Median Dose Intensity Research Articles

XELIRI regimen plus continuous treatment with bevacizumab is well-tolerated and effective in metastatic colorectal cancer patients in a second-line setting involving the sequential administration of XELOX and XELIRI.

The aim of the present study was to present a retrospective review of 42 metastatic colorectal cancer (mCRC) patients treated using the XELIRI regimen as second-line chemotherapy during the period between 2010 and 2012. Patients were treated with capecitabine, 1,600 (≥65 years) or 2,000 mg/m2 (<65 years), on days 1-15, 200 mg/m2 irinotecan (CPT-11) on day 1, with or without 7.5 mg/kg bevacizumab on day 1 and every 21 days. A total of 21 patients underwent XELIRI and 21 underwent XELIRI plus bevacizumab treatment. Fifteen patients received continuous administration of bevacizumab in the first- and second-line settings [bevacizumab beyond progression (BBP)+], whereas 27 patients did not receive the treatment (BBP-). Forty patients (95.2%), including all the patients in the BBP+ group, received sequentially administered XELOX and XELIRI regimens from the first- to the second-line setting. The disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were compared between the BBP- and BBP+ groups. The median relative dose intensity was similar (93.9% for capecitabine and 96.3% for CPT-11 in the BBP- group vs. 94.8% for capecitabine and 91.5% for CPT-11 in the BBP+ group). The DCR was 25.9% in the BBP- and 66.6% in the BBP+ groups (P=0.020). The median PFS was 3.5 months in the BBP- and 7.2 months in the BBP+ groups (P=0.028). The BBP+ group exhibited a higher median OS time compared to the BBP- group (12.5 months in the BBP- group vs. not reached in the BBP+ group; P=0.0267). The most common grade 3/4 adverse event (n≥20) was hypertension observed in the BBP+ group [three patients (20%)]: these three patients were well-controlled with a single antihypertensive drug. Treatment with sequentially administered XELOX and XELIRI regimens did not aggravate adverse events in the 40 patients. The results showed that the XELIRI regimen, involving continuous treatment with bevacizumab, was well-tolerated and effective as a second-line chemotherapy and sequentially administering XELOX and XELIRI was feasible and manageable for patients with mCRC.

Estimation of drug cost avoidance (DCA) and pathology cost avoidance (PCA) through participation in NCIC clinical trials group (NCIC-CTG) phase III clinical trials in Canada.

6560 Background: Cost avoidance (CA) occurs when, due to the provision of a drug therapy (DCA) or a pathology test (PCA) via trial participation, payment for standard treatment or testing is not required. The aim of this study was to estimate the total DCA and PCA for Canadian patients (pts) enrolled in NCIC-CTG conducted phase 3 trials. Methods: Phase 3 trials that had completed accrual and resulted in DCA or PCA were identified. PCA was calculated based on the number of pts screened and test cost. DCA was estimated based on pts randomized, protocol dosing regimen, drug cost, median dose intensity and median duration of therapy. If this information was incomplete, assumptions were made based on published literature. Costs for Canadian pts accrued are presented in Canadian dollars. No adjustment was made for inflation. Results: From 1999-2011, 4 trials resulted in PCA (1,479 pts) and 17 trials resulted in DCA (3195 pts). Total PCA was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). Total DCA was estimated at $27,935,957, of which targeted therapy comprised 42.6% of DCA (5 trials). The combined PCA and DCA was $32,130,806. Conclusions: Over the time period studied, these NCIC-CTG trials resulted in total CA (PCA and DCA) of approximately $7514/pt. Although not all trials lead to CA, these savings should be taken account when considering the financial impact of conducting clinical research. Trial (drug with CA) Mean DCA per pt ($) Total DCA for trial ($) CO.13 (irinotecan) 10,565 1,595,249 CO.20 (cetuximab) 22,588 7,544,519 CRC.2 (oxaliplatin) 13,665 3,689,425 CRC.5 (bevacizumab) 17,430 1,115,520 PA.2 (5FUFA) 93 3,993 MA.27 (exemestane, anastrazole) 9,034 9,519,856 MA.31 (trastuzumab) 31,784 1,239,595 MAC.1 (CMF/AC) 535 6,959 MAC.4 (tamoxifen) 639 21,000 MAC.5 (tamoxifen) 639 39,319 MAC.7 (anastrazole) 2,005 88,209 REC.1 (interferon) 4,290 68,643 OV.16 (paclitaxel) 3,011 710,586 OV.17 (paclitaxel) 4,996 169,858 HN.6 (cisplatin) 90 14,391 LY.12 (rituximab, cytarabine) 6,660 2,104,412 BRC.3 (etoposide) 1,106 4,423

First safety results of an international phase II study evaluating oral vinorelbine as a single agent as first-line chemotherapy for metastatic breast cancer patients with bone metastases (NorBreast-228 trial).

1048 Background: Oral chemotherapy (CT) is an attractive treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by a hormone therapy. In our phase II study, we evaluated the role of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. In this abstract, first safety results of this trial are presented. Methods: Main eligibility criteria included: age ≥18 years, documented bone involvement previously untreated by CT, hormone receptor positive disease previously treated by at least one hormone therapy, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment. Results: Main pts characteristics in the full population were (n=70): median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior hormone therapy 100% (53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.5 months (range 0.9-18.3), median number of cycles: 6 (range: 1-18);61% of pts received at least 6 cycles, 37% of ptsreceived more than 6 cycles and 29% received at least 9 cycles; median relative dose intensity: 83.5%; dose escalation was performed in 79% ofpts.Grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, neutropenic infection 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusions: In this particular population of metastatic pts, with hormone receptor positive disease and bone involvement, OV showed an optimal safety profile. These data shows that OV is a well tolerated first-line CT option in this setting, allowing prolonged active treatment in non-progressing pts.

