Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2598-2598
Author(s):  
Beata Holkova ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Sheryl S. Cooke ◽  
Wen Wan ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Chronic Myelogenous Leukemia ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Level 3

Abstract Abstract 2598 Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors, particularly in B-cell malignancies (e.g., myeloma and lymphoma). However, investigation of this strategy in acute leukemias has been limited. Very recent preclinical findings have shown marked synergism between the HDAC inhibitor belinostat and the proteasome inhibitor bortezomib administered at very low (sub-micromolar) concentrations, in various cultured and primary acute myelogenous leukemia and acute lymphocytic leukemia specimens (Dai Y et al. Br J Haematol. 2011). These interactions were associated with multiple perturbations in survival signaling proteins, including inactivation of NF-kappa B, down-regulation of Bcl-xL and XIAP, and up-regulation of the pro-apoptotic protein Bim. These findings prompted initiation of a phase I trial with the primary objective of determining the recommended phase II doses (RPTDs) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 13 patients have been enrolled. Patients with the following disease types have been treated: acute leukemia (n=9), MDS (n=3), and CML-BC (n=1). Patient characteristics include male/female ratio n = 6 (46%)/7 (54%), with a median age of 59 years [range 27–75]. ECOG performance score 0–2. The median number of prior therapies was 2 [range 2–5]. The schedule of administration was belinostat 30 minutes intravenous (IV) infusion on days 1–5 and 8–12; and bortezomib IV bolus preceding belinostat on days 1, 4, 8, 11; on a 21 day cycle. Dose level enrollment was: Level 1 = bortezomib 1.0 mg/m2, belinostat 500 mg/m2 (n=6); Level 2 = bortezomib 1.3 mg/m2, belinostat 500 mg/m2 (n=6); and Level 3 = bortezomib 1.3 mg/m2, belinostat 650 mg/m2 (n=1). The study is currently enrolling to dose level 3. No dose-limiting toxicities (DLTs) have been observed to date. Non-DLTs (CTCAE v4) include: leukopenia (grade 4, 23%), thrombocytopenia (grade 3, 15%), and peripheral sensory neuropathy (grade 2, 23%). No serious adverse events have occurred at unexpected frequency or severity. Two deaths have occurred due to disease progression. Of the 13 patients treated, 12 have been evaluable for response. There has been 1 complete response in this heavily pretreated population. This response was achieved in a patient with biphenotypic acute leukemia, refractory to 7+3 and Flag-Ida. The patient proceeded to allogeneic hematopoietic stem cell transplantation. Four patients had stable disease, and 7 patients had progressive disease. Correlative studies examining leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP pre- and post-treatment are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC. The maximum tolerated dose (MTD) has not been reached. Pending identification of the RPTDs, phase II evaluation of this therapeutic strategy, if warranted, should define its activity more definitively. Disclosures: No relevant conflicts of interest to declare.

Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3588-3588
Author(s):  
Beata Holkova ◽  
Prithviraj Bose ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Wen Wan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Chronic Myelogenous Leukemia ◽  
Dose Level ◽  
Phase I Trial ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Acute Leukemias

Abstract Abstract 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leukemia (n=19), MDS (n=4), and CML-BC (n=2). The male:female ratio was n=11 (44%):14 (56%); the median age was 62 (range 27–83) years; ECOG performance scores ranged from 0–2; and the median number of prior therapies was 2 (range 1–5). The schedule of administration was belinostat, 30 minutes intravenous (IV) infusion, on days 1–5 and 8–12; and bortezomib, IV bolus, preceding belinostat on days 1, 4, 8, 11; on a 21-day cycle. Dose levels were, in mg/m2(bortezomib/belinostat): 1.0/500 (n=6); 1.3/500 (n=6); 1.3/650 (n=4); 1.3/850 (n=3); 1.3/1000 (n=4); 1.3/1200 (n=2). The study is currently enrolling to dose level 6 (1.3/1200). No dose-limiting toxicities (DLTs) have been observed to date. Non-DLT ≥ grade 2 (CTCAE version 4) treatment-related adverse events have included: fatigue (grade 2, 36%), leukopenia (grade 4, 12%), nausea (grade 2, 12%), peripheral sensory neuropathy (grade 2, 12%), and thrombocytopenia (grade 3, 20%). No serious adverse events have occurred at an unexpected frequency or severity. Two deaths have occurred due to disease progression, and one death has occurred due to a cerebrovascular accident that was related to pre-existing comorbidities and not to study-therapy. Of the 25 patients treated, 22 have been evaluable for response, 2 are too early to evaluate, and 1 patient was not evaluable for response. There have been 2 partial responses (PRs) and 1 complete response (CR) in this heavily pretreated population. The CR was achieved at dose level 1 in a patient with biphenotypic acute leukemia refractory to 7+3 and Flag-IDA. The patient proceeded to allogeneic hematopoietic stem cell transplantation (SCT) after 4 cycles of treatment. In addition, 1 patient with CML-BC had stable disease (SD) by protocol criteria but a CR with incomplete blood count recovery (CRi) by standard criteria, and is undergoing evaluation for allogeneic hematopoietic SCT. The patient is currently in cycle 8 at dose level 4. One of the PRs was achieved in a patient with AML transformed from MDS (2 prior regimens); after 4 cycles of treatment at dose level 5, the patient proceeded to allogeneic hematopoietic SCT. The second PR was achieved in an AML patient after cycle 2; a bone marrow biopsy revealed chronic myelomonocytic leukemia, and the response was deemed sufficient to proceed to allogeneic hematopoietic SCT. Also of note, a patient with AML transformed from MDS is currently on treatment in cycle 5 at dose level 5 with SD. An additional 6 patients have had SD, and 11 patients have had progressive disease. Correlative studies examining pre- and post-treatment leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC and shows evidence of activity. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, should determine its activity more definitively. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome

