (13%) had HI in D-0007, 2 patients (7%) in 91–01, 8 patients (12%) in 95–11, and 13 patients (15%) in 97–19. The D-0007 trial design dictated that patients who maintained a CR for 2 cycles be removed from therapy. As a result, the median number of cycles delivered was 3, with only 48% of patients receiving ≥4 cycles. In the Phase 2 studies, the median number of cycles is clearly higher (median 4), with the majority of patients receiving at least 4 cycles and approximately one-third of patients receiving ≥6 cycles. Conclusion: While response rates of ≥17% were demonstrated in these trials, the optimization of hypomethylating agents for maximum efficacy is very likely to include prolonged therapy, which may correlate with increases in response rate and duration.

Tipifarnib (ZARNESTRATM in Previously Untreated Poor-Risk AML of the Elderly: Updated Results of a Multicenter Phase 2 Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 874-874 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Jason Gotlib ◽  
Ivana Gojo ◽  
Eric J. Feldman ◽  
Lawrence Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Hospitalization Rate ◽  
Phase 2 ◽  
Overall Response ◽  
Poor Risk ◽  
Phase 2 Trial ◽  
Multicenter Phase

Abstract Farnesyltransferase inhibitors (FTI) make up a novel class of anti-cancer agents that competitively and selectively inhibit farnesyl protein transferase. Early trials of the orally bioavailable non-peptidomimetic FTI tipifarnib (ZARNESTRATM, Johnson & Johnson PRD) demonstrated both clinical responses and excellent tolerability in patients with poor-risk or refractory acute myeloid leukemia (AML). (Karp, et al. Blood97:3361, 2001). We herein report updated results of a multicenter phase 2 trial of tipifarnib in an elderly, previously untreated poor-risk AML population who refused or were deemed unfit for conventional induction chemotherapy. Tipifarnib was administered orally in the outpatient setting at a dose of 600 mg BID for 21 days, followed by a 1–3 week recovery period. Up to 4 cycles of tipifarnib were permitted in patients with complete responses (CR). The primary endpoint was overall response rate (CR + PR). Secondary endpoints included toxicity rates, measurement of markers of farnesylation (HDJ-2) in bone marrow cells, measurement of signaling intermediates ERK and AKT, and RNA microarray expression patterns. Accrual to the trial is complete. 170 patients have been enrolled, 148 of whom are evaluable for response (AML=160; high-risk MDS=4; high-risk CMML=6). The median age was 73 years (range 34–85), and 76 patients (45%) were age = 75. M/F ratio was 2:1. An unfavorable karyotype and/or antecedent MDS was present in 47% and 79% of patients, respectively. The median number of cycles received was 1, and the median number of days of drug received was 36 days. Dose reductions were implemented in 38% of patients, more commonly in cycles subsequent to cycle #1. The overall response rate (CR + PR) was 34%. CR occurred in 18% of patients. Responses were evenly distributed across study centers. In patients ≥ 75 years, the overall response rate was 30% (CR 20 %). Median CR duration was 6.4 months (range 1.5–11+ months). Median overall survival was 5.6 months for all patients. CR patients had a median survival of 14.4 months, with 63% alive at 12 months. In non-responders, median survival was 3.1 months. The incidence of grade = 3 tipifarnib-related non-hematologic adverse events was 43%, comprised mainly of infectious and gastrointestinal complications. The hospitalization rate for tipifarnib-related toxicity was 18% (median duration: 12 days). The death rate from tipifarnib-related toxicity at 6 weeks was 5%. Microarray analysis of pre-and post-treatment bone marrow samples is being performed to identify both predictive and pharmacodynamic gene markers of response to tipifarnib. In summary, tipifarnib is a novel outpatient treatment with activity in previously untreated poor-risk AML. The low hospitalization rate may reflect the low incidence of severe non-hematological toxicity.

Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7006-7006
Author(s):  
Stéphane De Botton ◽  
Karen W. L. Yee ◽  
Christian Recher ◽  
Andrew Wei ◽  
Pau Montesinos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Median Duration ◽  
Interim Analysis ◽  
Phase 1 ◽  
Median Number ◽  
Clinical Activity ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Transfusion Independence

7006 Background: Olutasidenib, a potent, selective, oral, small molecule inhibitor of mutant IDH1 (m IDH1), has exhibited favorable tolerability and clinical activity in high-risk AML patients (pts) in a phase 1 trial (Watts, Blood 2019). Here, we present interim analysis results of a phase 2 trial (NCT02719574) in R/R m IDH1 AML pts receiving olutasidenib monotherapy 150 mg twice daily. Methods: The efficacy evaluable (EE) set comprised m IDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR+CRh (complete remission [CR] or CR with partial hematologic recovery [CRh] according to modified IWG 2003 criteria) rate. CRh was defined as bone marrow blasts <5%, absolute neutrophil count >0.5×109/L, and platelet count >50×109/L. Overall response rate (ORR) comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial response (PR). Duration of treatment (DOT), duration of response (DOR), and overall survival (OS) were estimated using Kaplan-Meier methodology. Results: This clinical trial met its pre-specified early enrollment-stopping criteria for efficacy. A total of 153 pts with R/R AML received olutasidenib; median DOT, 5.5 mo (95% CI: 4.4, 8.7). 43 pts (28%) remain on treatment and 110 (72%) discontinued, most commonly due to: disease progression, 31%; AEs, 14%; death, 10%; and transplant, 8%. For the EE set (123 pts), the median age was 71 y (range: 32‒87) with a median number of prior therapies of 2 (1‒7). The CR+CRh rate was 33% including 30% of pts in CR (Table). Median duration of CR+CRh was not reached (NR) and 13.8 mo in a sensitivity analysis when HSCT or relapse was deemed end of response. ORR was 46% and median duration of ORR was 11.7 mo. Of responders who were transfusion-dependent at baseline, 56-day platelet transfusion independence (TI) and RBC TI were gained by 100% and 83%, respectively, of pts who achieved CR+CRh, and by 56% and 50% who did not. Median OS was 10.5 mo (EE set). In CR+CRh responders, median OS was NR and the estimated 18-mo OS was 87%. TEAEs in ≥25% of pts were nausea, 38%; constipation, 25%; leukocytosis, 25%. Grade 3/4 all-causality TEAEs in >10% of pts were febrile neutropenia, 20%; anemia, 19%; thrombocytopenia, 16%; neutropenia, 13%. Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 21 pts (14%); most cases resolved with treatment management; one case was fatal; 19 pts had concomitant leukocytosis. Conclusions: Olutasidenib was well tolerated and induced durable CR in a subset of high-risk R/R m IDH1 AML pts. TI was achieved in all response groups. Clinical benefit, per DOR and OS, extended beyond CR+CRh responders. Clinical trial information: NCT02719574. [Table: see text]

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

5-Azacitidine Therapy in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia: a Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4963-4963
Author(s):  
Alessandra Freyrie ◽  
Gianluigi Reda ◽  
Daniele Vincenti ◽  
Mariarita Sciumé ◽  
Francesca Binda ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Median Number ◽  
Observation Time ◽  
Chronic Myelomonocytic Leukemia ◽  
Female Ratio ◽  
Number Of Cycles ◽  
Male To Female ◽  
Myelomonocytic Leukemia