A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin administration.

The aim of this study was to systematically review the literature on the influence of oxaliplatin administration (e.g. cumulative dose, dose intensity, number of cycles and combination regimen) on the long-term prevalence of oxaliplatin-induced peripheral neuropathy (O-IPN) at least 12 months after termination of chemotherapy. A computerized search of literature on databases PubMed and Cochrane was performed. Published original articles were included if they reported about long-term O-IPN and gave concomitant information about oxaliplatin therapy given to the patients. All articles were assessed for quality. We included 14 articles (n=3,869 patients), and the majority of these studies were of high quality. All included patients who were treated for colorectal cancer, mainly with oxaliplatin in combination with 5-fluorouracil/leucovorin. Median cumulative doses and dose intensity varied between 676 and 1,449 mg/m2 and 30.8 and 42.6 mg/m2/week, respectively. Neuropathy assessment differed between studies, and the National Cancer Institute-Common Terminology Criteria (NCI-CTC) was used most often. The degree of neuropathy ranged from grade 0 to 3. Only six studies directly assessed the relationship between oxaliplatin administration and neuropathy. Of these studies, five did find a relation between neuropathy and higher cumulative dose, while one study did not find a relation. O-IPN is still present in a great amount of patients in ≥12 months after termination of therapy. A higher cumulative dose is likely to have an influence on the development of long-term O-IPN. More studies are needed that assess long-term neuropathy and oxaliplatin administration by means of validated neuropathy assessments.

Phase II trial of S-1 plus split cisplatin (SSP) in patients with advanced gastric cancer (HGCSG0702): Final report.

113 Background: On the basis of SPIRITS trial, S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with advanced gastric cancer (AGC) in Japan (Koizumi W, et al. Lancet Oncol, 2008). However, conventional S-1 plus cisplatin (60mg/m2) regimen requires hospitalization for hydration. Therefore, we conducted phase II trial of S-1 plus split Cisplatin (SSP) for outpatient chemotherapy. Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 75, ECOG performance status (PS) of 0 to 1; adequate organ function; and written informed consent. S-1 (40 mg/m2) was given orally, twice daily for 21 days, and cisplatin (30 mg/m2) was given intravenously on day 1 and 15, followed by 2-week rest period, within a 5-week cycle. Primary endpoint was the response rate (RR), and secondary endpoints were progression-free survival, overall survival, safety profile, and non-hospitalized survival. Results: Between Mar 2008 and Mar 2012, 40 pts were enrolled. Patients characteristics were as follows: median age 63 years (range 41-75), Male: female 30:10, PS 0:1 33:7, diffuse: intestinal 23:17. Median number of cycles was 3. The main grade 3-4 AE were neutropenia (37.5%), anemia (30%), anorexia (30%) and fatigue (15%). These toxicities were safely managed. The median relative dose intensity of S-1 was 0.782, and cisplatin was 0.824. Response rate was 57.5% (95%CI 42.2-72.8%) and disease control rate was 90.0%. Median progression-free survival was 6.1 months (95%C.I. 3.0-9.1 months) and median survival time was 15.8 months (95%C.I. 12.7-18.8 months). Conclusions: SSP showed comparable tolerability and efficacy to SPIRITS trial. In addition, most patients underwent the treatment without hospitalization. SSP may be one of practical alternatives for AGC.

Tolerability study of adjuvant modified FOLFOX6 treatment in curatively resected stage II/III colon cancer (JFMC41-1001-C2: JOIN trial).

530 Background: Adjuvant FOLFOX is a widely accepted standard regimen for resected colon cancer. The incidence of grade ≥ 3 peripheral sensory neuropathy (PSN) was 12.4% and 5.7% in Western MOSAIC and Eastern MASCOT (outside Japan) trials, while that of grade ≥ 3 allergic reactions (AR) was 2.9% and 3.1%, respectively. JOIN Trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese patients (UMIN ID: 000004443). Methods: Twelve cycles of mFOLFOX6 were given to patients fitting the following criteria, which were the same as those of MOSAIC: stage II/III resected colon cancer, PS of 0-1, 20 years or older, starting FOLFOX within 7 weeks of surgery, and adequate organ function. The primary endpoint was the incidence of PSN persisting for at least 8 days that interfered with daily activities and that of grade ≥ 3 AR. Target sample size was 800, assuming the expected incidence of grade ≥ 3 PSN and grade ≥ 3 AR would be 12.0% and 3.0%, and the two-sided 95% confidence interval (CI) would not include the corresponding threshold levels (16.5% for PSN and 6.5% for AR) with a 95% probability. Results: From Nov 2010 to Mar 2012, 882 patients were enrolled at 198 institutions. The safety data was analyzed in 828 patients whose data were finalized out of 848 patients received mFOLFOX6, and patient characteristics included: median age of 64 years (21-83); Male/ Female: 444/384; PS 0/1: 776/52; colon/rectosigmoid: 633/195; and stage IIA/IIB/IIC/IIIA/IIIB/IIIC: 96/33/23/61/437/178. The incidence of persistent PSN was 3.3% (95% CI: 2.2%-4.7%), while that of grade ≥ 3 AR was 1.7% (95% CI: 1.0%-2.8%), and the primary endpoint was met. Only grade ≥ 3 neutropenia showed a ≥ 10% incidence (28.7%). The incidence of grade ≥ 3 PSN was 5.8% and interstitial pneumonitis was observed in one case. There was no treatment-related death. The median number of cycles of chemotherapy was 12, and the completion treatment rate was 67.0%. The median total dosage of oxaliplatin (L-OHP) was 811.1 mg/m2. The median relative dose intensity of L-OHP, fluorouracil (FU) bolus and FU infusion were 90.0%, 76.9% and 81.7%, respectively. Conclusions: Adjuvant mFOLFOX6 is tolerable in Japanese patients with colon cancer. Clinical trial information: UMIN000004443.

