Gemcitabine In Treatment Of Patients Research Articles

PrE0204: A multi-institutional, single arm, two-stage phase II trial of nab-paclitaxel and gemcitabine for first-line treatment of patients with advanced or metastatic cholangiocarcinoma—A PrECOG LLC study.

4072 Background: Pts with advanced or metastatic cholangiocarcinoma (CCA) have limited response to current chemotherapy regimens and poor overall survival (OS). Nab-Paclitaxel (nabPAC) can increase the intra-cellular concentration of gemcitabine (GEM) through depletion of its metabolizing enzyme, cytidine deaminase (CDA). We investigated the nabPAC+GEM combination in a ph II single arm trial in advanced or metastatic CCA pts with exploratory biomarker evaluation, including CDA, hENT1, SPARC and circulating tumor cells (CTCs). Methods: Key eligibility criteria: advanced or metastatic CCA with no prior systemic chemotherapy, age > 18, ECOG PS 0-1 and Child-Pugh < 8. Pts received nabPAC (125 mg/m2 IV) and GEM (1000 mg/m2 IV) days 1, 8 and 15 Q4 weeks until progression. Primary endpoint: progression-free survival (PFS) rate at 6 months. Secondary endpoints: safety, time to progression (TTP), objective response (ORR) and disease control rates (DCR), median PFS and OS, as well as correlation of change in CA 19-9 to clinical efficacy. The study required > 43 of 67 evaluable patients alive and progression-free at 6 months to conclude the 6-month PFS rate is at least 70% against a null hypothesis of 55% based on historical data. Results: 73 eligible patients (41.1% male, 91.8% Caucasian, 45.2% ECOG PS 0) were enrolled across 22 sites with a median age of 62 (range 36-87) years and received a median of 6 (range 1-18) cycles. The primary endpoint of PFS rate at 6 months was 54.7% on intention to treat analysis. Response evaluation is underway and will be reported at the meeting. The median PFS and OS were 6.5 (95% CI, 5.1-7.7) and 10.3 (95% CI, 9.1-14.6) months, respectively. The safety profile of nabPAC+GEM was similar to that reported in ph III MPACT trial. The most common treatment-related G3/4 toxicities were neutropenia (24.3%), fatigue (13.5%) and anemia (12.2%). Five patients remain on the trial. Exploratory analyses are pending. Conclusions: The observed PFS rate at 6 months with nabPAC+GEM in CCA is insufficient to reject the null hypothesis of 55% PFS at 6 months, and appears to be as effective as the historical control. Clinical trial information: NCT02181634.

Abstract OT2-01-17: A Phase II randomized trial of pembrolizumab with carboplatin and gemcitabine for treatment of patients with metastatic triple-negative breast cancer (mTNBC)

Abstract Background: Treatment for mTNBC is limited, and significant challenges persist in treating this disease, as outcomes remain largely dependent on chemotherapy without any effective targeted treatment. Pembrolizumab (MK-3475) is a highly selective, humanized monoclonal antibody against PD-1, blocking the negative immune regulatory signaling of the PD-1 receptor that is usually expressed by T-cells. Recent data showed that some patients with mTNBC may benefit from immune-based therapies (PD-1 or PD-L1 antibodies). Cumulative evidence suggest that stromal tumor infiltrating lymphocytes (sTILs) have a prognostic and predictive role in response to treatment in subsets of TNBC, particularly in response to carboplatin use. Preclinical data revealed that blocking PD-1/PD-L1 pathway in combination with platinum containing cytotoxic therapy improved response rates and survival. High levels of sTILs and an increased PD-L1 expression make mTNBC a candidate for PD-1–targeted therapy. As studies showed that the subset of TNBC with better response rates to carboplatin are heavily infiltrated with sTILs, pembrolizumab, becomes a very attractive drug to be tested in combination with carboplatin, with the goal of improving outcomes in mTNBC. A Phase II multicenter, randomized, trial has been initiated to evaluate the efficacy and safety of combining pembrolizumab with carboplatin and gemcitabine in patients with mTNBC. Methods: A safety run-in will assess the safety and tolerability of combining pembrolizumab with carboplatin and gemcitabine in patients with mTNBC. Following the completion of the safety run-in, patients will be randomized 2:1 to receive pembrolizumab (200 mg IV) on day 1 along with carboplatin (AUC 2, day 1 and day 8, IV) plus gemcitabine (800 mg/m2, day 1 and day 8, IV) of a 21-day cycle, or carboplatin plus gemcitabine (same aforementioned dose) alone. Patients will have histologically documented unresectable mTNBC. Prior systemic therapy for mTNBC, for up to 2 lines is allowed, and patients will have ECOG PS 0–2 and measurable disease (RECIST v1.1). Prior carboplatin/gemcitabine or cisplatin therapy is allowed in the adjuvant or neoadjuvant setting, as long as it occurred more than 12 months from the beginning of their enrollment. Subjects whose tumors progressed while on treatment with carboplatin or cisplatin are excluded. Known CNS disease (except asymptomatic treated metastases), autoimmune disease or prior immune checkpoint blockade therapy is an exclusion to enrollment on this trial. Primary endpoint is assessing the objective response rate according to RECIST v1.1 . Other endpoints include clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Tumor biopsies will be obtained at baseline and just prior to initiation of cycle 3 to assess biomarkers of response and immune escape. PD-L1 expression will be evaluated in exploratory analysis with a planned assessment of response based on PD-L1 status. This trial will enroll 6-12 patients in the safety run-in portion, and 75 patients in the randomized part, at 7 sites in the United States. Clinical trial information: NCT02755272 www.clinicaltrials.gov. Citation Format: Obeid E, Miller KD, Sparano JA, Blackwell K, Goldstein LJ. A Phase II randomized trial of pembrolizumab with carboplatin and gemcitabine for treatment of patients with metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-17.

