A randomized phase II study of tremelimumab and durvalumab with or without radiation for patients with relapsed small cell lung cancer (SCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8515-8515 ◽  
Author(s):  
Taofeek Kunle Owonikoko ◽  
Kristin Ann Higgins ◽  
Zhengjia Chen ◽  
Chao Zhang ◽  
Rathi Narayana Pillai ◽  
...  
Keyword(s):  
Endocrine Disorders ◽  
Detailed Result ◽  
Best Response ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Biomarker Analysis ◽  
Finding Study ◽  
Grade 3 ◽  
Serial Samples ◽  
Tumor Biopsies

8515 Background: The combination of PD-1 and CTLA-4 inhibition has demonstrated activity in the second line therapy setting for SCLC. Radiotherapy enhanced the effectiveness of immunotherapy in NSCLC. We conducted this signal finding study to assess the efficacy of combined ICI with or without radiation in relapsed SCLC. Methods: Patients with relapsed SCLC who have received not more than 2 lines of therapy were enrolled and randomized to either Arm A: [Tremelimumab (T) 1500mg/durvalumab (D) 75mg i.v. every 4 weeks without SBRT] or Arm B: T/D with immune sensitizing SBRT to one selected tumor site (9 Gy x 3 fractions). Treatment continued until progression or maximum of 2 years. Paired tumor biopsies and serial samples of peripheral blood were employed for correlative endpoints (changes in intratumoral and circulating lymphocyte repertoire and immune cytokines). The study was designed to show a promising efficacy signal in either Arm with a hypothesized median PFS of 7 months (10 patients give 87% power at 1-sided alpha of 0.1). Results: Study randomized 17 patients to Arm A (8 patients) or B (9 patients); median age of 70 yrs; females 41.2%; White, 70%, Black 17.6%. Best response in 14 overall evaluable patients was PD in 9 (64.3%), PR in 2 (14%) and SD in 3 (21.4%); median PFS of 2.76 months and OS of 4.47 months. There was no significant difference in efficacy between Arms A and B but a trend of improved PFS and OS with T/D plus SBRT (see table): Median PFS of 2.1 vs. 3.3 months [HR: 2.44 (0.75-7.93); p = 0.122] and median OS of 2.6 vs. 5.7 months [HR: 1.50 (0.45-4.99); p = 0.5068]. Observed grade ≥ 3 adverse events were: Cytopenia (4), Dyspnea (1), and endocrine disorders (3) in Arm A; diarrhea (3) and cytopenias (1) in Arm B. There was an increase in circulating CD8(+) lymphocytes on treatment versus baseline in patients with objective tumor response. Conclusions: The study did not show sufficient signal of efficacy for ICI with or without SBRT in relapsed SCLC. Detailed result of the biomarker analysis will be available at the meeting. Clinical trial information: NCT02701400. [Table: see text]