Retrospective Comparison of CAPOX and FOLFOX Dose Intensity, Toxicity, and Clinical Outcomes in the Treatment of Metastatic Colon Cancer

The treatment of metastatic colon cancer (mCC) utilizes either combination therapies or sequential monotherapy followed by combination therapy in subsequent lines of treatment. Patients often receive therapy consisting of oxaliplatin with intravenous 5-fluoruacil (5-FU) (FOLFOX) or oral capecitabine (CAPOX). A retrospective analysis was performed comparing median dose intensity (MDI), overall survival (OS), progression-free survival (PFS), and toxicity profiles of these two regimens in mCC. One hundred twenty-two mCC patients (pts) received either FOLFOX6 (n = 46) or CAPOX (n = 76). Age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis were balanced between groups. MDI was compared by calculating a percent of target dose achieved in the average cycle for each patient and taking the median of this value. Oxaliplatin MDI trended towards being lower in those treated with CAPOX compared to FOLFOX (87.5 vs 93 %, p = 0.0874), and capecitabine (CA) MDI was significantly lower than 5-FU (82.0 vs 100 %, p < 0.0001). There was a trend to more dose-limiting toxicities (DLTs) in pts treated with CAPOX (68.42 vs 54.35 %, p = 0.1268), and grade ≥ 2 toxicities were more frequent in CAPOX-treated pts (38.16 vs 15.22 % of patients, p = 0.0079). Survival analysis demonstrated trends towards improved median OS (9.86 vs 7.46 months, p = 0.1183) and median PFS (4.34 vs 3.33 months, p = 0.1674) with CAPOX. In multivariate analysis, CAPOX was associated with improved OS (p = 0.0156, hazard ratio (HR) 0.559) and disease-free survival (DFS) (p = 0.0094, HR 0.549). Patients treated with CAPOX received lower doses of oxaliplatin and fluoropyrimidine compared to FOLFOX and had toxicities of higher grade but did not have worsened clinical outcomes.

Feasibility Study for Biweekly Administration of Cisplatin plus Vinorelbine as Adjuvant-Chemotherapy for Completely Resected Non-Small Cell Lung Cancer Patients in a Japanese Population

Purpose: To evaluate the feasibility of biweekly administration of cisplatin and vinorelbine as adjuvant chemotherapy for patients with completely resected non-small cell lung cancer (NSCLC). Patients and Methods: This was a single-arm, single-institutional study. Patients with completely resected NSCLC (p-Stage IB-IIIA) with no previous chemotherapy or radiotherapy were eligible. Simon’s optimal two-stage design was applied. Both cisplatin (50 mg/m2) and vinorelbine (25 mg/m2) were given on days 1 and 15, every 28 days. The primary endpoint of this study was the feasibility of this combination in the four cycles of treatment. Results: Twenty patients (19 lobectomies and 1 pneumonectomy) were enrolled in this study. 10 (50%) of patients had grade 3/4 neutropenia, and 3 (15%) had grade 3/4 anemia. Severe non-hematologic toxicities were uncommon in this series. No treatment-related death was encountered. 18 (90%) patients completed the planned 4 cycles of chemotherapy. The median intensity was 24.3 (range 18.1 to 25) mg/m2/week with an average of 23.6 (21 - 25) mg/m2/week cisplatin and 12.5 (range 10 to 12.5) mg/m2/week with an average of 12.3 (10 - 12.5) mg/m2/week vinorelbine. The median relative dose intensity of cisplatin was 97.5% (range 72.5% to 100%) with an average of 94.6% (72.5% - 100%) and that of vinorelbine was 100% (range 80% to 100%) with an average of 97.8% (80% - 100%). Conclusion: This regimen is feasible in the treatment of patients with completely resected NSCLC. A phase III trial is warranted to assess the efficacy of this regimen at promoting survival and preventing recurrence.

Abstract P4-12-09: Results from a phase 2a study of trastuzumab emtansine, paclitaxel, and pertuzumab in patients with HER2-positive metastatic breast cancer

