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

ABSTRACT: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ?1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ?25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, 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). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

SUBMITTER: Zhen DB

PROVIDER: S-EPMC7458140 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Zhen David B DB Griffith Kent A KA Ruch Joshua M JM Camphausen Kevin K Savage Jason E JE Kim Edward J EJ Sahai Vaibhav V Simeone Diane M DM Zalupski Mark M MM

Investigational new drugs 20160721 6

Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dos ...[more]

PMID: 27439894

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Project description:PurposeTH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer.Patients and methodsPatients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety.ResultsTwo hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation.ConclusionPFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC.Materials and methodsThis was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS).ResultsTwenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2 . The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months).ConclusionGemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study.Implications for practiceGemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.

Project description:BackgroundIn the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.MethodsIn this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.Findings114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups.InterpretationOur results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small.FundingCancer Research UK.

Project description:BackgroundMasitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Patients and methodsPatients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic.ResultsThree hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable.ConclusionsThe present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation.Trial registrationClinicalTrials.gov:NCT00789633.

Project description:Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine.Tumors were measured by [18F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline.Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m2 and 125 mg/m2 cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m2 had a 4-month survival advantage over those who received 100 mg/m2. All patients in the nab-paclitaxel 125 mg/m2 cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m2 cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman r s = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m2 cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%.The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC.NCT00398086.

Dataset Information

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

Publications

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

Similar Datasets

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