A phase I clinical study of biweekly carboplatin and gemcitabine in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12024-12024
Author(s):  
P. Kumar ◽  
M. Keshtgarpour ◽  
H. Kumar ◽  
A. Dudek
Keyword(s):  
Performance Status ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
Primary Tumors ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Tumor Types ◽  
Dose Levels

12024 Background: Carboplatin (CBDCA) and gemcitabine (GEM) in combination is used commonly in lung cancer and is administered on a 21 day cycle. The purpose of this study was to determine the maximum tolerated dose (MTD) of CBDCA and GEM administered on a biweekly schedule and to assess safety and efficacy of this schedule. Methods: GEM was given intravenously (IV) over 30 minutes followed by CBDCA also given IV over 30 minutes. This combination was given on day 1 every 2 weeks. The dose levels examined are shown in the Table . A total of 26 patients were studied (18 male, 8 female) with median age of 56 (range 41–83 years); ECOG performance status of 24 patients were 0 (5), 1 (16), 2 (2), 3 (1); prior chemotherapy ranged from 0 to 4 regimens; median number of cycles administered per patient was 3 (range 1–9) with a total of 81 cycles. The primary tumors were lung (11), melanoma (4), head and neck (3), squamous cell penile/toe (2), bladder (2), kidney (1), gastric (1), esophageal (1) and ovary (1). Results: No DLTs were seen in any of these patients and the MTD was not reached. Delay in treatment was seen in total of 6 cycles due to myelosuppression and 1 cycle due to nausea and anorexia. Grade 3/4 hematological toxicity rates: anemia - 3/81 cycles (3.7%), neutropenia - 20/81 cycles (25%), and thrombocytopenia - 4/81 cycles (5%). Non-hematological toxicity was mild. The median time to progression was 40 days (range 4–133) and of 18 evaluable patients partial response or stable disease was seen in 7 (38.8%). Conclusions: Even at maximum tested dose of GEM at 2000 mg/m2 and CBDCA at AUC of 3.0, this schedule is well tolerated. Hematological toxicity such as neutropenia and thrombocytopenia was minimal. We plan to study this schedule of GEM and CBDCA in appropriate tumor types in combination with biologic agents. [Table: see text] [Table: see text]

A phase I trial of cabozantinib (XL184) and gemcitabine in advanced pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 334-334 ◽  
Author(s):  
David Bing Zhen ◽  
Kent A. Griffith ◽  
Joshua Michael Ruch ◽  
Meredith Morgan ◽  
Edward Jae-hoon Kim ◽  
...  
Keyword(s):  
Performance Status ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Tumor Control ◽  
Days Of Therapy ◽  
Grade 3 ◽  
Number Of Cycles

334 Background: Hepatocyte growth factor (HGF) and its receptor (c-Met) are activated in pancreatic ductal adenocarcinoma (PDAC). Preclinical data showed a combination of cabozantinib (cabo) and gemcitabine (gem) improved tumor control through inhibition of c-Met. We sought to determine the maximum tolerated dose (MTD) of cabo and gem in patients with advanced PDAC. Methods: Patients with unresectable or metastatic PDAC with ≤1 prior treatment and adequate organ function/performance status were eligible. Cabo was given orally once daily for 7 days and continued with gem infused IV over 30 min on days 1, 8, and 15 of a 28 day schedule. Doses were assigned in accordance with a Time to Event Continual Reassessment Method (TITE-CRM) per table below. Primary endpoint was MTD, defined as the highest dose level at which ≤25% of patients incurred a dose-limiting toxicity (DLT) in the first 35 days of therapy. Secondary endpoints included response rate, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were treated from July 2012 – May 2015. Median number of cycles given was 3 (range: 1-6). MTD was not determined. The probability of DLT was >25% for all dose levels attempted. Four of 10 evaluable patients experienced DLT (shown in table below), including grade 3 ALT/AST elevations (n=3) and thrombocytopenia (n=2). Five of 6 patients who continued therapy beyond cycle 2 incurred at least one grade 3 adverse event. Three patients had a partial response, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95% CI: 1.4 – 9.7) and 10.1 months (95% CI: 3.6 – 20.6), respectively, in treated patients. Conclusions: While the combination of cabo and gem demonstrated activity in PDAC, this regimen is impractical due to DLT at low doses and continuing toxicities despite dose reductions and schedule changes. Clinical trial information: NCT01663272. [Table: see text]

scholarly journals Beneficial Treatment Management with Trifluridine/Tipiracil in a Patient with Metastatic Colorectal Cancer and Pronounced Hematological Event History during Previous Treatments