Abstract Introduction The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged PFS and OS vs standard therapy in a phase 3 study of patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with H and a taxane. Preclinical data suggest synergy when T-DM1 is combined with paclitaxel (T) or pertuzumab (P). In the phase 1b study TDM4652g, the maximum tolerated doses of T-DM1 + T ± P were defined. Here we present results from the phase 2a expansion, which further explored feasibility and safety. Methods TDM4652g is a phase 1b/2a open-label study of pts with HER2-positive locally advanced or MBC. Pts had no prior T-DM1 or P, no baseline peripheral neuropathy (PN; phase 2a only), and had LVEF ≥50%. Pts in phase 2a were randomized to T-DM1 3.6 mg/kg q3w + T 80 mg/m2 qw ± P 840 mg loading dose [LD], then 420 mg q3w. The primary objective, feasibility, was assessed by the percent of evaluable pts receiving ≥12 doses of T within 15 weeks of cycle 1, day 1, and those receiving 12 consecutive weeks of T. Results Forty-four pts were enrolled (T-DM1 + T, n = 22; T-DM1 + T + P, n = 22); the data snapshot date was May 23, 2013. Median age was 52.5 years (range, 35–81); median number of prior agents for MBC was 6 (range, 0–12). 43 (98%) pts had previously received H, and 36 (82%) pts had received taxane therapy. Median dose intensities were T-DM1, 94% (range 54–105); T, 50% (range 9–100) and P, 100% (range 67–100). 2 pts were not evaluable for feasibility (progressive disease [PD] before receiving 12 doses of T). 21/42 (50%) pts received ≥12 doses of T within 15 weeks; 6/42 (14%) pts received 12 consecutive doses by week 12, and 33/42 (79%) pts received ≥8 doses within 12 weeks. Grade 3/4 adverse events (AEs) were reported for 18 (82%) and 17 (77%) pts in the T-DM1 + T and T-DM1 + T + P groups, respectively (see Table for AEs and best responses). Ten pts discontinued early due to PD (n = 6), PD-related death (n = 2), AEs (n = 1), or withdrawal from the study (n = 1). 21 pts discontinued T due to AEs, most commonly PN (n = 12). Grade 3/4 AEs occurring in &amp;gt;1 patientAE, n (%)All patients (N = 44)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw (n = 22)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw + P 840 mg LD, 420 mg q3w (n = 22)Neutropenia10 (23)6 (27)4 (18)Peripheral neuropathy9 (20)3 (14)6 (27)Fatigue6 (14)3 (14)3 (14)Thrombocytopenia6 (14)5 (23)1 (5)Anemia3 (7)2 (9)1 (5)Abdominal pain2 (5)2 (9)0Decreased hemoglobin2 (5)1 (5)1 (5)Muscosal inflammation2 (5)1 (5)1 (5)Muscular weakness2 (5)02 (9)Nausea2 (5)1 (5)1 (5)Best response,* n (%)CR2 (5)1 (5)1 (5)CR confirmed1 (2)1 (5)0PR27 (61)13 (59)14 (64)PR confirmed8 (18)3 (14)5 (23)SD10 (23)6 (27)4 (18)PD3 (7)1 (5)2 (9)*At any time point with responses ordered CR&amp;gt;PR&amp;gt;SD&amp;gt;PD. Conclusions Overall, 50% of pts received ≥12 doses of T within 15 weeks. Adding P to the combination of T-DM1 + T did not appear to increase the incidence of grade 3/4 AEs. Data support further investigation of T-DM1 + T ± P in larger studies in early breast cancer. Final data from all phase 2a patients will be available for the full report. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-09.

Impact Of Route Of Bortezomib (B) Administration On Dose Intensity and Time To Dose Reduction In Previously Untreated Patients (Pts) With Multiple Myeloma (MM)

BackgroundIn the US and EU, B is approved for the treatment of MM using either SC or IV administration. The MMY-3021 study in relapsed/refractory MM pts demonstrated the non-inferiority of SC vs IV B (in terms of response rate after 4 cycles of treatment) and some improvements in the safety profile of B with SC vs IV administration, including lower rates of peripheral neuropathy (Moreau et al, Lancet Oncol 2011). Therefore, SC administration may improve the tolerability of B, potentially impacting patterns of B treatment. The aim of this non-interventional study was to analyze the impact of initial route of B administration on time to dose reduction and dose intensity delivered to pts. MethodsIn this retrospective observational cohort study, previously untreated MM pts aged ≥18 yrs who initiated B-based treatment within the McKesson Specialty Health/US Oncology Network between January 1, 2011 and November 30, 2012 and had ≥2 MM-related visits and ≥6 months of follow-up through May 31, 2013 were included. Pts enrolled in randomized clinical trials and/or diagnosed with other cancer were excluded. Data were collected via programmatic data queries of the iKnowMed (iKM) electronic health records (EHR) database. In the base case analysis, the intent-to-treat (ITT) approach was used; baseline pt demographics and disease characteristics, and B dosing patterns (including dose, dose intensity [normalized to dose intensity per month due to asymmetric follow-up periods between groups], rate of dose reduction in the first 16 weeks of treatment, and time to dose reduction) were compared between pts initially receiving SC vs IV B. Some pts switched route of B administration, and sensitivity analyses were conducted using only pts who did not switch. Non-parametric tests were used to test variables described here. Results1058 MM pts were included, of whom 652 (62%) initially received IV B, and 406 (38%) initially received SC. Baseline characteristics were generally similar between the IV and SC groups: mean (SD) age was 66 (12) yrs and 67 (12) yrs, with 56% and 60% of pts aged ≥65 yrs, 56% and 54% were male, mean (SD) body mass index was 28.6 (7.0) and 28.1 (5.8), and 18%/27%/44% and 22%/25%/42% had ISS stage I/II/III disease, respectively. Karnofsky performance status (KPS) was poorer in the IV vs SC group, with 8%/30%/26%/27% vs 15%/31%/26%/25% having a KPS of 100/90/80/≤70 (p=0.0164), and the rate of general comorbidities (weight loss, anorexia, dehydration, diarrhea, dyspnea, hyper-/hypovolemia, malaise, nausea, pain, sepsis) at baseline was higher in the IV vs SC group (21% vs 15%, p=0.0178). The groups were well balanced in terms of other comorbidities, practice region, payer status (Medicare, private, other), and MM subtypes. Treatment regimens differed between the IV and SC groups (p<0.0001), and included B+dexamethasone (62% vs 49%) plus lenalidomide (24% vs 28%) or cyclophosphamide (7% vs 17%), B-melphalan-prednisone (4% vs 4%), or other combinations (2% vs 2%). Median dose intensity with IV and SC B was 5.78 mg/m2/month (range 1.05–10.19) and 6.09 mg/m2/month (1.26–11.03), respectively (p=0.02). Overall, 20% vs 14% of pts receiving IV vs SC B had dose reductions in the first 16 weeks (p=0.017). Kaplan-Meier distributions of time to dose reduction are shown in the figure. Among pts with dose reductions, median time to dose reduction with IV vs SC B was 50 days (95% CI: 41, 59) vs 58 days (95% CI: 37, 63), p=0.0332. In total, 243 (23%) pts switched route of administration during treatment – 216 (89%) from IV to SC and 27 (11%) from SC to IV. In analyses excluding these pts, B dose intensity remained lower with IV vs SC (median 5.88 mg/m2/month [range 1.05–10.19] and 6.18 mg/m2/month [1.26–11.03], p=0.0456), rate of dose reductions remained higher (18% vs 13%, p=0.0514), and time to dose reduction remained shorter (median 49 vs 58 days, p=0.0163). [Display omitted] ConclusionsThese data indicate that initiation of therapy with SC B is associated with a higher dose intensity per month, fewer dose reductions within 16 weeks, and longer time to dose reduction compared with IV B in the front-line MM setting. When pts who switched route of B administration were excluded from the analyses, similar results were found. As these data continue to mature, further analyses will be required to evaluate in more depth the corresponding clinical outcomes by route of B administration. Disclosures:Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Chen:McKesson Specialty Health: Employment. Dhanda:McKesson Specialty Health: Employment. Rembert:McKesson Specialty Health: Employment. Ba-Mancini:Millennium: The Takeda Oncology Company: Employment. Ma:Millennium: The Takeda Oncology Company: Employment. Zhu:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Niculescu:Millennium: The Takeda Oncology Company: Employment.