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 303-303 ◽  
Author(s):  
Rachid Baz ◽  
Thomas G. Martin ◽  
Melissa Alsina ◽  
Kenneth H. Shain ◽  
Hearn J. Cho ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advisory Committees ◽  
Overall Response ◽  
Best Response ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background: Pomalidomide-dexamethasone results in an overall response rate of 33% and median PFS of 4.2 months in patients with prior lenalidomide and bortezomib (Richardson et al. Blood 2014). In this randomized phase II trial, we compared pomalidomide-dexamethasone (arm B) versus the addition of oral weekly cyclophosphamide to pomalidomide-dexamethasone (arm C) in patients with lenalidomide-refractory multiple myeloma (MM). We have previously reported that the recommended phase II dose of cyclophosphamide with standard-dose pomalidomide + dexamethasone was 400 mg PO D1, 8, 15. Patients and Methods: Eligible patients had relapsed and refractory MM after at least 2 prior therapies and were lenalidomide refractory. Patients had a platelet count ≥ 50,000/mm3 and ANC ≥ 1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count was ≥ 30,000/mm3and ANC could be supported with GCSF during screening and therapy). Patients were randomized (1:1) to receive pomalidomide 4 mg PO D1-21 and dexamethasone 40 mg PO D1, 8, 15, 22 (20 mg if older than 75 years) (arm B) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28-day cycle (arm C). Patients randomized to arm B were allowed to cross over to arm C in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin, or LMWH. The primary endpoint was overall response rate using IMWG criteria. Secondary endpoints included an evaluation of PFS, OS and safety of the two arms. Results: Between 7/2012 and 3/2014, 36 patients were randomized to arm B and 34 to arm C. Patients characteristics were not different between the 2 arms (table below). The median number of prior therapies was 4 (2-12). All patients were lenalidomide refractory and none received prior pomalidomide. After a median follow up of 15 months, the overall response rate (partial response or better) was 39% and 65% (p=0.03) for arm B and C, respectively. The clinical benefit rate (minimal response or better) was 64% and 79% (p=0.2) for arm B and C, respectively. The median PFS was 4.4 months (95% CI 2.3-5.9) for arm B and 9.2 months (95% CI 4.6-16) for arm C (log rank p=0.04). As of July 2014, 28 patients had died (16 arm B, 12 arm C) with median overall survival of 10.5 versus 16.4 months (p=0.08) for arm B and C, respectively. Hematologic grade 3/4 adverse events were more frequent in arm C, although this was not statistically significant (see table). Thirteen patients crossed over and oral weekly cyclophosphamide was added to their tolerated dose of pomalidomide dexamethasone. For those patients, the best response was as follows: 2 PR, 2 MR, and 6 SD, 3 PD. Conclusions: Pomalidomide-dexamethasone in combination with oral weekly cyclophosphamide resulted in a superior response rate and PFS compared to pomalidomide-dexamethasone alone in patients with relapsed and refractory MM. The increased hematologic toxicities, as a result of the addition of oral cyclophosphamide, were manageable. Table Arm B (N=36) Arm C (N=34) P value Age, years, median (range) 63 (50-78) 64 (47-80) 0.7 Male, n (%) 23 (64) 18 (53) 0.3 Number of prior therapies, median (range) 4 (2-12) 4 (2-9) 0.5 Bortezomib refractory, n (%) 28 (78) 24 (71) 0.3 Carfilzomib refractory, n (%) 16 (44) 13 (38) 0.5 Prior high-dose therapy, n (%) 27 (75) 28 (82) 0.6 Prior alkylating agent, n (%) 32 (89) 32 (94) 1 B2-microglobulin, median (range) 3.2 (1.6-10) 3.6 (1.5-13.9) 0.5 Serum creatinine, median (range) 1 (0.5-2.3) 0.9 (0.6-2.1) 0.6 High-risk cytogenetics, n (%) 5 (24) 6 (28) 0.8 Deletion 17p, n (%) 3 (14) 4 (20) 0.8 t(4;14), n (%) 3 (14) 3 (14) 0.9 Trisomy or tetrasomy 1q, n (%) 11 (55) 6 (33) 0.4 Best response (partial response or better), n (%) 14 (39) 22 (65) 0.03 Clinical benefit rate (MR or better), n (%) 23 (64) 27 (79) 0.2 Grade 3/4 neutropenia, n (%) 12 (33) 17 (50) 0.2 Grade 3/4 febrile neutropenia, n (%) 4 (11) 6 (18) 0.5 Grade 3/4 thrombocytopenia, n (%) 2 (5) 5 (15) 0.2 Grade 3/4 anemia, n (%) 3 (8) 7 (20) 0.2 Grade 3/4 pneumonia, n (%) 4 (11) 3 (9) 1 Grade 3/4 fatigue, n (%) 2 (5) 4 (12) 0.4 Number of serious adverse events 17 20 Disclosures Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Karypharm: Research Funding; Sanofi: Research Funding. Off Label Use: Pomalidomide cyclophosphamide dexamethasone in relapsed refractory myeloma. Martin:Sanofi: Research Funding; Novartis: Speakers Bureau. Alsina:Triphase: Research Funding; Millenium: Research Funding. Shain:Onyx / Amgen: Research Funding; Treshold: Research Funding. Chari:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Membership on an entity's Board of Directors or advisory committees. Jagannath:Celgene: Honoraria; Millennium: Honoraria; Sanofi: Honoraria.