2018 ◽  
Vol 11 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Volker Kaechele ◽  
Jürgen Hess ◽  
Wolfgang Schneider-Kappus
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Performance Status ◽  
Recommended Dose ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
History Of ◽  
Grade 3

Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival in patients with metastatic colorectal cancer (mCRC). The most common treatment-related event (grade ≥3) was hematological toxicity. We here report long-term disease-stabilizing FTD/TPI treatment of an mCRC patient (KRAS wild-type, ECOG performance status 1 at baseline and at the end of FTD/TPI therapy) with multifocal synchronous metastases and a longstanding history of extensive hematological events during previous treatments. Finally, this 62-year-old male patient was treated for 10 months with FTD/TPI by consecutive alteration of treatment parameters: (i) initial daily dose reduction to 80 mg (72% of the recommended dose), (ii) 20 days dose delay, (iii) a second and later third dose reduction to 70 mg and 60 mg (about 64% and 55%, respectively, of the recommended dose), and (iv) 30 µg per day of granulocyte colony-stimulating factor administration first for 3 days, and later for 5 days, for each treatment cycle.

Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical Activity

2000 ◽  
Vol 18 (5) ◽  
pp. 1116-1116 ◽  
Author(s):  
Alex A. Adjei ◽  
Cheri E. Klein ◽  
Helen Kastrissios ◽  
Richard M. Goldberg ◽  
Steven R. Alberts ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Intravenous Infusion ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Clinically Significant ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Tumor Types ◽  
Dose Levels

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non–small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2.

A phase II study of capecitabine and oxaliplatin (CAPOX) in metastatic adenocarcinoma of the small bowel (SBA) or ampulla of Vater

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14025-14025
Author(s):  
M. J. Overman ◽  
S. Chedid ◽  
J. Morris ◽  
S. Waldrum ◽  
R. A. Wolff
Keyword(s):  
Small Bowel ◽  
Performance Status ◽  
Complete Response ◽  
Ampulla Of Vater ◽  
Ecog Performance Status ◽  
Ampullary Adenocarcinoma ◽  
Highly Active ◽  
Common Grade ◽  
Grade 3 ◽  
Tumor Types

14025 Background: Metastatic SBA and ampullary adenocarcinoma (AAC) are incurable, aggressive malignancies. Limited data exists regarding the role of systemic chemotherapy in these diseases. Given the marked activity of CAPOX in other cancers of the gastrointestinal tract, we have investigated the activity of this combination in these two tumor types. Methods: Patients (pts) with either metastatic or unresectable SBA and AAC who had adequate organ function, ECOG performance status (PS) ≤2 and measurable disease per modified RECIST criteria were enrolled. Prior use of 5-FU or capecitabine as adjuvant therapy, neoadjuvant therapy, or with radiation was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130mg/m2 IV on day 1 and capecitabine 750mg/m2 PO BID days 1–14. Up to 30 pts will be enrolled. The primary endpoint is overall response rate (ORR). Results: Eleven pts have been enrolled from 11/04 to 12/05 (6 with AAC and 5 with SBA). Ten pts have received ≥2 cycles and are evaluable for response. All pts had metastatic disease and none had received prior chemotherapy. Patient (pt) characteristics: median age 59 (49–76); M/F (4/7); 91% PS 0–1. Grade 3/4 toxicities included fatigue (5), neuropathy (1), anorexia (1), thrombocytopenia (1), hypokalemia (1), hyponatremia (1), and musculoskeletal (1). Common grade 1/2 toxicities included neuropathy (8), nausea (8), diarrhea (6), and fatigue (5). Four pts required dose reduction and 1 pt discontinued due to toxicity (grade 3 fatigue). Six pts, 3 AAC and 3 SBA, responded with an ORR of 60% (95% CI 31 to 83%). Five responses have been confirmed and 1 AAC pt obtained a complete response after 5 cycles of treatment. Median time to progression was 6.8m (95% CI 4.4 to 9.3+m). Conclusions: The combination of CAPOX is both well-tolerated and highly active. The ORR of 60% is one of the highest yet reported in the literature for the treatment of adenocarcinoma of the small bowel and ampulla of Vater. Enrollment continues on this trial. (Supported by a research grant from Sanofi-Aventis). [Table: see text]