2014 ◽  
Vol 56 (2) ◽  
pp. 395-400 ◽  
Author(s):  
Gail J. Roboz ◽  
H. Jean Khoury ◽  
Elias Jabbour ◽  
Wilena Session ◽  
Ellen K. Ritchie ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase I Trial ◽  
Kinase Inhibitor

Phase I Study of Vorinostat in Combination with Decitabine in Patients with Relapsed or Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3651-3651 ◽  
Author(s):  
Mark Kirschbaum ◽  
Ivana Gojo ◽  
Stuart L Goldberg ◽  
Lisa Kujawski ◽  
Ehab Atallah ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Dose Level ◽  
Preliminary Data ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Best Response ◽  
Acute Myelogenous ◽  
Dose Levels ◽  
Refractory Aml

Abstract Epigenetic therapies, eg decitabine (dec) a DNA methyltransferase inhibitor (MTI), have added treatment options for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). However, response rates remain relatively low. Preclinical and clinical data suggest that broadening epigenetic targeting by adding HDAC inhibitors to MTIs may improve responses. Preclinical data suggest that outcomes may differ according to the sequence in which epigenetic agents are combined. We present preliminary data from a phase I, open-label, multicenter, dose-escalating study, aiming to find the maximum-tolerated dose and recommended phase II dose of vorinostat combined concurrently or sequentially with dec in patients (pts) with MDS or AML. Other endpoints included tolerability and exploratory assessments of activity. Pts diagnosed with intermediate-high risk MDS, refractory or relapsed AML (≥18 years), or untreated AML(≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2 were eligible. See table for vorinostat dosing schedules. Dec 20 mg/m2 IV was administered over 1 h, daily on days 1–5. Therapy continued up to 24 months or until progressive disease (PD). 63 pts were randomized to treatment: median age (range, years) 68 (18–85); 65% males; 9 pts with MDS; 27 pts with untreated AML; 24 pts with relapsed/refractory AML. 35 pts have discontinued due to PD/lack of efficacy (n=19), withdrawal of consent (n=8), adverse events (AEs) (n=6), physician decision (n=1), and protocol deviation (n=1). AEs were reported by 50 pts (79.4%), mainly mild to moderate and commonly included nausea (n=19), fatigue (n=18), constipation (n=16), leukopenia (n=16), diarrhea (n=15), and vomiting (n=12). 37 AEs were treatment related. 42 pts (66.7%) had serious AEs, including febrile neutropenia (n=22), grade 3/4 neutropenia (n=7), and pneumonia (n=9). 12 deaths occurred during the study. In 60 pts evaluable for response, the median (range) number of cycles received were 2 (1–4), 6 (4–7), 3 (1–5), 2 (2–5), 2 (1–2), and 1 (1–7) for dose levels 1, 2, 3, 1a, 2a, and 3a, respectively. Dose levels 3 and 3a were expanded. Complete response (CR) was achieved by 22% pts with MDS, 26% with untreated AML, and 8% with relapsed/refractory AML. Hematologic improvement (HI) was reported in 4% and 22% of pts with untreated AML and MDS, respectively. A similar proportion of pts achieved stable disease (SD) in all disease groups (range 30–46%). Overall, best responses recorded in evaluable pts were: CR, n=11 (3 cytogenic CR); partial response (PR), n=1; HI, n=3; SD, n=25. PD was reported in 6 pts. Best response for 14 pts not yet reported. A best response of CR, PR, HI, and SD was achieved in 26%, 3%, 6%, and 32% of pts treated with concurrent therapy, and 10%, 3%, and 45% of pts receiving sequential regimens reported a best response of CR, HI, and SD, respectively. In pts with untreated AML receiving concurrent therapy, CR was achieved in 8 pts, PR in 1 pt, HI in 2 pts, and SD in 10 pts. In those receiving sequential therapy, CR was achieved in 3 pts, HI in 1 pt, and SD in 13 pts. Preliminary data indicate that the combination of vorinostat with dec, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Concurrent initial schedule (28-day cycle) Sequential initial schedule (28-day cycle) Dose Level 1:Vorinostat 400 mg QD for 7 days (days 1–7) Dose Level 1a:Vorinostat 400 mg QD for 7 days (days 6–12) Dose Level 2: Vorinostat 400 mg QD for 14 days (days 1–7 and days 15–21) Dose Level 2a: Vorinostat 400 mg QD for 10 days (days 6–15) Dose Level 3: Vorinostat 400 mg QD for 14 days (days 1–14) Dose Level 3a: Vorinostat 400 mg QD for 14 days (days 6–19)

