scholarly journals Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial

2018 ◽  
Vol 36 (32) ◽  
pp. 3203-3210 ◽  
Author(s):  
Arnaud Pigneux ◽  
Marie C. Béné ◽  
Louis-Rachid Salmi ◽  
Pierre-Yves Dumas ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Proportional Hazards ◽  
Complete Response ◽  
Allogeneic Transplantation ◽  
Primary Objective ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Standard Chemotherapy ◽  
Open Label ◽  
Significant Difference

Purpose Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin. Patients and Methods Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety. Results From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( P = .01). The proportional hazards assumption was rejected for OS ( P = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( P = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( P = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( P = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( P = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( P = .04), and fewer patients required a second treatment after ICL. Conclusion Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.

Addition of Lomustine (CCNU) to Induction and Post-Remission Chemotherapy for Fit Elderly AML Patients without Unfavorable Cytogenetics: Results of the Lamsa-2007 Goelams Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3736-3736 ◽  
Author(s):  
Arnaud Pigneux ◽  
Christian Recher ◽  
Marie C Bene ◽  
Julien Asselineau ◽  
Ariane C. Mineur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Complete Response ◽  
Primary Objective ◽  
Open Label ◽  
Mutational Status ◽  
Elderly Aml ◽  
Significant Difference ◽  
Open Label Phase ◽  
Pre Treatment

Abstract Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010). Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR <3), with non-unfavorable cytogenetics. Secondary AML to MDS and MPS were excluded, but not AML secondary to chemotherapy or radiotherapy. As induction therapy, the patients received idarubicin 8 mg/m2/d iv on days 1-5, cytarabine 100 mg/m2/d iv on days 1-7 ± lomustine, 200 mg\m2 orally at day 1. Patients achieving complete response (CR) or CRi received then a first consolidation with idarubicin 8 mg/m2/d iv on days 1-3 and cytarabine 100 mg/m2/d s/cut on days 1-5 ± lomustine, 80 mg orally at day 1, then 6 courses of reduced doses consolidation with idarubicin 8 mg/m2/d iv on day 1 and cytarabine100 mg/m2/d s/cut on days 1-5 ± lomustine, 40 mg orally at day 1. This was followed by 6 months maintenance therapy with alternating courses of purinethol and methotrexate. The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free (EFS) survival, as well as safety. Results: From February 2008 to December 2011, 459 patients were enrolled and 424 were evaluable. The median age of analyzed patients was 68 yo (60-81), 58% were male. Cytogenetics was favorable (5.2%), intermediate (90.3%) or failure (4.5%). Overall, 26% of the patients had a favorable genotype based on NPM, CEBPa and FLT3 ITD mutational status. The two arms were comparable for pre-treatment characteristics. There were 3.7% induction deaths in the IC arm and 7.7% in the ICL arm (p=0.11). The rate of primary resistant AML was 21.4% after IC versus 7.7% after ICL (p<10-4). CR or CRi was achieved in 74.9% of IC patients versus 84.7% in ICL patients (p= 0.01). At two years, OS was much better than expected for such a population, and improved in the ICL arm at 56% versus 48% in the IC arm. As expected at this age, a significant number of events occurred after two years, resulting in the absence of statistical significant difference for OS over the whole period of follow-up. At two years, EFS was improved in the ICL arm at 41% versus 26% in the IC arm (p=0.01). The CIR at two years was 41.2% in the ICL arm versus 60.9% in the IC arm (p=0.003). Grade 3 and 4 toxicities were significantly different between treatment arms after induction and after the first consolidation. Neutropenia <0.5 G/L was prolonged of 2 days in the ICL arm (23 versus 21 for the IC arm, p=0.0001) after induction and of 4 days (11 versus 7 for the IC arm, p<0.0001) after first consolidation. Thrombopenia < 20G/L was prolonged of 5 days in the ICL arm (19 versus 14 for the IC arm, p<0.001) after induction and of 7 days (11 versus 4 for the IC arm, p<0.001) after first consolidation. Conclusion: Thisschedule using the same drugs at decreasing doses during induction, consolidation and reinductions provided unusually good results in the IC arm, further improved in the ICL arm by the addition of lomustine, in fit elderly AML patients without unfavorable cytogenetics, with acceptable toxicity. The higher rate of CR, reduced relapse incidence and improved EFS in the ICL arm support the anti-leukemic effect of lomustine in elderly AML patients, even if it does not translate in a significantly prolonged long term overall survival. New strategies for maintenance therapy remain to be improved in this setting to sustain this positive effect. Disclosures Vey: Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

