A Phase I Study of Combination Chemotherapy with Gemcitabine and Oral S-1 for Advanced Pancreatic Cancer

4122 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib (PTK787/ZK 222584) is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Previous adjuvant chemoradiotherapy with fluorouracil was allowed. Gemcitabine was given by fixed-dose rate infusion weekly x 3 in a 28-day cycle, and vatalanib was given orally daily. Dose-limiting toxicities (DLT) are defined as any grade 3/4 toxicity during the first cycle. The dose levels are as follows: Results: To date, 11 patients are evaluable for toxicity (5M/6F; median age 62 years, range 40–82 years; median KPS 90%). Thus far, 42 cycles have been given, with a median of four cycles per patient. Two patients have experienced DLT. The first patient (cohort 1) experienced grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The second patient (cohort 3) developed grade 3 deep vein thrombosis. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (3), thrombocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Three of eleven patients (27%) did not complete treatment to the first evaluation timepoint (2 cycles); two discontinued due to toxicity and one discontinued due to disease progression. Two of eleven patients (18%) had a partial response by RECIST. Six of eleven patients (55%) had stable disease as the best response ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated with most grade 3/4 toxicities occurring late in the treatment course. Antitumor responses have been observed at initial dose levels and accrual to the final cohort with BID dosing of vatalanib continues. [Table: see text] No significant financial relationships to disclose.

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Phase I trial of imexon, Inj. plus gemcitabine in patients with advanced previously untreated pancreatic adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15058 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15058-15058

Author(s):

S. J. Cohen ◽

M. Zalupski ◽

M. Modiano ◽

P. Conkling ◽

D. Mahadevan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase I ◽

Pancreatic Adenocarcinoma ◽

Phase I Study ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Maximum Tolerated Dose ◽

Pancreatic Cancer Cells ◽

Dosing Regimens ◽

Ecog Ps

15058 Background: Imexon for inj. (Amplimexon®, AMP) is an aziridine-containing iminopyrrolidone which causes G2 arrest, accumulation of reactive oxygen species, and induction of apoptosis in pancreatic cancer cells. AMP demonstrated synergy with gemcitabine (GEM) in preclinical pancreatic cancer models. This phase I study of AMP plus GEM was undertaken to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary endpoints were pharmacokinetics for both agents (PK) and tumor response. Methods: Patients (pts) with previously untreated advanced pancreatic adenocarcinoma received one of two dosing regimens. The first 19 received 30 minute AMP IV days 1–5 and 15–19 followed by 30 minute GEM IV days 1, 8 and 15 Q4 wks (Regimen A). Dosing was modified after 19 pts to administer both AMP and GEM over 30 minutes days 1, 8 and 15 every 4 weeks (Regimen B). Dose levels (AMP/GEM, in mg/m2) for Regimen A: 200/800, 280/800, 200/1000, and 280/1000, and for Regimen B: 280/1000, 335/1000, 390/1000, 540/1000, and 750/1000. The current cohort is 1000/1000. Pts were assessed for response after cycles 2, 5 and 8. PK and pharmacodynamic (plasma thiol depletion) measurements were obtained during cycle one. Results: Forty-six pts have been treated to date, with 36 having complete toxicity data and evaluable. Pt characteristics: M/F (24/12), Age (mean 60.4 years, range 43–75), ECOG PS 0/1 (56%, 44%), metastatic/locally advanced (91%, 9%). The 36 pts have completed 122.5 cycles of therapy (median 2, range 0.5–12). Common toxicities: anemia (77%), fatigue (71%), nausea (60%), fever (54%), and leukopenia (54%). DLT were 1/6 at 280/1000 (Regimen A - febrile neutropenia), 1/6 at 280/1000 (Regimen B - gr 3 hypotension, gr 4 renal failure), and 1/9 at 390/1000 (gr 3 hyperbilirubinemia). Accrual continues at 1000/1000. Of 36 pts, 4 have had partial responses and 14 stable disease. PK and plasma thiol analysis are ongoing. Conclusions: Imexon can be administered safely with full dose gemcitabine. Accrual continues to define the combination MTD. The response rate in this phase I study compares favorably with historical gemcitabine monotherapy, and further phase II evaluation of this combination in advanced pancreatic cancer is warranted. No significant financial relationships to disclose.

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A phase I study of imexon inj plus gemcitabine as first-line therapy for advanced pancreatic cancer with preclinical mechanistic study of dose limiting toxicity

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.4619 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 4619-4619 ◽

Cited By ~ 1

Author(s):

S. J. Cohen ◽

M. M. Zalupski ◽

M. R. Modiano ◽

P. R. Conkling ◽

Y. Z. Patt ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase I ◽

Phase I Study ◽

Advanced Pancreatic Cancer ◽

Mechanistic Study ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Dose Limiting Toxicity

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Phase I/II trial of gemcitabine (Gem) plus irinotecan (CPT-11) for metastatic pancreatic cancer (MPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.301 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 301-301

Author(s):

Takuo Yamai ◽

Tatsuya Ioka ◽

Hironari Sueyoshi ◽

Ryoji Takada ◽

Nobuyasu Fukutake ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Phase I ◽

Phase Ii ◽

Combination Chemotherapy ◽

Phase I Study ◽

Progressive Disease ◽

Metastatic Pancreatic Cancer ◽

Refractory Ascites ◽

Recommended Phase Ii Dose

301 Background: Treatment options for patients with metastatic pancreatic cancer are still limited. Recently, new strategies to prolong disease control are reported. We conducted phase I/II trial of GEM+CPT-11 combination chemotherapy for MPC to evaluate the effectiveness and safety. Methods: As phase I study, traditional 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose. Four escalating dose levels of GEM/CPT-11 (800/60 mg/m2, 1000/60 mg/m2, 1000/80 mg/m2, and 1000/100 mg/m2) were studied. As results of this investigation, the recommended phase II dose was GEM 1000 mg/m2 and CPT-11 100 mg/m2, biweekly. Phase II eligibility included naïve MPC, PS0-2, Pathological diagnosis, no refractory ascites and pleural effusion, and adequate organ function. Primary endpoint was overall survival. Results: Eighteen patients were entered phase I study. The DLTs were anorexia, and nausea/vomiting. Severe neutropenia was rare. MTDs were determined GEM 1000 and CPT-11 100 mg/m2. After that, we investigated phase II trial in 40 patients. There were 6 partial response, 14 stable disease, 18 progressive disease and 2 in-evaluable. Response rate was 16%. The median overall survival was 7.5 months; progressive disease 4.0 months. Grade 3 to 4 toxicity included neutropenia (7%), anemia (7%), diarrhea (7%), ALT elevation (10%), pneumonitis(7%). There was no treatment-related death. Conclusions: This combination chemotherapy is not effective as first-line chemotherapy for metastatic pancreatic cancer. But this is safe and generally well tolerated. This chemotherapy could be effective of salvage chemotherapy with low toxicity after standard chemotherapy such as FOLFIRINOX.

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