Abstract Abstract 4963 Overall survival (OS) is significantly improved by 5-azacitidine in intermediate-2 (int-2) and high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) with 10–29% marrow blasts, and acute myeloid leukemia (AML) with 20–30% marrow blasts, compared with conventional treatments, and currently appears as the standard of care, at least in patients who are not candidates to allogeneic stem cell transplantation (alloSCT). We retrospectively evaluated the efficacy and tolerability of 5-azacitidine in 25 patients treated at our institution from 2009 to 2012, outside of clinical trial. Our series was composed by 17 cases of MDS with IPSS risk int-2 or high, 6 AML with marrow blasts between 20% and 30% and 2 CMML. Patients were treated with 5-azacitidine at a dosage of 75 mg/m2/d subcutaneously for 7 days every 28 days (schedule 5 day on, 2 day off and 2 day on). Median age of our cohort was 72 years (range 37–81 y), male to female ratio was 0. 6 and the median number of cycles received was 7 (range 1–26). According to the MDS-specific comorbidity index 9 pts (53%) were classified as low-risk, 7 pts (41%) as intermediate risk and 1 pt (6%) as high risk. Seventeen (68%) patients (13 MDS, 3 AML, 1 CMML) who had received at least 4 cycles of therapy were evaluable. Median age of these 17 patients was 71 years (range 37–81 y), male to female ratio was 0. 8 and median number of cycles administered was 8 (range 4–26). The overall response rate (ORR) was 59% (10/17 patients). According to International Working Group (IWG) 2006 criteria, five patients (29%) reached complete remission (CR) after a median of 5 cycles of therapy (range 4–6), two patients (12%) obtained hematologic improvement with bone marrow complete remission (marrow CR) after 6 and 11 cycles of therapy respectively, three patients (18%) showed hematologic improvement (HI) after 5 cycles (range 4–6), while stable disease (SD) and progressive disease (PD) were observed in 4 (23%) and in 3 patients (18%) respectively after 5 cycles (range 4–7). Median duration of response was 12 months (range 6–26 mo); median overall survival from the beginning of 5-azacitidine, for all patients treated, was 14. 4 months (range 7–33 mo). We did not observe any differences in response rate according to age, bone marrow fibrosis, cytogenetics and transfusion requirements. In the responder group (10 patients) we did not observe grade 3 or 4 non-hematologic toxicity after a median observation time of 10 months (range 5–33 mo). Among non-responding patients, four (57%) recurred to hospitalization due to infectious or hemorrhagic complications (median observation time 15 months, range 7–33). 5-azacitidine confirmed to be an active therapy for patients with int-2 and high risk MDS and AML with low marrow blast counts not candidate to high intensity treatment for age and or comorbidities, showing high response rate and good tolerability. The low rate of serious adverse events and need of hospitalization improved patient's quality of life and reduced the utilization of medical resources. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1831-1831 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Guillermo Montalban-Bravo ◽  
Koji Sasaki ◽  
Naval G. Daver ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Immune Checkpoint Inhibitor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Median Number ◽  
Front Line ◽  
Genetics Research ◽  
Number Of Cycles

Abstract Introduction: Myeloid cells express PD1 and CTLA-4. Expression of these molecules is enhanced by azacitidine (AZA). Treatment of patients (pts) with nivolumab (Nivo) and anti-PD1 antibody or ipilimumab (Ipi) and anti-CTLA-4 antibody results in the upregulation of CTLA-4 in patients treated with Nivo and reversely of PD1 in patients treated with Ipi, potentially as a mechanism of evasion. In view of the activity of Nivo and Ipi in MDS (Garcia-Manero, ASH 2016), we hypothesized that dual combination of Nivo + Ipi with AZA could have significant activity in high risk MDS. Methods: To study this, we designed a basket exploratory phase 2 trial of ICPI in MDS. Patients with MDS age 18 or older with adequate renal and hepatic function without history of autoimmune disorders were eligible. Patients were divided into front-line and HMA-failure cohorts. Front-line patients were treated with AZA 75mg/m2 iv daily days 1-5 of a 28 day cycle with Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. Patients with HMA failure where treated with Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. The maximum size per cohort was 20 pts. The primary endpoint was to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 IWG criteria. The study included stopping rules for response and toxicity. Results: The median follow up was 4.7 months [range 0-10 months]. From January 2017 to April 2018, 14 patients were treated, 6 pts on front-line cohort and 8 on HMA failure. The median age was 69 years [range 52-80]. A total of 4 (29%) pts had Int-1 risk, 6 (43%) had Int-2 and 4 (29%) had High risk by IPSS. Next generation sequencing on whole bone marrow extracted DNA was performed using a 28 gene panel in 5 pts and an 81-gene panel in 9 pts. Cytogenetic abnormalities and identified mutations are shown in Table 1. Median number of marrow blasts was 10 [range 1-16]. Median Hgb was 9.5g/dL [range 7.3-10.9 g/dL], median WBC was 1.5x109/L [range 0.9-4.7] and platelets was 29x109/L [range 8-117]. A total of 13 pts are evaluable for response at the time of analysis. A total of 3 (38%) pts in the HMA failure cohort received AZA after 6 cycles of therapy. The median number of cycles was 4 [range 1-10] with a median number of cycles to response of 3 [range 1-4]. The overall response rate was 50% (3/6) in the frontline cohort, all of them complete responses, and 29% (2/7) in the HMA failure cohort, including 1 complete response and 1 hematological improvement. Adverse events are shown in Table 2. Treatment with Ipi or NIvo had to be held due to rash in 2 pts, due to elevation of creatinine in 2 pts. Early mortality was observed in 1 patient and this was due to pneumonia complicated with respiratory failure and renal failure. The median overall survival is NR in the frontline cohort and is 8.4 months in the HMA failure cohort (Figure 1). Conclusion: Preliminary results suggest double immune checkpoint inhibitor blockade with Ipi and Nivo in combination with AZA in the frontline setting, or in pts with HMA failure is associated with a tolerable safety profile and clinical activity. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Daver:Incyte: Research Funding; Novartis: Consultancy; Alexion: Consultancy; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; Otsuka: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Sunesis: Research Funding; Karyopharm: Consultancy; BMS: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Karyopharm: Research Funding; Kiromic: Research Funding; ImmunoGen: Consultancy. DiNardo:Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Medimmune: Honoraria; Bayer: Honoraria. Ravandi:Xencor: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Bose:Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Research Funding. Pemmaraju:plexxikon: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding. Cortes:novartis: Research Funding. Kadia:Jazz: Consultancy, Research Funding; BMS: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding.

Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 330-330 ◽  
Author(s):  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Carmen D Schweighofer ◽  
Raymonde Busch ◽  
Jasmin Renschler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Overall Response ◽  
Grade 3

Abstract Introduction: Bendamustine, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin’s lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL. Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine on day 1 and 2 combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgVH) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups. Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter’s syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgVH status were responsive to BR. Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.

Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 385-385 ◽  
Author(s):  
Daver Naval ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Naveen Pemmaraju ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advisory Board ◽  
Standard Chemotherapy ◽  
Overall Response ◽  
Board Membership

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%). Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing. Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 >70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study. Disclosures Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.

scholarly journals Phase 2 March Study: ATG-010 Plus Low Dose Dexamethasone in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Treated with an Immunomodulatory Agent (IMiD) and a Proteasome Inhibitor (PI)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4770-4770
Author(s):  
Lugui Qiu ◽  
Weijun Fu ◽  
Zhongjun Xia ◽  
Zhengzheng Fu ◽  
Wenming Chen ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Supportive Care ◽  
Median Duration ◽  
Low Dose ◽  
Response Rate ◽  
The Elderly ◽  
Phase 2 ◽  
Common Grade ◽  
Grade 3

Abstract Background: ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2, registrational study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled Chinese pts were previously refractory to PI, IMiD, and last line of therapy. ATG-010 (80mg) plus dexamethasone (20mg) was administered twice weekly. The primary endpoint was overall response rate (ORR) per independent review committee. The planned 82 pts would provide ~80% power to test against null hypothesis (H 0) of 15% ORR at one-sided α of 0.025 at the primary analysis, which is presented here. Results: As of 6 th May 2021, 9 (11%) of the 82 pts were still on treatment. Median follow-up was 10.6 months (mo) (range: 2.3-19.6). Median age was 60 years (39% ≥ 65yrs). Median duration from MM initial diagnosis was 3.2 years. A total of 61 pts (74.4%) had cytogenetic abnormalities (del(17p): 22.0%), 18 (22.0%) with baseline plasmacytoma, and 18 (22.0%) with creatinine clearance &lt; 60ml/min. Median number of prior regimens were 5 (range 1-16); 23 pts (28.0%) had received daratumumab (triple-class exposure), 20 pts were triple-class refractory (TCR), and10 pts (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI: 19.7, 40.4), rejecting H 0, including 4 VGPR (very good partial response). Median duration of response (DOR) was 4.7 mo, median progression free survival (PFS) was 3.7 mo, and median overall survival (OS) was 13.2 mo. Among 20 TCR pts, ORR was 25.0% (95% CI:8.7, 49.1), mDOR 10.2 mo, mPFS 2.9 mo, and mOS 11.9 mo. Efficacy was evident in elderly pts (≥ 65yrs), with ORR 25% (95% CI: 11.5, 43.4) and mPFS 2.8 mo. Median OS and DOR were not reached. Sd also demonstrated a similar response rate in pts with high-risk cytogenetic abnormalities, with an ORR of 24.6% (95% CI: 14.5, 37.3). Efficacy of Sd was generally consistent across cytogenetic risk subgroups, including del (17p) pts with ORR 22.2% (95% CI: 6.4, 47.6), mDOR 3.8mo, and mPFS 2.9 mo. The most common non-hematologic treatment-emergent adverse events (TEAEs) of any grade included nausea (78%), hyponatremia (67.1%), weight loss (65.9%), decreased appetite (62.2%), asthenia (59.8%)/fatigue (15.9%), and vomiting (50.0%). The most common grade≥3 non-hematologic TEAE were hyponatremia (29.3%), pneumonia (26.8%), hypokalemia (12.2%) and asthenia (9.8%)/fatigue (2.4%). The most common grade≥3 hematologic TEAEs were anemia (57.3%), lymphopenia (76.8%), thrombocytopenia (51.2%), and neutropenia (40.2%). TESAE occurred in 54.9% of pts, with the most common being thrombocytopenia and pneumonia (14.6% each). TEAE led to death in 7 pts (8.5%). Elderly pts had no significantly increased risk of adverse events, however, given their limited physical state, drug exposure was shorter in the elderly subgroup (12.6 vs 16.1 weeks), suggesting more active supportive care is required. Conclusions: MM refractory to both IMiD and PI remains a high unmet medical need, especially in China. The MARCH study demonstrates statistically significant and clinically meaningful ORR with Sd in Chinese RRMM pts, and efficacy was consistent across subgroups, including the elderly and pts with high-risk cytogenetics. Adverse events were as expected and manageable with appropriate supportive care and dose modification. These data are compatible with the STORM study and offers a new, oral therapeutic option for MM patients. Disclosures Yu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2526-2526
Author(s):  
Lewis R. Silverman ◽  
David R. McKenzie ◽  
Bercedis L. Peterson ◽  
Carlos M. De Castro ◽  
John Ellerton ◽  
...  
Keyword(s):  
Median Duration ◽  
Initial Response ◽  
Response Rates ◽  
Median Number ◽  
Response Criteria ◽  
Best Response ◽  
Published Report ◽  
Males And Females ◽  
Number Of Cycles ◽  
New Treatments