Randomized phase II study comparing dose-escalated weekly paclitaxel (wPTX) versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
Daisuke Takahari ◽  
Kohei Shitara ◽  
Satoshi Yuki ◽  
Michio Nakamura ◽  
Chihiro Kondo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Dose Escalation ◽  
Standard Dose ◽  
Sensory Neuropathy ◽  
Weekly Paclitaxel ◽  
Severe Toxicity ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Previously Treated ◽  
Grade 3

64 Background: wPTX is one of the standard second-line chemotherapies for AGC. Meanwhile, retrospective analysis of neutropenia during wPTX showed better overall survival (OS) among patients with neutropenia compared to patients without neutropenia. Therefore, we conducted randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated AGC. Methods: Patients with AGC that progressed during 1 or more previous chemotherapy regimens were randomized to a standard dose of weekly paclitaxel (80 mg/m2, standard dose arm) or an escalated dose of weekly paclitaxel (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2on day 15 unless severe toxicity nor neutropenia<1500 is observed, escalated dose arm). The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and safety Results: From September 2010 to November 2011, a total of 90 patients were randomised. Number of previous line of chemotherapy was 1 in 55% and 2 or more in other 45%. Among the 44 patients of dose escalated arm, the dose of wPTX was escalated to 100 mg/m2 in 41 patients (93.2%) and then to 120 mg/m2in 29 patients (65.9%). Median PFS was significantly longer in dose escalated arm than standard dose (4.3 months. vs. 2.5 months, HR, 0.61; 95% CI, 0.39-0.95; p=0.03). ORR was 30.3% with dose escalation and 17.1% with standard dose (p=0.2). DCR was significantly higher with dose escalation (78.8% vs. 48.6%, p=0.009). Frequency of neutropenia (grade 1-4) was significantly higher with dose escalation (88.7% vs. 60.0%, p=0.002), but no significant difference was observed in grade 3/4 (40.9% vs.31.1%, p=0.34). Grade 3 peripheral sensory neuropathy was relatively common in dose escalated arm (13.6% vs. 6.7%, p=0.27). Conclusions: Dose escalated wPTX was associated with significantly longer PFS and higher DCR in patients with previously treated AGC in comparison with standard dose. The result of OS will be presented at the meeting Clinical trial information: UMIN000004055.

Efficacy and safety of pembrolizumab in patients with advanced adrenocortical carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4112-4112
Author(s):  
Nitya Prabhakar Raj ◽  
Youyun Zheng ◽  
Virginia Kelly ◽  
Seth Katz ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Treatment Options ◽  
Response To Treatment ◽  
Efficacy And Safety ◽  
Complete Evaluation ◽  
Best Response ◽  
Patient Decision ◽  
Mutation Burden ◽  
Biomarker Analysis ◽  
Grade 3 ◽  
Adrenocortical Carcinomas

4112 Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.

FOLFOX versus POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel plus FOLFOX) as a first-line treatment in advanced gastric cancer (AGC): A multicenter, randomized phase II trial, FNF-004 trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 6-6
Author(s):  
Rongbo Lin ◽  
Hui Li ◽  
Yigui Chen ◽  
Jinfeng Zhu ◽  
Peicheng Lin ◽  
...  
Keyword(s):  
Response Rate ◽  
Phase Ii Trial ◽  
Abdominal Cavity ◽  
Local Concentration ◽  
First Line ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
First Line Treatment

6 Background: Double regimens are commonly accepted for AGC in East Asia. However, triple regimens are recommended in west countries. POF regimen (reported in 2007, 2008, 2009, 2010 ASCO) appeared to be of good efficacy and was well tolerated in patients with AGC. Intraperitoneal paclitaxel showed high local concentration in abdominal cavity and low systemic toxicity. The aims of this study were to find out if the POF and IP PAC was more effective with manageable side effects than FOLFOX in AGC (reported in 2017 ASCO-GI for feasibility analysis). Methods: The patients with AGC were randomized to three groups. The POF consisted of a 3-hour infusion of paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-Fu bolus. The IP PAC consisted of paclitaxel 80 mg/m2 intraperitoneally plus FOLFOX. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression. The primary endpoint was PFS. Results: Between Nov 2015 and May 2018, 89 pts (30 POF, 29 IP PAC, 30 FOLFOX) were randomly allocated. PFS, OS and RR were seen in the table below. POF was better in PFS and RR than FOLFOX, although no statistically significant difference in RR. IP PAC was trend to be better in PFS than FOLFOX, but not in RR. OS was unmatured. The most common adverse events of grade 3 or 4 were neutropenia and neuropathy, but no significant difference among three groups. Conclusions: Both POF and IP PAC improved survival compared to FOLFOX. Only POF, not IP PAC, improved response rate compared to FOLFOX. Clinical trial information: NCT02845908. [Table: see text]

Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4520-4520 ◽  
Author(s):  
Do-Youn Oh ◽  
Kyung-Hun Lee ◽  
Dae-Won Lee ◽  
Tae Yong Kim ◽  
Ju-Hee Bang ◽  
...  
Keyword(s):  
Genome Instability ◽  
Standard Of Care ◽  
Tract Cancer ◽  
Damage Repair ◽  
Biomarker Analysis ◽  
Common Grade ◽  
Frequent Mutations ◽  
Pre Treatment ◽  
Grade 3 ◽  
Tumor Biopsies

4520 Background: In aBTC, GemCis is the standard of care as 1st-line treatment. Immunotherapies have shown early promising efficacy in some BTC patients (pts). We assessed D (anti-PD-L1) ± T (anti-CTLA-4) and GemCis in 1L BTC pts, including an extensive biomarker analysis (NCT03046862). Methods: Pts were first enrolled in the biomarker cohort (BMC) to receive 1 cycle of Gem 1000 mg/m2 + Cis 25 mg/m2 on D1 & D8, followed by GemCis + D 1120 mg and T 75 mg, Q3W until disease progression (PD). Subsequent pts were allocated to GemCis + D (3 combo cohort [3C]) or GemCis + D+T (4 combo cohort [4C]) until PD. In all cohorts, tumor biopsies were obtained pre-treatment, after 1 cycle, and at PD. Blood samples for ctDNA were obtained every cycle. Results: 121 pts were enrolled. Median follow-up durations were 28.5 months (m; 95% CI, 26.5-30.5), 11.3 m (95% CI, 9.1-13.5), and 11.9m (95% CI, 8.4-15.4) in the BMC, 3C, and 4C arms, respectively. Efficacy data are shown (Table). The most common adverse events (AEs, any grade) were neutropenia (54.5%), nausea (59.5%), and pruritus (55.44%). The most common grade 3/4 AEs were neutropenia (50.4%), anemia (35.5%), and thrombocytopenia (16.5%). In the BMC cohort, frequent mutations were found in DNA damage repair, cell cycle regulation, and genome instability genes (eg, ATM, BRCA2, POLE, MSH2, CDKN2A). Distinct somatic variants were detected in responders vs non-responders. Baseline tissue TMB did not correlate with PFS or OS. Reductions in ctDNA variant allele frequency (VAF) were more prominent among responders during early D+T cycles. ctDNA VAF on C3, D1 was significantly correlated with ORR ( P< 0.015). Pretreatment PD-L1 expression was not associated with efficacy, but PD-L1 expression after 1st GemCis cycle trended with improved PFS. Conclusions: These are the first clinical data of D±T plus chemotherapy in chemo-naïve aBTC pts. The addition of immunotherapy to chemotherapy was tolerable and showed very promising efficacy. Biomarker analyses show early signs of markers associated with response. The combination of GemCis + D is being investigated in the Phase 3 TOPAZ-1 trial (NCT03875235). Clinical trial information: NCT03046862 . [Table: see text]

scholarly journals Randomized, Phase II Study Prospectively Evaluating Treatment of Metastatic Esophageal, Gastric, or Gastroesophageal Cancer by Gene Expression of ERCC1: SWOG S1201

2020 ◽  
Vol 38 (5) ◽  
pp. 472-479 ◽  
Author(s):  
Syma Iqbal ◽  
Shannon McDonough ◽  
Heinz-Josef Lenz ◽  
David Ilson ◽  
Barbara Burtness ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Interactive Effects ◽  
Randomized Phase Ii ◽  
Esophagogastric Cancer ◽  
Significant Difference ◽  
Grade 3 ◽  
Ercc1 Expression

PURPOSE Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral ERCC1 levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non–platinum-containing regimen of irinotecan and docetaxel (IT) differed according to ERCC1 levels. PATIENTS AND METHODS Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of ERCC1 level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of ERCC1 low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high ERCC1 levels, and to assess for interactive effects between ERCC1 expression and treatment arm. RESULTS Eighty-six percent of patients had ERCC1 values < 1.7. Thus, evaluation of the ERCC1-high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 v 2.9 months; hazard ratio, 0.68; P = .02). In patients with ERCC1 levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS. CONCLUSION The evaluation of ERCC1 in patients with upper GI tumors was thwarted by an overwhelming predominance of low ERCC1 mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low ERCC1 expression, FOLFOX was superior in efficacy to IT.