Differential response rates in early-phase cancer clinical trials (EPCCT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3133-3133
Author(s):  
Rozana Abdul Rahman ◽  
Neethu Billy Graham Mariam ◽  
Hitesh Mistry ◽  
Sreeja Aruketty ◽  
Matt Church ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Rates ◽  
Primary Objective ◽  
Cox Proportional Hazards ◽  
Sustained Response ◽  
Phase Ii Trials ◽  
Significant Difference

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2590-2590
Author(s):  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Ari Rosenberg ◽  
Jared Weiss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Kidney Injury ◽  
Complete Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label

2590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 are an effective treatment for a variety of cancers. However, the majority of patients (pts) exhibit resistance to ICIs. Overcoming this resistance represents a major challenge in immuno-oncology. Emerging evidence suggests radiation therapy (RT) produces an immunomodulatory effect that may act synergistically with ICIs. However, RT dose and ultimate efficacy are limited by toxicity to surrounding healthy tissues. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase RT dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Preclinical data suggest NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders, or convert ICI non-responders to responders. Methods: This is a multicenter, open-label, phase I trial [NCT03589339] to evaluate NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation, and metastases from any primary cancer eligible for anti-PD-1 (nivolumab or pembrolizumab) treatment specifically localized in the lung (2) or liver (3), respectively. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection. Results: Nine pts have been treated: 3 HNSCC, 4 lung, 2 liver. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/RT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. A complete response in the injected lymph node lasting over 1 year was observed in 1 anti-PD-1 naïve pt. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs related to anti-PD-1 (G4 diabetic ketoacidosis, G4 acute kidney injury). SBRT-related safety profile was as expected. Updated results will be presented. Conclusions: Data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in pts with advanced cancers, show NBTXR3 ITI is feasible and well-tolerated. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy. Of particular interest, NBTXR3/RT can overcome ICI resistance in pts having progressed on prior anti-PD-1, supporting further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs. Clinical trial information: NCT03589339.

Olanzapine for Prevention of Vomiting in Children and Adolescents Receiving Highly Emetogenic Chemotherapy: Investigator-Initiated, Randomized, Open-Label Trial

2020 ◽  
Vol 38 (32) ◽  
pp. 3785-3793 ◽  
Author(s):  
Ramavath D. Naik ◽  
Sreenivas V ◽  
Vishwajeet Singh ◽  
Ashwati S. Pillai ◽  
Deepa Dhawan ◽  
...  
Keyword(s):  
Safety Evaluation ◽  
Complete Response ◽  
Primary Objective ◽  
Emetogenic Chemotherapy ◽  
Control Group ◽  
Study Group ◽  
Open Label ◽  
Highly Emetogenic Chemotherapy ◽  
Acute Period ◽  
Open Label Trial

PURPOSE Chemotherapy-induced nausea and vomiting (CINV) is a significant toxicity of chemotherapy. Olanzapine is recommended in adult patients for the prevention of CINV but has not been prospectively investigated in children. METHODS This investigator-initiated, randomized, open-label trial evaluated olanzapine in children (ages 5-18 years) scheduled to receive the first cycle of highly emetogenic chemotherapy (HEC). All participants received aprepitant, ondansetron, and dexamethasone during and 2 days after chemotherapy. Participants in the study group additionally received oral olanzapine 0.14 mg/kg/day (rounded to the nearest 2.5 mg; maximum, 10 mg) during the chemotherapy block and 3 days postchemotherapy. The primary objective was to compare complete response (CR) rates (no vomiting and no rescue medication) between the groups in the acute, delayed, and overall periods. Nausea comparison and safety evaluation were secondary and additional objectives, respectively. The collection of outcomes and adverse events was performed daily until the completion of the overall period. RESULTS A total of 240 patients underwent randomization. We performed a modified intention-to-treat analysis on 231 patients (116 in the control group and 115 in the study group). A higher proportion of patients in the olanzapine group achieved CR in the acute period (78% v 59%; P = .001), delayed period (74% v 47%; P < .001) and overall period (64% v 38%; P < .001) than in the control group. The proportion of patients with no nausea was significantly higher in the olanzapine group in the acute period (74% v 52%; P < .001), delayed period (74% v 47%; P < .001), and overall period (64% v 37%; P < .001). Grade 1/2 somnolence was greater in the olanzapine group (35% v 11%; P < .001). There was no grade 3/4 somnolence reported. CONCLUSION Olanzapine significantly improved CR rates for vomiting in children receiving the first cycle of HEC.