Randomized phase II study of biweekly gemcitabine (gem)-paclitaxel (pac), gem-carboplatin (carb) and gem-cisplatin (cis) as first-line treatments in metastatic breast cancer (MBC) after anthracycline failure

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1099-1099 ◽  
Author(s):  
B. Xu ◽  
Z. Jiang ◽  
S. Kim ◽  
S. Yu ◽  
J. Feng ◽  
...  
Keyword(s):  
Performance Status ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
Dominant Type ◽  
Tumor Involvement ◽  
Number Of Cycles ◽  
Ecog Ps ◽  
Tumor Types

1099 Background: Biweekly gem-pac and gem-cis regimens have shown promising activity and safety in different tumor types. In MBC biweekly gem-pac is active and well tolerated. The aim of this multi-country study is to evaluate the efficacy and safety of gem in combination with pac, carb or cis on a biweekly schedule in patients (pts) with MBC. Methods: Major eligibility criteria included: tissue diagnosis of stage IV breast carcinoma; prior anthracycline therapy; ECOG performance status (PS) of 0 or 1; and written informed consent. Pts were randomized to receive gem 2500 mg/m2 in combination with pac 150 mg/m2 (Arm A), carb AUC 2.5 (Arm B) or cis 50 mg/m2 (Arm C) on day 1 of 2-week cycles. The primary endpoint was response rate, with safety a secondary endpoint. Results: This interim analysis was planned to occur when patient enrollment had reached 50% (75/150 pts), at which point there were 26 pts in Arm A, 25 in Arm B and 24 in Arm C, with 12 pts still on treatment. The baseline characteristics were similar in the three arms, including mean age (Arm A 50.2 yr, Arm B 46.1, Arm C 47.3); ECOG PS (PS 0: 50.0%, 64.0%, 54.2%); mean number of sites of tumor involvement (2.9, 2.6, 2.7); dominant type of metastasis (visceral: 73.1%, 80.0%, 79.2%); and disease-free interval (<24 mo: 53.8%, 60.0%, 41.7%). The mean number of cycles was 6.4, 6.0 and 5.8. There was a partial response in 5/26 efficacy qualified pts (19.2%), 5/25 pts (20.0%) and 2/23 pts (8.7%) in Arms A, B and C, respectively, stable disease in 10 pts (38.5%), 9 pts (36.0%) and 9 pts (39.1%), and progressive disease in 5 pts (19.2%), 6 pts (24.0%) and 6 pts (26.1%). There were no treatment-related deaths. Conclusions: The three regimens appear to show activity and have manageable toxicity when given on a biweekly schedule. [Table: see text] No significant financial relationships to disclose.

Phase I study of bortezomib plus cetuximab in patients with tumors expressing epidermal growth factor receptor (EGFR)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18143-18143 ◽  
Author(s):  
A. Dudek ◽  
P. Gada ◽  
K. Mulamalla ◽  
N. Shehadeh
Keyword(s):  
Head And Neck ◽  
Day Treatment ◽  
Growth Factor Receptor ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Human Antibody ◽  
Chimeric Mouse ◽  
Grade 3 ◽  
Dose Levels