Voriconazole Increase the Risk of PN in Multiple Myeloma Patients Treated with Bortezomib-Based Chemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5394-5394
Author(s):  
Yan Xu ◽  
Shuhui Deng ◽  
Gang An ◽  
Zengjun Li ◽  
Xiaoqi Qin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Primary Objective ◽  
M Protein ◽  
Comparable Efficacy ◽  
Best Response ◽  
Median Dosage ◽  
Significant Difference ◽  
Grade 3

Abstract Background Bortezomib (btz) is the major and potent agent in multiple myeloma (MM) treatment and intravenous (IV) injection is its standard administration route. Our previous study showed that Subcutaneous (SC) administration of btz was an important alternative with comparable efficacy but better safety profile, significantly decreased and delayed the development of peripheral neuropathy (PN) in patients with MM. However, PN still always limited the use of btz. The primary objective is try to identify some correlative factors for PN, then to decrease the risk of PN and the grade of PN. Methods This retrospective study was undertaken at a single centre in China. Patients with NDMM were assigned to receive up to nine 21-day cycles of Btz based regimens, including PAd/VDd/BCd (btz 1.3mg/m2, on days 1, 4, 8 and 11; adriamycin 9mg/m2 intravenously on days 1 - 4; or PLD 30mg/m2, intravenously on days 1, or CTX 500mg/m2, orally on days 1, 8, 15, and dexamethasone 20mg/day, orally or intravenously on days 1, 2, 4, 5, 8, 9, 11 and 12). Btz was administered by SC injection or IV infusion. The basic characteristics, drug combination (especially drugs for fungi), the effect and adverse events were recorded. Then the correlation were analysed. Results 252 (male, n=159) NDMM patients were received Btz based treatment from Oct. 2008 to Nov. 2014. The median age were 56 (26-77). In this group, patients were treated with a median 4 cycles of btz-based chemotherapy. 98, 101 and 53 patients received PAd, BCd and VDd regimen, respectively. 114 patients received IV btz, and 148 received SC btz. The median total Btz dosage was 20.4 (2.6-56.6) mg/m2. Patients achieved at least PR at median 1 (1-7) cycle, and achieved the best response at median 2 (1-9) cycles. The overall response rate (ORR, >=PR) was 95%, with 33.3%, 12.4%, 22.4% achieved CR, nCR and VGPR, respectively. With median follow up 24 months, the median PFS and OS were 28 months, and not arrived, respectively. There was no significant difference between IV and SC group. During their course, 49, 19, 73, and 46 cases received fluconazole, itraconazole, voriconazole, and caspofungin respectively as prophylaxis or treatment for fungi. 140 (55.56%) patients developed PN during their courses, with 17.06% were ≥ grade 3. The median dosage of btz when PN developed was 15.6 mg/m2. In the subgroup which combined voriconazole, 59 (80.82%) patients developed PN, with 39.07% were ≥ grade 3. The median dosage of btz when PN developed was 12.3mg/m2 in this subgroup. In addition, 10 patients (13.70%) developed diarrhea of grade 3/4 and 20 cases (27.4%) developed paralytic ileus of any grade, which may be related to the neuropathy toxicity of btz too. Correlation analysis showed that only voriconazole combination was significantly correlated with PN development (p<0.0001). However, any other factors, including age, sex, the percentage of plasma cells in bone marrow, the level of M-protein, IL-6, TNF-α, β2-MG, ALB, calcium, the type of M-protein, etc, were all without correlation with the development of PN. Conclusions Voriconazole combination significantly increased the risk and the grade of PN in patients treated with btz-based chemotherapy. If this combination can't be avoided, patients should be observed more closely or btz dosage should be decreased earlier. Disclosures No relevant conflicts of interest to declare.

Time finding study of chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L) and oxaliplatin (O) (chronoIFLO) against metastatic colorectal cancer: Results from randomized EORTC 05011 trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2566-2566 ◽  
Author(s):  
C. Garufi ◽  
C. Focan ◽  
S. Tumolo ◽  
B. Coudert ◽  
S. Iacobelli ◽  
...  
Keyword(s):  
Phase Ii Trial ◽  
Median Number ◽  
Dose Delivery ◽  
Tumor Bearing ◽  
Minimal Dose ◽  
Randomized Phase Ii ◽  
Negative Prognostic Factor ◽  
Finding Study ◽  
Grade 3 ◽  
Pm 10

