Toxic and Therapeutic Activity of 4'-Epi-Doxorubicin

1982 ◽  
Vol 68 (2) ◽  
pp. 105-111 ◽  
Author(s):  
Valeria Bonfante ◽  
Fabrizio Villani ◽  
Gianni Bonadonna
Keyword(s):  
Malignant Melanoma ◽  
Antitumor Activity ◽  
Acute Toxicity ◽  
Phase I ◽  
Cardiac Toxicity ◽  
Objective Response ◽  
Therapeutic Activity ◽  
Cardiac Damage ◽  
Noninvasive Methods ◽  
Advanced Malignancy

A Phase I-II study with 4'-epi-doxorubicin (epi-DX) was performed in 108 patients with various types of advanced malignancy. The pattern of acute toxicity was similar to that of doxorubicin (DX). However, epi-DX was better tolerated than DX because of comparative lower incidence of vomiting, stomatitis, complete alopecia and severe myelosuppression. Cardiac toxicity was studied by utilizing noninvasive methods, and the electrocardiographic results suggested a slightly lower cardiac damage after epi-DX compared to DX. Antitumor activity was documented in a variety of neoplasms, and objective response was also observed in those considered refractory to DX such as malignant melanoma and renal cancer.

Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Amita Patnaik ◽  
Soonmo Peter Kang ◽  
Anthony W. Tolcher ◽  
Drew Warren Rasco ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Preliminary Evidence ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Multiple Tumor ◽  
Label Dose ◽  
Grade 3 ◽  
Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

SGN-40 (Anti-huCD40 mAb) Monotherapy Induces Durable Objective Responses in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma: Evidence of Antitumor Activity from a Phase I Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 695-695 ◽  
Author(s):  
Ranjana Advani ◽  
Andres Forero-Torres ◽  
Richard R. Furman ◽  
Joseph D. Rosenblatt ◽  
Anas Younes ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Maximum Dose ◽  
Single Agent ◽  
Objective Response ◽  
Pharmacokinetic Parameters ◽  
Hepatic Transaminases

Abstract CD40 is a member of the TNF receptor family and is widely expressed on B-cell malignancies. SGN-40 is a humanized antibody against CD40 with effector cell function and partial agonistic activity. Based on potent in vitro and in vivo preclinical activity, a multi-institutional, multi-dose phase I study was conducted to test the safety, pharmacokinetic properties, immunogenicity, and antitumor activity of intravenous SGN-40 in patients with relapsed NHL. Patients with multiple histologic subtypes of NHL were enrolled on this study, including diffuse large B-cell (DLBCL; 14), follicular (FCL; 9), mantle cell (MCL; 9), marginal zone (MZL; 2) and small lymphocytic (SLL; 1). After dose-dependent inflammatory symptoms were identified following the first infusion of SGN-40 in a separate phase I study (i.e. cytokine release syndrome, including headache, fever, muscle aches), this study was modified such that patients were treated with a dose-loading schedule: 1 mg/kg of SGN-40 on day 1 and day 4 and subsequent intra-patient dose-escalation during weeks 2–5 to a maximum dose of 3, 4, 6, or 8 mg/kg over four cohorts. Subsequently, a rapid dose-loading schedule was tested in one cohort (40% increase in total SGN-40 administered during cycle 1). Responding patients or those with stable disease were eligible for a second cycle, consisting of four consecutive weekly infusions at the cohort-specific maximum dose of SGN-40. Most adverse events were grade 1 or 2 and included fatigue (31%), headache (26%), chills (17%), pyrexia (17%), elevated hepatic transaminases (11%), and hypotension (11%). Transient drug-related grade 3 adverse events included conjunctivitis and unilateral loss of visual acuity, anemia, and elevated hepatic transaminases, each in a single patient. There was no difference in the incidence or severity of adverse events at higher doses of SGN-40 nor was there a difference in the safety profiles of the gradual vs. rapid dose-loading schedules. Ten of 35 enrolled patients received a second cycle of treatment without any evidence of cumulative toxicity. No immune responses against SGN-40 have been detected among 16 NHL patients tested to date. Preliminary pharmacokinetic parameters are similar to those seen in preclinical toxicity studies. Durable objective responses have been observed in heavily pre-treated patients. Eight patients with DLBCL completed cycle 1 and received a maximum dose of at least 3 mg/kg SGN-40 with an objective response rate of 37.5% (i.e. 1 CR and 2 PR) and 2 SD. Additional objective responses were seen in one patient with MCL (CR) and one patient with MZL (PR). The median duration of response for these 5 patients has not yet been reached (range 8–37 weeks). Analyses are ongoing to evaluate the role of CD40 expression levels and the relationship of FcγR polymorphisms to response. In conclusion, SGN-40 has favorable safety data and encouraging antitumor activity. A phase II study of single-agent SGN-40 in patients with relapsed DLBCL is planned.