Nilotinib Following Molecular Suboptimal Response (SoR) To Imatinib In Japanese Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP): 12 Month Follow-Up From The SENSOR Study

BackgroundNilotinib has shown superiority over imatinib for treating pts with newly diagnosed CML-CP. Additionally, pts who are resistant or intolerant to imatinib can often achieve improved responses by switching to nilotinib. However, the value of switching pts to nilotinib due to molecular SoR on imatinib is not well characterized. The Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR) was therefore conducted to evaluate the efficacy and safety of nilotinib 400 mg BID in pts with CML-CP with SoR to frontline imatinib. Here, we present results of a planned 12-mo interim analysis. MethodsSENSOR (NCT01043874) is an open-label, multicenter, phase IV study. Adult pts with CML-CP in complete cytogenetic response but not in major molecular response (MMR; defined as BCR-ABL ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo on frontline imatinib (SoR as defined by 2009 European LeukemiaNet criteria) were eligible to enroll and switch to nilotinib 400 mg BID. Molecular responses were assessed prior to enrollment, at 1, 2, and 3 mo and every 3 mo thereafter. Mutational analyses were performed at baseline (BL) and at end of study in all pts, every 3 mo in pts with BL mutations, and with any ≥ 5-fold increase in BCR-ABL from the lowest level in pts not in MMR. All of these assays were done at a single central laboratory. The primary endpoint was the rate of MMR at 12 mo. Planned enrollment was 45 pts in order to provide a ≥ 25% lower limit of the 95% CI with an expected MMR rate of 40%. Planned follow-up was 24 mo. ResultsPlanned enrollment of 45 pts was completed between Dec 2009 and Feb 2012. Median age of pts was 47 years (range, 19-80). Pts had received imatinib for a median of 23.0 mo (range, 17.0-103.3) at a median daily dose of 400 mg (range, 297-628). Median BL BCR-ABL/ABL ratio was 0.24% (range, 0.11-3.49). At the cutoff date, 19 pts (42%) had completed the study (24 mo follow-up), and 21 (47%) had nilotinib treatment ongoing. Median nilotinib duration was 19.1 mo (range, 0.1-22.7) and median dose intensity was 733 mg/day (range, 183-800). Five (11%) pts discontinued from study treatment for the following reasons: adverse events (AEs; n = 2), disease progression (n = 1), withdrawal of consent (n = 1), and administrative problems (n = 1).At 12 mo, the MMR rate was 51.1% and the median BCR-ABL/ABL ratio was 0.10% (range, ≤ 0.0032-1.62). The cumulative rate of MMR by 12 mo was 66.7%. Among 34 pts with MMR at any time, median time to first MMR was 2.28 mo. No pt who achieved MMR had confirmed loss of MMR (BCR-ABLIS > 0.1% with a ≥ 5-fold increase in BCR-ABL transcripts from the lowest level achieved on study in 2 consecutive samples) by the cutoff date (Table). Two pts (4.4%) achieved BCR-ABLIS ≤ 0.0032% at 12 mo.BCR-ABL mutations were detected at BL in 5 pts (E255K, E459K + exon 8/9 35 base pair insertion, Q252R, M244V, and exon 7 deletion), all of whom achieved MMR on nilotinib. Mutations were identified during treatment in 13 pts, 2 of whom had the same mutation at BL; 10 of these pts achieved MMR. One pt developed a T315I mutation, progressed at 5.4 mo, and died at 9.4 mo. These were the only reported events for progression-free survival and overall survival (1 each).The safety profile of nilotinib was consistent with previous studies. Drug-related AEs (any grade) occurring in ≥ 20% of pts included hyperbilirubinemia (53.3%), increased ALT (28.9%), headache (28.9%), hypophosphatemia (26.7%), rash (26.7%), and increased lipase (24.4%). Grade 3/4 newly occurring/worsening abnormal hematology values were hemoglobin (6.7%), neutrophils (4.4%), platelet count (2.2%), and decreased total white blood cells (2.2%). Six pts had serious AEs (2 with suspected relation to study drug [anemia and erythema multiforme]). ConclusionsAfter switching to nilotinib, MMR was rapidly achieved in the majority of pts. These results support the clinical benefit of switching to nilotinib in pts with molecular SoR to imatinib. Disclosures:Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Miyamoto:Kyushu University Hospital: Employment. Kurokawa:Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Yamamoto:Novartis: Honoraria, Research Funding. Taniwaki:Novartis: Honoraria. Kimura:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Ohyashiki:Novartis: Honoraria, Research Funding. Kawaguchi:Novartis: Honoraria. Matsumura:Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Tsurumi:Novartis: Honoraria. Hino:Novartis: Research Funding. Tadokoro:Novartis: Guest speaker in a scientific meeting sponsored by Novartis Other. Hyodo:Hiroshima University: Employment. Kubo:Aomori Prefectural Central Hospital: Employment; Novartis: Honoraria. Kondo:Novartis: Employment. Amagasaki:Novartis: Employment. Kawahara:Novartis: Employment. Yanada:Novartis: Consultancy.