2566 Background: We previously showed that a) irinotecan (I) could be combined with chronoFLO in MMC patients; b) least toxic times (LTT) for combined I and oxaliplatin respectively correspond to the middle of the rest-phase and the middle of acivity-phase in tumor-bearing mice; c) chrono I showed adequate activity in a randomized phase II trial; and d) MMC resistance can be partly overcome with chronoIFL. Methods: The objective was to identify the LTT for I characterized by a minimal dose reduction/delay among the first 3 courses (c). Assuming that the toxic effect of I had a 24-h periodicity patients were randomized in 6 groups with I peak delivery (180 mg/m2, 6-h sinusoidal infusion on day 1) at 1:00, 5:00, 9:00 am, 1:00, 5:00, or 9:00 pm. . All the groups received also chronoFLO on days 2–5, q 3 weeks (F 700 mg/m2/d & L 150 mg/m2/d; from 22:15 to 9:45 with peak delivery at 4:00 , O 20 mg/m2/d from 10:15 to 21:45, with peak delivery at 16:00). Based on a logistic regression model, a 15% reduction in toxic events in the first 3 c, 186 patients were considered necessary to estimate the LTT with a 95% CI (calculated by bootsrap) of less than 6 h. Results: 197 of 199 randomized MMC patients were considered for tolerability and safety with median age 61 years (30–81), sex (M 68% - F 32%) and PS (0/1/2 73/23/4%); therapy was 1st line in 77 patients and 2nd line in 23%. Thithy-one percent of severe protocol violations occurred, 16% of pump malfunctions (>10% dose delivery deviation). Median number of c was 6 (1–18). There were 3 toxic deaths. The observed LTT for I tolerability was 3:15 am (95 CI: 3:40–1:50 pm, NS). Grade 3–4 diarrhea ranged from 34 to 51.6% with LTT at 1:53 pm (4:29 -2:53 am, not significant, NS); neutropenia from 9 to 25% with LTT at 3:26 pm (10:50 - 4:55 am, NS). Age was a negative prognostic factor for diarrhea (p =0.01). Conclusion: This trial failed to show a statistically significant LTT for this combination in MCC patients. The safety profile of I combined with ChronoIFLO was acceptable, with diarrhea and neutropenia within previously reported range. No significant financial relationships to disclose.

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4080-4080 ◽  
Author(s):  
K. E. Bullock ◽  
H. I. Hurwitz ◽  
H. E. Uronis ◽  
M. A. Morse ◽  
G. C. Blobe ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Progressive Disease ◽  
Bowel Perforation ◽  
Median Number ◽  
Volume Depletion ◽  
Mtor Inhibition ◽  
Best Response ◽  
Grade 3 ◽  
Tumor Biopsies ◽  
Anti Tumor Activity

4080 Background: For patients (pts) with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC. Methods: 25 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. Results: At this time, 19 pts (10M: 9F) are evaluable for toxicity; 17 for efficacy. Median age 57 years (range 35–78). Median number prior regimens 3. All pts had prior B exposure; 17 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia. Grade 3 AE related to treatment were bowel perforation/fistula, (n=2), hyperglycemia (3), hypokalemia (3), hypertension (2), fatigue (1), alk phos elevation (1; lab only), hypoalbuminemia (1), and volume depletion (1). Other events of interest were: Gr1–2 mucositis (n=10), Gr1 hyperlipidemia (11). Of 17 pts evaluable for response, 4 pts had SD as best response (median 24 wks, range 17–31+ wks); there were 3 minor responses in pts who had progressed on B (median 16 wks, range 16–27 wks). No CR or PR were seen. Biomarker data is pending. Conclusions: B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. Patient accrual is continuing and updated data will be presented. [Table: see text]

A phase I trial of panobinostat with ipilimumab in advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9547-9547 ◽  
Author(s):  
Nikhil I. Khushalani ◽  
Joseph Markowitz ◽  
Zeynep Eroglu ◽  
Iulia Giuroiu ◽  
Viktoriya Ladanova ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Escalation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Advanced Melanoma ◽  
Dose Finding ◽  
Biomarker Analysis ◽  
Finding Study ◽  
Tumor Biopsies

9547 Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of effector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, ↑ lipase, ↓ sodium, & ↑ glucose (all n = 1). Three pts had previous anti-PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN > 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study. Supported by grant P50 CA168536, Moffitt Skin Cancer SPORE. Clinical trial information: NCT02032810.

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