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

A phase I trial of S-1 plus vinorelbine in patients with unresectable advanced or metastatic non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19098-e19098
Author(s):  
H. Suyama ◽  
Y. Shigeoka ◽  
T. Igishi ◽  
S. Matsumoto ◽  
M. Kodani ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung

e19098 Background: We reported the efficacy of the combination treatment of tegafur-uracil (UFT) and vinorelbine (VNR) for the elderly patients (pts) (>70) with advanced non-small cell lung cancer (NSCLC) in ASCO 2007 (Abstract - No. 18075). Although the cisplatin-based doublets are still milestone for the pts with advanced NSCLC, non-platinum based doublet regimens remain as a matter of development judging from recent meta-analysis. Tegafur-5-chloro-2,4-dihydroxypyridine-potassium oxonate (S-1), a new oral fluoropyrimidine, has been studied extensively, and appears promising for various kinds of cancers including NSCLC. Thus, we conducted this phase I trial using VNR and new oral fluoropyrimidine, S-1. Methods: Pts with advanced NSCLC, who had received at least one prior platinum-containing regimen, were eligible. In this phase I study, VNR was infused on days 1 and 8, and S-1 was administered from day 2 to day 6 and from day 9 to day 13 of a 3-week cycle. The starting dose of S-1 was 80 mg/m2/day and, if necessary, the dose was decreased to 65 mg/m2/day; VNR was increased from 20 to 25 mg/m2 in this trial. Results: From August 14, 2007 to April 1, 2008, 8 pts enrolled in this study. Median age was 61 (range 49–75). Dose limiting toxicity (DLT) was evaluated during the first 6 weeks of the treatment. No DLT was observed at dose level I (80 mg/m2/day S-1, 20 mg/m2 VNR). At dose level II (80 mg/m2/day S-1, 25 mg/m2 VNR), DLT in the form of neutropenia, hyperglycemia and hyponatremia was observed in 3 of 5 pts. The maximum tolerated dose (MTD) for the present treatment was 80 mg/m2/day S-1 and 25 mg/m2 VNR; the recommended tolerable dose for future phase II trials is therefore 80 mg/m2/day S-1 and 20 mg/m2 VNR. Conclusions: Three-week cycle of VNR (20 mg/m2), infused on days 1 and 8; S-1 (80 mg/m2/day), administered from day 2 to day 6 and from day 9 to day 13, is being examined in our phase II trial for first-or second-line treatment of NSCLC. No significant financial relationships to disclose.

A phase I trial of ABT-751 and carboplatin (C) in patients (pts) with previously treated non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17098-17098 ◽  
Author(s):  
K. H. Dragnev ◽  
J. R. Rigas ◽  
W. M. Disalvo ◽  
S. A. Simeone ◽  
A. E. Hagey ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Xenograft Model ◽  
The United States ◽  
Buccal Swabs ◽  
Previously Treated ◽  
Dose Levels