Final Results Of a Phase II Study Of Lenalidomide In Combination With Rituximab For The Treatment Of Indolent Non Follicular Non Hodgkin Lymphoma

BackgroundAdvanced-stage, relapsed indolent non follicular lymphomas (INFLs) have a relatively poor prognosis, with low complete response to conventional chemotherapy and short survival. Thus, there is a need for innovative treatment with high efficacy and a good safety profile. Lenalidomide (R®) is an immunomodulatory drug with a direct tumoricidal effect and action on T, NK and stromal cells that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab (R). To test the efficacy of R® combined with R (R2), we have conducted a multi center, open label phase II clinical trial in patients (pts) with relapsed INFL. MethodsEligible pts must have indolent non follicular B-cell lymphoma relapsed after at least 2 but less than 4 prior lines of R-containing immuno-chemotherapy with measurable disease. Patients received oral R® 20 mg once daily on days 1-21. R is administered at a dose of 375 mg/m2 at day 14 of every course. Treatment is repeated every 28 days for up to 6 courses. The primary objectives of the study were to evaluate the antitumor activity of oral R® when given in combination with R and to assess the safety of R2 regimen evaluated by standard criteria (CTC-NCI 3.0). The secondary objectives were the evaluation of progression free survival (PFS) and overall survival (OS). ResultsFrom July 2010 and March 2013, 44 pts entered the protocol. Six out of 44 pts were excluded from this analysis as 2 withdrew informed consent and 4 refused to start treatment immediately after signing the informed consent. Enrolled pts (38 cases) had: 18 small lymphocytic lymphoma (SLL), 12 lymphoplasmacytic lymphoma (LPL) and 8 marginal zone lymphoma (MZL). Median age was 68 years (51-75) and 58% were male. LDH value was increased in 21% of pts and β-2-microglobulin in 75%; 51% of pts had Hb<12 g/dL and 66% had bone marrow involved (median infiltrating 40%). Of the 38 pts, 7 achieved a complete remission and 14 a partial remission with an ORR of 55%. Seven pts had a stable disease and 5 a lymphoma progression. In general, the regimen R2 was relatively well-tolerated. Grade 3-4 hematological events were observed in 22 pts. The most common adverse events were neutropenia (58%), thrombocytopenia (11%), anemia (10%) and infection (10%). Grade 3-4 non hematological events were fever (5%), dyspnea (3%), allergic reaction to R (3%), renal failure (3%) and erythema (3%). Growth factors were administered in 58% of pts. The median dose intensity was 0.94 for R and 0.98 for R®. With a median follow-up of 19 months (range 1-43), overall 6 pts died, 5 for lymphoma progression and 1 for treatment related toxicity. The 2-years OS and the 2-years PFS were shown in Figure 1. Figure 2 shows the PFS by histology. The percentage of 2-years PFS (71%) for MZL appear impressive. [Display omitted] [Display omitted] ConclusionsThe chemo-free R2 scheme as treatment for relapse INFLs produces response in about 50% of pts and remission appear durable in pts with MZL. The toxicity profile of the combination is tolerable with manageable hematologic side effects. These results support the design of clinical trial with this chemo-free combination as first line treatment for INFLs, in particular for MZL. Disclosures:No relevant conflicts of interest to declare.

Safety and Efficacy Of Obinutuzumab (GA101) Plus CHOP Chemotherapy In First-Line Advanced Diffuse Large B-Cell Lymphoma: Results From The Phase 2 Gather Study (GAO4915g)