18143 Background: Bortezomib is a proteasome inhibitor that augments EGFR inhibitor activity (Cancer Research 2007; 67:(2),1–8). Cetuximab is a chimeric mouse-human antibody against EGFR that has been found to induce tumor responses in patients with colon cancer and head and neck cancer. The purpose of this study was to establish a maximum tolerated dose (MTD) for the combination of bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumors. Methods: A 21-day treatment cycle was given with a maximum of six cycles per patient. Bortezomib was administered intravenously on days 1 and 8 via dose escalation, beginning with a minimum dose of 1.3 mg/m2 and increasing in one-tenth increments to 2.0 mg/m2 for a total of eight dose levels. Cetuximab was delivered with an initial dose of 400mg/m2 on day 1 cycle 1, with subsequent doses of 250mg/ m2 on days 1, 8 and 15. Results: Twenty patients (13 male and 7 female) with an ECOG PS <2 were enrolled in this study from November 2005 to December 2006. The median age was 59.5 (range: 41- 68), and the median number of prior chemotherapy regimens was 5 (range 1–7). Primary tumor sites included lung (9), head and neck (4), kidney (3), pancreas (2), bladder (1), and ovary (1). A total of 54 cycles of chemotherapy were administered; the median number of cycles per patient was 2.5 (range 1–6). Thirteen patients discontinued therapy because of disease progression. Two patients completed all six cycles of therapy. One dose-limiting toxicity (DLT) was seen at dose level 4 (bortezomib 1.6 mg/m2), which included grade 3 nausea, vomiting and dysphagia based on evaluation using CTCAE (version 3.0). Level 4 was expanded to enroll 3 additional patients, and no further grade 3 or 4 toxicities were observed. Grade 3/4 non- hematological toxicities were observed in 14 patients after their first cycle of therapy. Nine patients had delay in treatment. Conclusions: MTD for bortezomib plus cetuximab was not achieved at dose levels 1–6. This combination therapy has shown limited clinical activity in our extensively pretreated group of patients with solid tumors. Complete results for all dose levels, including dose levels 7–8, will be reported at the 2007 meeting of the American Society of Clinical Oncology. [Table: see text]

Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13506-e13506 ◽  
Author(s):  
T. M. Kadia ◽  
S. Faderl ◽  
Z. Estrov ◽  
M. Konopleva ◽  
S. George ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Vascular Leak ◽  
Ecog Performance Status ◽  
Acute Leukemias ◽  
Number Of Patients ◽  
Dose Levels

e13506 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule. No significant financial relationships to disclose.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15624-e15624 ◽  
Author(s):  
J. K. Bjerregaard ◽  
K. R. Schønnemann ◽  
H. A. Jensen ◽  
L. W. Vestermark ◽  
T. P. Hansen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Haematological Toxicity ◽  
Median Number ◽  
National Board ◽  
Line Therapy ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Cost

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8507-8507 ◽  
Author(s):  
F. Stephen Hodi ◽  
Mario Sznol ◽  
David F. McDermott ◽  
Richard D. Carvajal ◽  
Donald P. Lawrence ◽  
...  
Keyword(s):  
Performance Status ◽  
Tumor Burden ◽  
Clinical Activity ◽  
Ecog Performance Status ◽  
Activated T Cells ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

8507 Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. This study describes the activity and safety of BMS-936558 in patients (pts) with previously treated advanced MEL and underscores the importance of the PD-1/PD-L1 pathway in MEL therapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 95 MEL pts were treated with BMS-936558 at 0.1 (n=13), 0.3 (n=17), 1 (n=28), 3 (n=17), or 10 mg/kg (n=20). ECOG performance status was 0/1/2 in 56/36/3 pts. The majority of pts (60/95) had received prior immunotherapy (IT), primarily interferon-alpha or IL-2 (prior anti-CTLA-4 excluded). Prior B-raf inhibitor therapy was noted in 7/95 pts. The number of prior therapies was 1 (n=35), 2 (n=34), or ≥3 (n=26). Sites of metastatic disease included lymph node (n=60), liver (n=32), lung (n=55), and bone (n=10). Median duration of therapy was 15 wk (max 120 wk), with 40 pts still receiving treatment. The incidence of grade 3-4 related AEs was 19% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity was observed at all dose levels (Table). Of 20 pts with OR at the time of data lock, 12 had OR duration ≥1 yr and 6 pts were on study with OR duration between 1.9 and 11.3 mo. OR were seen in pts with visceral or bone metastases. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. Conclusions: BMS-936558 had durable clinical benefit in pts with advanced MEL, including those who had received prior IT. Further development of BMS-936558 in MEL is ongoing. [Table: see text]

A phase I/II study to evaluate the ability of decitabine and panobinostat to improve temozolomide chemosensitivity in metastatic melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3056-3056
Author(s):  
Chang Xia ◽  
Douglas Earl Laux ◽  
Jeremy Michael Deutsch ◽  
Melanie Frees ◽  
Brian Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Performance Status ◽  
Safety Data ◽  
Stage Iv ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Endpoints ◽  
Number Of Cycles ◽  
Ecog Ps

3056 Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.

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