An Update on the Role of Thalidomide (THAL) in Total Therapy 2 (TT2) for Newly Diagnosed Patients with Multiple Myeloma (MM): Analysis of Subgroups Defined by Standard Prognostic Factors (SPF) and Gene Expression Profiling (GEP)-Derived Subgroups.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3389-3389 ◽  
Author(s):  
John D. Shaughnessy ◽  
Jeffrey Haessler ◽  
Jerry Zeldis ◽  
Yongsheng Huang ◽  
Fenghuang Zhan ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Risk Groups ◽  
Complete Response ◽  
Low Risk ◽  
Phase Iii ◽  
Significant Difference ◽  
And Control ◽  
Standard Risk

Abstract Background: THAL, whose activity in MM was discovered in the setting of advanced and refractory disease in the late 1990’s (Singhal, NEJM, 2000), has become the standard front-line therapy in combination with dexamethasone (DEX). In a randomized phase III tandem transplant trial, TT2, a higher complete response (CR) rate and longer event-free survival (EFS) had been observed on the THAL arm (Barlogie, NEJM, 2006). The similar overall survival (OS) on THAL and control arms had been attributed to the routine use of THAL as salvage therapy for the patients randomized to the No-THAL arm and the shorter post-relapse OS among patients randomized to the THAL arm. Patients and Methods: With a median follow-up on TT2 of 53mo, 107 patients have relapsed and 219 died. Subset analyses were performed to determine whether THAL confers an OS advantage in any subgroup of patients. Results: 6-yr EFS and OS rates are 48%/63% on THAL and 38%/58% on control arm (p=0.01/0.67). Post-relapse OS is now similar with median durations of 5.3mo/4.3mo among control/THAL arms (p=0.11). According to multivariate analyses of 11 standard prognostic factors, EFS was shorter among patients treated without THAL, in the presence of cytogenetic abnormalities (CA), B2M and LDH elevations and low albumin, whereas CR was favorable; OS was inferior with CA, high LDH, low albumin and in patients not receiving 2nd transplant or not achieving CR. Randomization to THAL was beneficial only in the >2 risk factor group: 6-yr OS was 47% in 31 patients on THAL and 12% in 31 control patients (Figure 1, p=0.01). When examined in the context of GEP (70 gene model-based high versus low risk groups) and inter-phase FISH data (amp1q21), available in 260 patients, the 57 with GEP low risk and absence of amp1q21 receiving THAL had 5-yr OS of 90% compared to 74% among 73 controls (p=0.13). Conclusion: With longer follow-up of 53mo on TT2, EFS remains superior among patients randomized to THAL; post-relapse survival is no longer inferior among those randomized to THAL; THAL benefited a high-risk subgroup with >2 standard risk factors, whereas no significant `difference has yet emerged among genetically defined subgroups. Figure Figure

Azacitidine in the Treatment of Elderly Patients with Acute Myelogenous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4164-4164
Author(s):  
Heather L. Benjamin ◽  
James M. Rossetti ◽  
Aaron J. Lampkin ◽  
Christie Hilton ◽  
Entezam Sahovic ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Open Label ◽  
Drug Induced ◽  
Acute Myelogenous ◽  
Prospective Phase ◽  
Blast Count ◽  
The Mean