A randomized, multicenter, double-blind, placebo-controlled study of the Bruton tyrosine kinase inhibitor, ibrutinib, versus placebo in combination with nab-paclitaxel and gemcitabine in the first-line treatment of patients with metastatic pancreatic adenocarcinoma (RESOLVE).

TPS483 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and short survival. Nab-paclitaxel/gemcitabine (Nab-P/GCB) is a preferred regimen for front-line treatment. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (ibr) shows antitumor activity in preclinical PDAC models, in part, due to modulation of the tumor microenvironment. Ibr treatment inhibits mast-cell degranulation and decreases tumor-associated inflammation and desmoplasia with simultaneous enhanced presence and activity of cytotoxic T cells in tumors (Affara et al, Cancer Cell, 2014; Masso-Valles et al, Cancer Res, 2015). This randomized trial will evaluate the efficacy of ibr in combination with Nab-P/GCB. Methods: The randomized, multicenter, double-blind RESOLVE trial (NCT02436668; PCYC-1137-CA) will compare ibr vs. placebo in combination with Nab-P/GCB in approximately 320 patients with untreated metastatic PDAC. Key eligibility criteria include histologically confirmed metastatic PDAC; stage IV diagnosis within 6 weeks of randomization; adequate hematologic, hepatic, and renal function; and Karnofsky performance score ≥ 70. Key exclusion criteria include prior therapies (chemotherapy for primary PDAC, BTK inhibitor, or radiotherapy), neuroendocrine or acinar pancreatic carcinoma, known brain or leptomeningeal disease, and history of stroke or intracranial hemorrhage < 6 months prior to enrollment. Patients will be randomized to oral ibr (560 mg) or matched placebo given daily in combination with Nab-P (125 mg/m2) and GCB (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle until disease progression or treatment is no longer tolerated. A safety run-in phase will evaluate the ibr combination prior to the randomization portion of the study. The primary endpoint is progression-free survival; secondary endpoints include overall survival and safety. Enrollment in the trial has been initiated. Clinical trial information: NCT02436668.

Masitinib plus carboplatin and gemcitabine for treatment of patients with advanced triple negative breast cancer: An open label phase Ib/II trial.

1070 Background: Masitinib (MAS) is a selective inhibitor of c-Kit and mast cell function, both of which have been linked to disease progression and poor prognosis in triple negative breast cancer ...

Pancreatic cancer – ASCO 2009

The publication of practice changing clinical data is a rare event in the field of pancreatic cancer. In line with this general statement, oncologists attending or following the ASCO Annual Meeting 2009 were not surprised by being confronted with the study results mainly confirming the already existing evidence. The following conference report will therefore in its first part cover the results of the most important clinical phase III-trials presented. The ESPAC 3(v2)-study established 5-Fluorouracil (5-FU) as an equally effective but more toxic alternative to gemcitabine in the adjuvant treatment of patients with resected pancreatic cancer. Concerning the palliative treatment of advanced disease the Italian GIP-1-study provided us with another set of data comparing gemcitabine with a gemcitabine/platinum-duplet, once again failing to document a survival benefit. The CONKO-004-study investigated the prophylactic application of a low-molecular-weight heparin (enoxaparin) in patients treated with chemotherapy for advanced pancreatic cancer. As one would expect, the rate of symptomatic venous thromboembolic events with this intervention was reduced. Whether this will translate into a survival benefit remains to be established, as the final analysis of this trial is still pending. Due to the paucity of presentations with further immediate practical relevance the second part of this short review will touch on two exciting abstracts dealing with the search for new therapeutic concepts, drugs and targets.

Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study

4617 Background: Masitinib, a tyrosine kinase inhibitor targeting c-Kit, PDGFR, FGFR3 and affecting the FAK pathway, can enhance the antiproliferative effects of gemcitabine (GEM) in human pancreatic cancer cells. This multicenter phase 2 study aimed to determine the efficacy and safety of masitinib in combination with GEM in the first-line treatment of patients with locally advanced (LAPC) or metastatic (MPC) pancreatic cancer. Methods: Patients received oral masitinib (9 mg/kg/d) and standard weekly infusion of GEM (1,000 mg/m2). Primary endpoint was time-to-progression (TTP). Our hypothesis for efficacy was a TTP over 2.1 months. Secondary endpoints included survival rates, tumor response (RECIST) and clinical benefit. Results: 22 patients, with LAPC (n=9) or MPC (n=13), KPS[80–100]/[70] (18/4) were enrolled and treated with masitinib plus GEM. Median TTP was 6.4 months, well beyond our threshold for efficacy (LAPC: 8.3 months, MPC: 2.7 months, KPS[80–100]: 6.4 months, KPS[70]: 0.8 months). At 12 months, 17% of LAPC and 14% of KPS[80–100] were progression-free; all MPC and KPS[70] patients had progressed. The disease control rate was 73% (LAPC: 89%, MPC: 62%, KPS[80–100]: 89%; KPS[70] patients progressed immediately). Median OS was 7.1 months (LAPC: 8.4 months, MPC: 6.8 months, KPS[80–100]: 8.0 months, KPS[70]: 4.4 months). At 18 months, the survival rate was 23%. However, when considering KPS[80–100] alone, it reached 28%. The 18-months survival rates were similar for LAPC (22%) and MPC (23%). 16% of the 19 patients evaluated experienced clinical benefit (LAPC: 38%, KPS[80–100]: 18%). One patient (5%) presented suspected grade 4 neutropenia. Main suspected grade 3 toxicity were anemia, lymphopenia (23%), leucopenia, neutropenia (18%), asthenia (14%), diarrhea, cytolytic hepatitis, and skin rash (9%). Altogether, the combination masitinib plus GEM did not seem to increase the toxicity commonly reported with GEM alone. Conclusions: The antitumor activity of the combination masitinib plus GEM is very promising and does not present limiting toxicities. Based on those encouraging data, a randomized phase III trial comparing masitinib plus GEM with GEM alone is now actively recruiting patients in the US and in Europe. [Table: see text]

Phase II study of Gemcitabine for treatment of patients with advanced stage marginal zone B-cell lymphoma: Consortium for Improving Survival of Lymphoma (CISL) trial

Therapeutic approaches to marginal zone B-cell lymphoma (MZL) continue to evolve. Localized MZL responds favorably to local treatments, including surgery and/or local radiation therapy. However, MZL manifests as a disseminated disease in one-third of the cases at diagnosis. Moreover, relapses involving distant sites after local therapy have been reported previously. Therefore, the search for effective forms of systemic therapy is a critical issue. We conducted this multi-center, phase II trial to assess the efficacy and safety of gemcitabine single chemotherapy for patients with stage III/IV MZL. Patients received gemcitabine 1250 mg/m(2) on days 1 and 8 of each cycle. The treatment was repeated every 3 weeks and continued for 6 cycles until disease progression, withdrawal due to toxicity, or withdrawal of consent. Between Sep. 2006 and Sep. 2008, a total of 16 patients were enrolled (with informed consent) into this trial from 6 institutes in Korea. Among these patients, 4 patients dropped out without evaluation. The median age of the 12 (9 males, 3 females) evaluated patients was 62 (range 25-73) years. Seven patients (58%) evidenced involvement of extranodal sites. All patients received previous treatment for MZL. The patients received a total of 69 cycles of gemcitabine chemotherapy (range 3-6 [median 6] cycles/person). There were 2 PR (17%; 95% Confidence Interval [CI], 0.0-41%), 9 SD (75%), and 1 PD (8%). There were 8/69 cycles (12%) of grade 3/4 neutropenia. Non-hematologic toxicities were mild and tolerable. There were 5 cycles (8%) of delayed chemotherapy (median 1 week) owing to neutropenia. Dose reduction was required in 12 cycles. However, no treatment-related death occurred in this study. The median TTP was 10.2 months (95% CI, 5.3-15.1). As the response rate in stage I did not justify progressing to stage II (> or = 8/15), this study had to be discontinued, in accordance with the established protocols. Gemcitabine as a single agent, in this dosage and at this schedule, evidenced minimal clinical activity in cases of advanced MZL.

Sequential cisplatin–gemcitabine–docetaxel vs docetaxel–gemcitabine in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): Interim results of an ongoing phase II trial

7113 Background: Chemotherapy doublet regimens remain the standard first-line treatment for patients with metastatic NSCLC and good performance status. Three-drug regimens may improve response desp...