Combination Chemotherapy with 1-Methyl-1-Nitrosourea and Cyclophosphamide in Metastatic Melanoma

1978 ◽  
Vol 64 (1) ◽  
pp. 89-94 ◽  
Author(s):  
Krsto Kolarić ◽  
Anton Roth ◽  
Vera Fuss
Keyword(s):  
Body Weight ◽  
Malignant Melanoma ◽  
Antitumor Activity ◽  
Lymph Nodes ◽  
Metastatic Melanoma ◽  
Combination Chemotherapy ◽  
Tumor Regression ◽  
Objective Response ◽  
Metastatic Malignant Melanoma ◽  
Melanoma Metastasis

Twenty one patients with advanced metastatic melanoma were treated with a combination of 1-methyl-1-nitrosourea (MNU) and cyclophosphamide. AH the patients had not previously been treated with cytostatics. MNU in the dose of 4 mg/kg and cyclophosphamide in the dose of 8 mg/kg body weight was administered daily. The drugs were given in 6 day cycles. Objective response (> 50% tumor regression) was obtained in 8 (38%) of the 21 treated patients, with 2 complete and 6 partial remissions. The duration of remission was 2–12 months (M = 6.2 months). Injections of MNU caused nausea and vomiting in approximately all the treated patients. Combination of these drugs, however, produced myelodepression in 33% of treated patients. This combination of drugs showed antitumor activity in metastatic malignant melanoma, particularly in melanoma metastasis of the lung, brain and lymph nodes and needs further investigation.

Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206

2005 ◽  
Vol 23 (35) ◽  
pp. 8968-8977 ◽  
Author(s):  
Antoni Ribas ◽  
Luis H. Camacho ◽  
Gabriel Lopez-Berestein ◽  
Dmitri Pavlov ◽  
Cecile A. Bulanhagui ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Phase I ◽  
T Lymphocyte ◽  
Phase I Trial ◽  
Cytotoxic T Lymphocyte ◽  
Objective Response ◽  
Local Treatment ◽  
Systemic Exposure ◽  
Response To Therapy

Purpose Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206. Patients and Methods Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose. Results Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response. Conclusion CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Outpatient Biochemotherapy With Interleukin-2 and Interferon Alfa-2b in Patients With Metastatic Malignant Melanoma: Results of Two Phase II Cytokine Working Group Trials

2001 ◽  
Vol 19 (13) ◽  
pp. 3194-3202 ◽  
Author(s):  
L. E. Flaherty ◽  
M. Atkins ◽  
J. Sosman ◽  
G. Weiss ◽  
J. I. Clark ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Antitumor Activity ◽  
Phase Ii ◽  
Working Group ◽  
Objective Response ◽  
Interleukin 2 ◽  
Metastatic Malignant Melanoma ◽  
Phase Iii ◽  
Group 2 ◽  
Group 1

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m2/d intravenously (IV) and cisplatin 25 mg/m2/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m2 subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m2, and in group 2, SC IL-2 was given at 5.0 mU/m2. RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.

Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

2009 ◽  
Vol 27 (7) ◽  
pp. 1075-1081 ◽  
Author(s):  
Luis H. Camacho ◽  
Scott Antonia ◽  
Jeffrey Sosman ◽  
John M. Kirkwood ◽  
Thomas F. Gajewski ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Cytotoxic T Lymphocyte ◽  
Single Agent ◽  
Objective Response ◽  
Complete Response ◽  
Dosing Regimen ◽  
Grade 3

PurposeCytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.Patients and MethodsTwenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose. During phase II, 89 patients received tremelimumab 10 mg/kg once every month or 15 mg/kg every 3 months.ResultsNo dose-limiting toxicity was observed in phase I once every month dosing. In phase II, 8 (10%) of 84 response-assessable patients attained objective antitumor responses; best overall objective response was one complete response and three partial responses in each dosing regimen. Most responses were durable (range, 3 to 30+ months). Most frequent treatment-related adverse events (AEs) were diarrhea, rash, and pruritus. Frequency of grade 3/4 AEs was 13% in the 15 mg/kg every 3 months arm and 27% in the 10 mg/kg once every month. Serious AEs were also less frequent in the 15 mg/kg once every 3 months cohort (9% v 23% in 10 mg/kg arm).ConclusionMultiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

scholarly journals A phase I study of the safety and activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiujie Cui ◽  
Haiyan Yang ◽  
Jue Liu ◽  
Donghui Chen ◽  
Jiong Hu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dose Escalation ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Marine Microorganisms ◽  
Open Label ◽  
Dose Escalation Study

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lack of effective therapeutic drugs. K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced PDAC. Methods In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3 + 3 design. K-001 was administered twice daily in four-week cycles, and dose escalation from 1350 mg to 2160 mg was evaluated twice daily. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed while tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST). Results Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and hemorrhoid bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%. Conclusions K-001 manifests satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted. Trial registration NCT02720666. Registered 28 Match 2016 - Retrospectively registered.

A phase I/II study of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR in advanced hepatocellular carcinoma (HCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4108-4108 ◽  
Author(s):  
Thomas Cheung Yau ◽  
Wattana Sukeepaisarnjaroen ◽  
Yee Chao ◽  
Chia-Jui Yen ◽  
Wirote Lausoontornsiri ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Migration And Invasion ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
First Line Therapy ◽  
Asian Patients

4108 Background: Hepatocyte growth factor (HGF)/MET signalling plays a pivotal role in tumor cell proliferation, migration and invasion in HCC and circulating levels of HGF correlate with poor prognosis. This phase I/II trial (MET111645) evaluated foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2 and VEGFR, as first-line therapy in Asian advanced-HCC patients. Methods: Asian patients with measurable, unresectable/metastatic HCC, no prior sorafenib or other multi-kinase inhibitors, ECOG PS 0-1, adequate organ function and Child-Pugh grade A were recruited. The phase I was a standard 3+3 dose escalation design with a phase II cohort expansion. The primary endpoint was safety and tolerability at the maximum tolerated dose (MTD) and the secondary endpoints included antitumor activity (objective response rate [ORR], disease stabilization rate [DSR; confirmed CR/PR or SD for at least 12 weeks], and time to progression [TTP] evaluated by central review according to modified RECIST), and overall survival (OS) at the MTD, plus pharmacokinetics (PK). Results: Thirteen patients were enrolled in phase I. Two dose-limiting toxicities (DLT) (renal failure, proteinuria) were observed at 45 mg once daily (QD) but no DLTs were observed at 30 mg QD. Thus, the MTD was determined to be 30 mg QD. A further 32 patients were enrolled at the MTD, for a study total of 39 patients treated at 30 mg QD. The most common AEs, independent of causality,were hypertension (36%), decreased appetite (23%), and pyrexia (21%). The most common SAEs were hepatic encephalopathy (10%) and ascites (8%). Two patients discontinued foretinib due to AEs. No dose reductions were reported. Thirty-eight patients were evaluable for efficacy. The ORR was 24% (95% CI 11-40), DSR 79% (95% CI; 63-90), and the median TTP was 4.2 months (95% CI 2.7-7.5). Mature OS data will be presented. Mean steady-state exposures (AUC/Cmax) were comparable after administration of foretinib at 30 and 45 mg. Conclusions: Foretinib has an acceptable safety, tolerability, and PK profile in an Asian HCC population. It has demonstrated promising antitumor activity that warrants further testing in a randomized setting.

Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2579-2579 ◽  
Author(s):  
Ruud van der Noll ◽  
Joo Ern Ang ◽  
Agnes Jager ◽  
Serena Marchetti ◽  
Marja Mergui-Roelvink ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Objective Response ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Capsule Formulation ◽  
Tumor Types

2579 Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsule and tablet formulations were studied. Capsule formulation data are presented; continuous O with C (P1; 21 day cycle), CPa (P2a; 21 day cycle) and weekly Pa (P2b; 28 day cycle) or intermittent O with CPa (P3; 21 day cycle). Primary and secondary objectives were safety/tolerability and antitumor activity (RECIST), respectively. Results: This analysis (non validated data) included 87 enrolled pts (P1 [n=25] P2a [n=20] P2b [n=12] and P3 [n=30]). Most common tumor types were breast (26%), melanoma (10%) and ovarian (7%). 12 pts had known gBRCA1/2 mutations. A tolerable continuous dosing schedule of O with CPa was not determined. Most common AEs (all grades) were myelosuppression (71%) notably neutropenia (54%) and thrombocytopenia (26%), and fatigue (77%). Excessive treatment cycle delays due to hematologic toxicity occurred with continuous O combined with standard doses of C or CPa. Two doses were identified as tolerable: continuous O 100 mg bd with weekly Pa 80 mg/m2 and intermittent O 200 mg bd (d1–10) with CPa AUC4/175 mg/m2 q 3 weeks. 14/87 pts (16%) had an objective response (complete response [CR] 5%; partial response [PR] 11%); 28% had stable disease for ≥4 months. Activity appeared greater in pts with BRCA1/2 mutations (CR 17%; PR 33%). Conclusions: Continuous O in combination with CPa exacerbated hematologic toxicities leading to schedule delays. Tolerability improved with intermittent O. Antitumor activity was highest in pts with a BRCA1/2 mutation. This study identified two tolerable O capsule treatment schedules for further development. Clinical trial information: NCT00516724. [Table: see text]

A phase I fixed-dose feasibility study of MK615 and gemcitabine in patients with advanced or metastatic pancreatic cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 510-510
Author(s):  
Ichiro Moriyama ◽  
Fumiyoshi Ikejiri ◽  
Koshi Kawakami ◽  
Masaya Inoue ◽  
Satoshi Kumanomido ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Treatment Cycle ◽  
Day Treatment ◽  
Objective Response ◽  
Metastatic Pancreatic Cancer ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Phase Ii Trials

510 Background: The medical agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes. Antitumor activity of MK615 and its additive effect when combined with gemcitabine in pancreatic cancer cell line. MIAPaCa-2 was previously reported by our group. The objective of this phase I trial was to evaluate safety and feasibility of combined MK615 and gemcitabine therapy in patients with advanced or metastatic pancreatic cancer. Methods: Patients with untreated pancreatic cancer or those who underwent chemotherapy without gemcitabine were enrolled. Gemcitabine was infused at 1000 mg/m2 over 30 minutes once weekly for 3 weeks of each 28-day treatment cycle. Three packets of MK615 were orally administered daily during each 28-day treatment cycle, until any discontinuation criteria were met. If severe toxicity occurred, dose was reduced. Results: All five patients enrolled were evaluable for toxicity and response. Median age was 72 (54-79) years. Three patients had performance status (PS) 0, one had PS 1, and one PS 2. Three of five patients had been treated with chemotherapy; two with FOLFIRINOX and one with S-1. One of five patients treated had grade 4 neutropenia and two were administered granulocyte-colony stimulating factor. No patient had febrile neutropenia or adverse event leading to death. Relative dose intensity was 96.6% and 69.8% for MK615 and gemcitabine, respectively. No patients had objective response (complete response + partial response), while 2 of 5 patients (40%) had disease control (objective response + stable disease). Conclusions: Combined MK615 and gemcitabine therapy was well-tolerated and showed antitumor activity in patients previously treated without gemcitabine or untreated patients with advanced or metastatic pancreatic cancer. Currently, we are planning phase II trials for elderly or frail people.

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