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and has an aggressive natural history. Rituximab (R), a type I anti-CD20 monoclonal antibody (mAb), plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), has improved patient (pt) survival and established a new standard of care. Nonetheless, 35%–40% of pts will relapse during/after first-line treatment and of these, <25% are cured with second-line therapy. Thus, there is a medical need to further improve cure rates, particularly in the first-line setting. Obinutuzumab (GA101; G) is a novel, glycoengineered type II anti-CD20 mAb with increased direct cell death and antibody-dependent cell-mediated cytotoxicity relative to R. Clinical activity of G in R/R DLBCL was confirmed in phase 1/2 studies. Phase 1b studies in indolent lymphoma found G-CHOP to be safe and effective. GATHER is a phase 2, open-label, multicenter study examining the safety and efficacy of G-CHOP in the first-line treatment of advanced DLBCL. MethodsPts with untreated CD20-positive DLBCL, clinical stage (CS) IIX (mass>7.5 cm), III, and IV, and International Prognostic Index (IPI) ≥2 (or any IPI if bulky disease) with measurable disease were treated with standard CHOP (day [d]1, 21-day cycles [c] 1–6) and G (1000 mg intravenously [IV]; d1, 21-d c 1–8 plus additional doses on d8 and d15 of c1). Prophylactic GCSF was not mandatory but allowed per ASCO guidelines. After the safety of regular-infusion G was established in the first 20 pts, Shorter Duration of Infusion (SDI) of G (SDI 120 min and SDI 90 min) was tested. Disease responses were assessed using FDG-PET and CT scans, according to the Cheson 2007 criteria, 6–8 weeks after completion of treatment. Efficacy endpoints were investigator- and independent central review facility-assessed overall response rate (ORR) and complete response (CR). G-CHOP Safety was measured by the incidence and severity of adverse events (AEs) and serious AEs and SDI safety by the incidence of grade (gr) 3/4 infusion-related (IR) AEs (any G-related AE during or within 24 h after infusion). Cell of origin and prognostic marker assessment was performed using mRNA (fluidigm microfluidic dynamic arrays) from baseline tumor samples. ResultsEighty pts were enrolled in 13 months: 59% males; median age 60.5 years (range, 24–80); CS IIX 14%, CS III 35%, CS IV 51%; IPI low risk/low-intermediate risk 54%, high-intermediate risk/high risk 46%. Most AEs were gr 1/2. Gr ≥3 and serious AEs with highest frequency are summarized (Fig). IR AEs were in 51 pts (64%), most commonly in c1d1 (48 pts). The majority of IR AEs were gr 1/2; only 2 gr 3 IR AEs occurred, both in c1 d1. There were no gr ≥4 IR AEs. 288 SDI infusions (120-min in 24, 90-min in 264) were administered and associated with 3 gr 1/2 IR AEs and no gr ≥3 IR AEs. G-CHOP was delayed >5 d in 3/79 (4%) in c2, 7/78 (9%) in c3, 8/78 (10%) in c4, 5/77 (6.5%) in c5, and 7/74 (9.5%) in c6. Early treatment discontinuation occurred in 11 pts; 5 for failure to resolve an AE in ≤14 d. The median overall dose intensity of chemo agents across all 6 cycles was 100% (range 17%–104%). The ORR was 66/80 (83%) (44/80 [55%] CR, 22/80 [28%] PR); 1 pt was not evaluable, and 4 had missing data. Nine pts had progressive disease at the end of treatment, and there were 3 deaths from disease progression. Response assessment by an independent central review facility and analysis of efficacy in prognostic molecular subgroups (including cell of origin) will be presented. ConclusionsG-CHOP was safely administered to pts with newly diagnosed DLBCL. Dose intensity of CHOP was maintained throughout treatment. Manageable, mild, and moderate IR AEs were frequent in the first cycle of G, but all pts continued the infusion after symptom resolution. Nonetheless, SDI of G was safe for all eligible pts. Neutropenia and febrile neutropenia appear to be the most important AEs. However, these could be addressed by prophylactic administration of G-CSF support. Preliminary efficacy is promising, but it is too early to evaluate progression-free and overall survival. The data provide further rationale for the ongoing randomized phase 3 study of G-CHOP vs R-CHOP in DLBCL.NCT01414855 [Display omitted] Disclosures:Zelenetz:Cancer Genetics: Scientific Advisor, Scientific Advisor Other; Genentech, GSK, Roche: Research Funding; GSK, Celgene, Cephalon, Gilead, Seattle Genetics, Sanofi-Avenits USA: Consultancy. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin's Lymphoma and other hematologic indications. Mobasher:Roche: Ownership of stock options, Ownership of stock options Other; Genentech: Employment. Costa:Genentech: Research Funding. Flinn:Genentech: Research Funding. Flowers:Celgene, Genentech, Oncology: Consultancy; Abbott, Celgene, Millennium/Takeda, Sanofi-Aventis, Spectrum, Janssen: Research Funding. Sandmann:Roche: Stock options, Stock options Other; Genentech, Inc.: Employment. Trunzer:F. Hoffmann-La Roche: Employment, Stock ownership Other. Vignal:F. Hoffmann-La Roche: Employment, Stock ownership Other.

MM-003 Phase 3 Study Of Pomalidomide In Combination With Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM): POM + Lodex Is Beneficial For Elderly Patients (> 65 Years of Age)

MM-003 Phase 3 Study Of Pomalidomide In Combination With Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM): POM + Lodex Is Beneficial For Elderly Patients (> 65 Years of Age)

Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer

IntroductionThis Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC).MethodsEligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0).ResultsNineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression.ConclusionsThe combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).

Temsirolimus in Daily Use: Results of a Prospective Multicentre Noninterventional Study of Patients with Metastatic Kidney Cancer

BackgroundTemsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis. ObjectiveThe aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC. Design, setting, and participantsMetastatic RCC patients treated with 25mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures. Outcome measurements and statistical analysisAll data were centrally analysed by an independent clinical research organisation. Results and limitationsThis interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79–100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0–23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2–5.6) and 11.6 mo (95% CI, 9.3–13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review. ConclusionsTEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.

Bi-weekly liposomal doxorubicin for advanced breast cancer in elderly women (≥70years)

We conducted a multicenter prospective trial to assess tolerability and activity of pegylated liposomal doxorubicin (PLD) in women ≥ 70 years with locally-advanced or metastatic breast cancer. All patients underwent Multidimensional Geriatric Assessment (MGA). Frail patients were excluded. Normal cardiac function was required for inclusion. A bi-weekly schedule of PLD at 20mg/mq was adopted. Thirty-two patients were enrolled with a median age of 78 years, 78.1% with visceral involvement, and 37.6% previously treated with chemotherapy for advanced disease. A mean of 7.8 cycles were delivered (range 1 to 20), with a median cumulative dose intensity of 8.9 mg/m(2)/week. Grade 3-4 toxicities were anemia (6.3%), palmar-plantar erythrodysesthesia (6.3%), mucositis (6.3%), infection (3.1%), and pulmonary embolism (3.1%). No cardiac events were registered. Causes of treatment interruption were maximal response (15.6%), progression (40.6%), refusal/loss to follow-up (28.1%), toxicities (9.4%), or other (6.3%). Response was obtained in 33.3% of 27 evaluable patients; median time to progression (TTP) was 10.3 months. MGA status (vulnerable vs. fit) did not have an impact on response, progression, and toxicity. Bi-weekly PLD is well tolerated in both fit and vulnerable patients, with an apparently fairly good response rate and TTP (possibly biased by subsequent endocrine therapy and loss to follow-up). Close observation of patients is recommended in order to avoid early refusal/loss to follow-up.