17098 Background: NSCLC is the leading cause of cancer mortality for men and women in the United States. More effective treatments are needed to prolong survival and improve quality of life. Platin-containing chemotherapy doublets are commonly used in NSCLC treatment. ABT-751 is a novel oral anti-microtubule agent targeting the colchicine binding site. As single agent, it was well-tolerated and showed a preliminary signal of activity in previously treated NSCLC. In vivo studies demonstrated additive activity between ABT-751 and cisplatin in a NSCLC xenograft model. Methods: A phase I trial of ABT-751 and C was conducted in pts with advanced previously treated NSCLC. Primary objective - maximum tolerated dose (MTD). Secondary objectives - toxicities, efficacy, and surrogate markers of response (cell cycle changes and cyclin D1 expression) in buccal swabs from pts at the phase II dose. Six dose levels - 1: ABT-751 100mg bid, C AUC 4.5; 2: ABT-751 125 mg bid, C AUC 4.5; 3: ABT-751 125 mg bid, C AUC 6; 4: ABT-751 150 mg bid, C AUC 6; 5: ABT-751 175 mg bid, C AUC 6; 6: ABT-751 200 mg bid, C AUC 6. ABT-751 was taken orally twice a day for 14 days in a 21 day cycle, C was administered intravenously on day 4 during cycle 1 and on day 1 on subsequent cycles. Rapid dose escalation was used for the first 3 dose levels followed by cohorts of at least 3 patients for the remaining dose levels. Results: Eight pts were enrolled, all stage IV NSCLC, 4 women, median age 62 (47–73), all KPS 80, 6 had one and 2 had 2 prior therapies. A median of 3.5 (1–4) cycles was administered. Dose-limiting toxiticies of grade 3 fatigue and grade 4 thrombocytopenia and neutropenia were observed in 2/5 patients on dose level 4. Common grade 2 toxicites were constipation and peripheral sensory neuropathy (levels 2–4). MTD was dose level 3. Seven pts were evaluable for response, 2 had partial responses (levels 2 and 4, both had one prior therapy), 4 had stable disease, 1 had disease progression. Median time to progression was 18.7 weeks (6–24+). Pharmacokinetic analyses and buccal swabs are being performed. Conclusions: The recommended phase II doses are ABT-751 125 mg twice daily for 14 days and carboplatin AUC 6 on a 21-day cycle. This regimen is well tolerated and shows preliminary evidence of activity for previously treated NSCLC. [Table: see text]

Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group 0502

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18137-18137
Author(s):  
T. Seto ◽  
T. Yamanaka ◽  
K. Eguchi ◽  
H. Okamoto ◽  
M. Shibuya ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Skin Toxicity ◽  
Combination Regimen ◽  
Oncology Research ◽  
Level 3 ◽  
Level 2

18137 Background: Optimal treatment for elderly patients with NSCLC has been under active investigation. This study evaluated the safety and initial efficacy of a novel combination regimen of oral fluoropyrimidine TS-1 plus gemcitabine (GEM) for elderly patients (pts) with advanced NSCLC. Methods: A phase I/II trial in 11 centers examined TS-1 and GEM in pts with age = 70, stage IIIB/IV previously untreated NSCLC. The starting dose was 60 mg/m2day (day 1–14) for TS-1 and 800 mg/m2 for GEM (day 8, 15). GEM was increased to 1,000 mg/m2 at dose level 2 and TS-1 was increased to 80 mg/mg2/day at dose level 3. Phase II portion of the study assessed the efficacy and tolerability of the combination regimen at the dose determined in the phase I portion. The primary endpoint was objective response rate. Results: Twenty two pts were enrolled in the phase I portion: 6 pts on dose level 1, 10 on dose level 2 and 6 on dose level 3. Median age of this group was 75 yrs (range 70–85). Dose limiting toxicities included Gr. 4 neutropenia (2 pts) and Gr.3 skin toxicity (4 pts). The recommended dose (RD) was TS-1 60 mg/day and GEM 1,000 mg/m2, with which 20 pts were subsequently treated in the phase II portion. The median age of 30 pts treated with the RD was 76 yrs (range 70–85). Grade (Gr) 3/4 toxicities include neutropenia (12 pts; 7 with Gr 4), thrombocytopenia (4 pts; 0 with Gr 4), skin toxicity (8 pts), thrombus (1 pt) and peumonitis (2 pts). Nine patients (30%, 95% confidence interval [CI] = 14 to 46%) had partial responses and 16 (53%, 95% CI = 35 to 71%) had stable disease. Conclusions: Encouraging antitumor activity and safety of TS-1 plus gemcitabine support further development of this combination therapy for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Hironori Ishigami ◽  
Shoichi Kaisaki ◽  
Hironori Yamaguchi ◽  
Hiroharu Yamashita ◽  
Shigenobu Emoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.

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