Abstract The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since the publication of these CALGB studies (8421, 8921, 9221), new response criteria for evaluating new treatments for MDS have been published by the IWG (Blood2000;96:3671). Two general differences between the CALGB and IWG response criteria are the required duration of improvement (CALGB: ≥4 weeks; IWG: ≥8 weeks) and peripheral blood values (CALGB: different criteria for hemoglobin targets for males and females; IWG: same criteria for males and females). The results reported here are based on re-collected data from patients described in the published report. After applying the IWG response criteria, the overall response rate (CR+PR+HI) in the azacitidine groups were similar across studies 8421, 8921, and 9221: 44% (21/48), 40% (28/70), and 48% (47/99), respectively. Best Response using IWG Response Criteria for MDS in Studies 8421, 8921, and 9221 Median duration of any response (CR, PR or HI) in the 114 azacitidine-treated responders was 366 days (range: 56 to 4641+ days). The median duration of CR in the 32 azacitidine-treated responders was 379 days (range: 92 to 4412+ days). The median number of cycles from first treatment with azacitidine to any response (CR, PR or HI) was 3 cycles (range: 1 to 17 cycles). Although 75% of the responders achieved a response by cycle 4, the other 25% achieved a response as late as cycle 17. The majority (90%) of responders achieved a response by cycle 6. Best response was observed, on average, 2 cycles after the initial response. In summary, reanalysis of the response rates using IWG criteria demonstrate consistent results across three sequential studies and further validate the superiority of azacitidine over supportive care alone.

scholarly journals Lipoplatin Treatment in Lung and Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Manuela Fantini ◽  
Lorenzo Gianni ◽  
Carlotta Santelmo ◽  
Fabrizio Drudi ◽  
Cinzia Castellani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Triple Negative ◽  
Response Rate ◽  
Toxicity Profile ◽  
Phase 2 ◽  
Breast Cancer Patients ◽  
Phase 3 ◽  
Cisplatin Analogues

The introduction of cisplatin in cancer treatment represents an important achievement in the oncologic field. Many types of cancers are now treated with this drug, and in testicular cancer patients major results are reached. Since 1965, other compounds were disovered and among them carboplatin and oxaliplatin are the main Cisplatin analogues showing similar clinical efficacy with a safer toxicity profile. Lipoplatin is a new liposomal cisplatin formulation which seems to have these characteristics. Lipoplatin was shown to be effective in NSCLC both in phase 2 and phase 3 trials, with the same response rate of Cisplatin, a comparable overall survival but less toxicity. A new protocol aiming to elucidate the double capacity of Lipoplatin to act as a chemotherapeutic and angiogenetic agent in triple-negative breast cancer patients is upcoming.

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