Feasibility and safety of dose-dense docetaxel after conventional epirubicin and cyclophosphamide as adjuvant treatment for early breast cancer patients

BackgroundAlthough dose-dense chemotherapy may reduce breast cancer recurrence and death, phase II studies show that dose-dense docetaxel is poorly tolerated following administration of dose-dense anthracycline-based chemotherapy mainly because of cutaneous toxicity. Material and methodsThis pilot study was designed to explore feasibility and safety of dose-dense docetaxel after conventional anthracycline-based therapy.Treatment consisted of sequential administration of 4 cycles of 3-weekly epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2), followed by 4 cycles of bi-weekly docetaxel with pelfilgrastim on day 2 of each docetaxel cycle. Two docetaxel dose levels were planned: 75 mg/m2 (D75) and 100 mg/m2 (D100). Patients could only be assigned to the higher docetaxel dose if no early treatment discontinuations due to toxicity were seen, and a median relative dose intensity of docetaxel >90% among the first 5 evaluable patients was achieved. ResultsFifty three patients received 4 cycles of epirubicin/cyclophosphamide (EC). Six patients withdrew from study before commencing docetaxel: four for toxicity, and two who declined further study participation.Eight patients, 2 in the first dose level and 6 in the second dose level, stopped treatment for toxicity after the first cycle of docetaxel and before densification. Therefore these events were not considered early treatment discontinuations. No patients required dose interruption after the second docetaxel administration. Overall 5 patients in the first dose level and 34 patients in the second dose level received 4 cycles of accelerated (dose-dense) docetaxel. No grade 3 or grade 4 toxicities occurred at the first dose level. No grade 4 toxicities occurred at the second dose level, while grade 3 toxicities occurring in >2 patients were myalgia and bone pain (5 and 8 patients respectively, 13% and 20%) and skin-nail toxicity (7 patients, 21%). No dose-reductions or significant treatment delays were required, translating to median relative dose intensity of 100% for docetaxel 75 mg/m2, and 99% for 100 mg/m2. ConclusionsAdministration of docetaxel 100 mg/m2 bi-weekly after conventional EC is feasible in selected early breast cancer patients. Lack of prior exposure to dose-dense anthracycline, as well as the use of stringent criteria implemented in the treatment protocol, might explain the improved safety profile and high treatment compliance observed in this study.

Dose reduction (DR) due to chemotherapy induced peripheral neuropathy (CIPN) in breast cancer (BC) patients (pts) in the neoadjuvant/adjuvant settings.

e20574 Background: CIPN is a common and potentially dose-limiting complication of many effective cytotoxic agents. Taxanes are the cornerstone of treatment in BC. Limited data are available regarding the prevalence and severity of DR due to CIPN following taxane use. Methods: Charts of 123 consecutive newly diagnosed BC pts treated with a taxane as part of standard neoadjuvant/adjuvant chemotherapy at the University of Maryland Greenebaum Cancer Center between 01/01/2008 and 12/31/2011 were reviewed. Treating physicians followed standard recommendations for DR. Results: Median age at diagnosis was 53 years (range, 32-78), 120 female/3 male, 48 Caucasian (C), 70 African-American (AA), 5 had a history of alcohol abuse, and 20 had a diagnosis of diabetes mellitus (DM). Seventy pts received docetaxel, 46 paclitaxel, 7 received both or nab-paclitaxel. Fifty (40%) pts required DR, with 21 (17%) due to CIPN and 29 (23%) due to other causes. The median relative dose intensity (received dose/planned dose) for the 21 CIPN-induced dose reduction pts was 88% (range, 62%-97%). A multivariable logistic regression model was used to compare pts who did and did not require DR based on the following possible risk factors: taxane received, DM, alcohol use, and race. Based on the effects estimated by statistical model, there was no difference between pts who did and did not undergo DR with regard to factors listed. However, diabetic pts were over twice as likely to require DR (OR = 2.4, 95% CI: 0.6-10.2, p=0.06). The univariable logistic regression model for 50 pts who had undergone DR revealed possible differences in developing CIPN between C and AA patients. The chances of DR due to CIPN are higher in AA pts (OR=4.3, 95% CI: 1.1-16.7, p=0.03). Pts who received paclitaxel are more likely to require DR due to CIPN than those treated with docetaxel (OR=10.4, 95% CI: 2.7-39.6, p=0.001). Conclusions: 1. CIPN-induced dose-reduction occurred in 17% of our study population. 2. The median relative dose intensity was 88%. 3. DM may increase the overall risk of dose reduction, and AA, paclitaxel therapy may confer a higher risk of CIPN-induced dose reduction.

Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): Landmark analysis of 4-year (y) data from ENESTnd.

7054^ Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up. Methods: Rates of major MR (MMR; BCR-ABLIS ≤ 0.1%), MR4.5 (BCR-ABLIS≤ 0.0032%), progression to AP/BC, overall survival (OS), and progression-free survival (PFS) in pts in the NIL 300 mg twice daily (BID; n = 282) and IM 400 mg once daily (QD; n = 283) arms of ENESTnd were evaluated based on 3-mo BCR-ABL levels (≤ 10% vs &gt; 10%). Results: More pts treated with NIL than IM achieved BCR-ABL ≤ 10% at 3 mo (91% vs 67%; Table). Other factors associated with MR at 3 mo included Sokal risk, spleen size, chromosomal abnormalities, white blood cell count, and median dose intensity (for NIL). On both arms, pts with BCR-ABL ≤ 10% at 3 mo had significantly higher rates of MMR and MR4.5and significantly improved PFS and OS than pts with BCR-ABL &gt; 10% at 3 mo. Of the pts with BCR-ABL &gt; 10% at 3 mo, 2 on NIL (8%) and 14 on IM (16%) progressed to AP/BC on study. Half of these progressions occurred between 3 and 6 mo. Analyses of outcomes based on BCR-ABL levels at 6 mo were similar to findings based on 3-mo data. Conclusions: BCR-ABL levels ≤ 10% at 3 mo were associated with superior outcomes, including higher rates of MR4.5 by 4 y and lower risk of disease progression. More pts treated with NIL than IM achieved this early level of MR. Clinical trial information: NCT00471497. [Table: see text]