Abstract Abstract 4164 BACKGROUND Effective treatment of the elderly patient with acute myelogenous leukemia (AML) remains a challenging task. Elderly patients with AML usually respond poorly to standard induction chemotherapy. Response rates in elderly patients are in the range of 30–50% compared to 80–90% in younger patients. Moreover, prolonged hospitalization with treatment related mortality as high as 30% is typical in this older population. In a prior retrospective analysis done at our institution, azacitidine showed an overall response rate of 60% with limited toxicity when administered to patients older than 55 years of age with AML. We present an interim analysis of the first 13 patients enrolled in our prospective, phase II open label study using single agent azacitidine for elderly patients with AML. METHODS This is a prospective, phase II open label study using azacitidine in patients ≥ 60 years with AML. Inclusion criteria: Newly diagnosed AML (de novo or secondary, WHO criteria) and ECOG≤ 2. Promyelocytic (M3) phenotype was excluded. Patients with circulating blast count ≥ 30,000/mcl were treated with hydroxyurea until < 30,000/mcl. Azacitidine was given at a dose of 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. G-CSF was given to patients with neutropenia (ANC < 1000/mcl) during all cycles excluding cycle one. RESULTS Thirteen patients have been enrolled to date. The mean age of patients is 75 years (range: 66–84). The mean baseline ECOG performance score was 1 with a mean during treatment of 1. Mean baseline bone marrow blast count was 57% (range: 21–100%). Overall response rate using the NCI response criteria (IWG criteria for patients with hematological improvement (HI) only) was 46% (6/13): complete response (CR; n=3; 23%), partial response (PR; n=1; 8%), and HI (n=2; 15%). One additional patient had a 94% reduction in marrow blasts, but failed to achieve transfusion independence. The mean number of days on treatment was 171+ (range: 13–606). The mean number of days hospitalized for diagnosis plus treatment or disease related complication was 21 (range: 7–72) with the majority of therapy being given in the outpatient setting. One patient required prolonged hospitalization after going on to allogeneic transplantation. The mean overall survival from diagnosis for all patients was 246+ days (range: 13–606). The mean overall survival for responders was 399+ days (range: 212–606). One patient continues on therapy with azacitidine at 606 days (CR). Of the other responders, one progressed at 420 days and is considering other options (CR), one died from an intra-cranial hemorrhage after receiving Mylotarg for disease progression at 454 days (CR), one progressed at 119 days and went on to another clinical trial (PR), and two died with disease at 212 and 347 days (HI). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 77% (10/13) each. No treatment related deaths were observed. The dose and schedule of therapy remained constant in all but three patients: One patient required a 25% dose reduction after cycle 3 followed by another 25% reduction after cycle 11 due to drug induced marrow suppression, one patient required a 25% dose reduction after cycle 2 due to drug induced marrow suppression, and one patient required and tolerated a 25% dose escalation to recapture a CR after cycle 15. CONCLUSION This interim analysis suggests that the administration of subcutaneous azacitidine in an accelerated dosing schedule to elderly patients with acute myelogenous leukemia is a feasible and well-tolerated alternative to standard induction chemotherapy. Disclosures: Benjamin: Celgene Corporation: Research Funding. Off Label Use: Use of azacitidine in AML.. Rossetti:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Sahovic:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Abdulhaq:Celgene Corporation: Research Funding. Shadduck:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Lister:Celgene Corporation: Research Funding.

Bendamustine in the Treatment of Chronic Lymphocytic Leukemia -Consistent Superiority Over Chlorambucil in Elderly Patients and Across Clinically Defined Risk Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2367-2367 ◽  
Author(s):  
Wolfgang Ulrich Knauf ◽  
Toshko Lissitchkov ◽  
Ali Aldaoud ◽  
Anna Liberati ◽  
Javier Loscertales ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Remission Rate ◽  
Risk Groups ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Response To Treatment ◽  
Open Label ◽  
Significant Difference ◽  
Binet Stage

Abstract Abstract 2367 Poster Board II-344 Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies. Chronic lymphocytic leukemia (CLL) is a disease of the elderly, and presents with a variety of clinical characteristics which influence the prognosis. We analyzed tolerability and efficacy of bendamustine (BEN) in comparison to chlorambucil (CLB) in clinical risk groups defined by age and specific indicators of disease activity. Patients and Methods: The efficacy and safety of BEN and CLB have been compared in a randomized, open-label, multicenter, phase III trial in patients with previously untreated advanced (Binet stage B/C) CLL. Patients were randomized to receive BEN (100 mg/m2 on days 1 + 2) or CLB (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The primary endpoints were overall remission rate (ORR), which was defined as complete or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis, while 312 were evaluable for safety. Median age was 64 years (35 to 78). The median number of treatment cycles was 6 in both study arms, regardless of an age above or below 65 years. The median observation time was 35 months. ORR was significantly higher with BEN than with CLB (68% versus 31%, P<0.0001). The median PFS was 21.6 months with BEN and 8.3 months with CLB (P<0.0001). So far, there is no difference in OS (median not reached with BEN versus 65.4 months with CLB; p = 0.16). No significant difference in the remission rates became apparent when comparing patients below and above the age of 65 years (ORR 71.6 % versus 63.5 % with BEN, p>0.3; and 28.4 % versus 32.5 % with CLB, p>0.6). PFS was not influenced by age above 65 years, stage of disease (Binet stage B versus C), or elevated LDH. However, patients without B symptoms had a longer median PFS with BEN than those patients with B symptoms (30.4 months versus 17.7 months; p<0.0001), whereas median PFS was not affected by the presence of B symptoms in patients with CLB (8.9 months in both patient groups). Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil in the elderly and across clinically defined major risk groups, even in the presence of B symptoms. BEN should be considered as first-line chemotherapy for patients with advanced CLL. Disclosures: Knauf: mundipharma: Consultancy, Honoraria; cephalon: Consultancy, Honoraria. Klein:mundipharma: Consultancy, Honoraria. Merkle:mundipharma: Consultancy, Honoraria. Montillo:mundipharma Italy: Consultancy, Research Funding.

Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4085-4085
Author(s):  
M. Saunders ◽  
E. Van Cutsem ◽  
R. Wilson ◽  
M. Peeters ◽  
R. Smith ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Colorectal Adenocarcinoma ◽  
Day Treatment ◽  
Primary Objective ◽  
Phase Iii ◽  
Preliminary Evaluation ◽  
Related Complication ◽  
Open Label ◽  
Once Daily ◽  
Grade 3

4085 Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m2 1.5-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46–48-hr i.v. infusion). If <2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.

Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8586-8586
Author(s):  
D. S. Siegel ◽  
D. M. Weber ◽  
C. S. Mitsiades ◽  
M. A. Dimopoulos ◽  
J. L. Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Combination Methods ◽  
Novel Drug

8586 Background: Novel drug combinations may improve patient outcome in relapsed/refractory multiple myeloma (MM), which remains especially challenging to treat. Preclinical studies suggest that the histone deacetylase inhibitor vorinostat may have synergistic potential when combined with lenalidomide and dexamethasone. This phase I, multicenter, open-label study evaluated vorinostat plus lenalidomide and dexamethasone in patients (pts) with relapsed or refractory MM. The primary objective was to determine the maximum tolerated dose (MTD); other endpoints included overall safety and tolerability, as well as activity of the combination. Methods: Pts aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels ( Table ) using a standard 3+3 design for ≤8 cycles. Barring dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. Response was assessed, and adverse events (AEs) were recorded. Results: Of 12 pts accrued to date, 11 (92%) have experienced ≥1 AE, with drug-related AEs reported by 6 pts (96% ≤Grade 2). The most common drug-related AEs (each in 4 pts) were fatigue and thrombocytopenia. Serious AEs in 2 pts (17%) were not considered drug-related. No pts discontinued due to AEs, and no DLT has been observed to date. Dose escalation to dose level (DL) 4 was achieved as no DLTs were observed in DLs 1–3. The MTD has not yet been reached. Of 11 pts evaluable for efficacy, best responses include: complete response in 1 pt, partial response in 2 pts, minimal response in 2 pts, and stable disease in 3 pts; 3 pts had progressive disease (PD). Currently, 9 pts remain on treatment, with 3 pts discontinuing treatment due to PD. Conclusions: These preliminary data suggest that vorinostat with lenalidomide and dexamethasone represents a well tolerated and active novel oral combination therapy for the treatment of relapsed/refractory MM. [Table: see text] [Table: see text]

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