scholarly journals Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives

2021 ◽  
Vol 13 ◽  
pp. 175883592110185
Author(s):  
Lisa Lellouche ◽  
Lola-Jade Palmieri ◽  
Solène Dermine ◽  
Catherine Brezault ◽  
Stanislas Chaussade ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Performance Status ◽  
Ductal Adenocarcinoma ◽  
Induction Treatment ◽  
Tumor Control ◽  
Small Subset ◽  
Second Line ◽  
Molecular Alterations ◽  
First Line Therapy

Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene ( BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase ( NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients’ outcomes in the near future.

scholarly journals Complete Radiologic Response of Metastatic Pancreatic Ductal Adenocarcinoma to Microwave Ablation Combined with Second-Line Palliative Chemotherapy

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Hakon Blomstrand ◽  
Karin Adolfsson ◽  
Per Sandström ◽  
Bergthor Björnsson
Keyword(s):  
Adjuvant Chemotherapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Palliative Chemotherapy ◽  
Lung Metastases ◽  
Performance Status ◽  
Progression Free Survival ◽  
Disease Recurrence ◽  
Ductal Adenocarcinoma ◽  
Second Line ◽  
First Line

Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis, especially for the majority of patients diagnosed with metastatic disease. The primary option for palliative treatment is chemotherapy, and responses beyond first-line treatment are rare and typically short. Here, we report a case of a 63-year-old woman with PDAC in the head of the pancreas who was initially successfully treated by pancreaticoduodenectomy followed by adjuvant chemotherapy with gemcitabine. However, disease recurrence with liver and para-aortic lymph node metastases was detected only two months after the completion of adjuvant chemotherapy. First-line palliative chemotherapy with gemcitabine-nab/paclitaxel was commenced. The results were discouraging, with disease progression (liver and lung metastases) detected at the first evaluation; the progression-free survival was just two months (64 days). Surprisingly, the response to second-line palliative chemotherapy with 5-fluorouracil-oxaliplatin was excellent; in combination with the ablation of a liver metastasis, this treatment regimen resulted in a complete radiological response and an 11-month treatment-free interval with a sustained good performance status.

A randomized noncomparative phase II study of maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM–PRODIGE 63 GERCOR D17-01 study).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4160-TPS4160
Author(s):  
Cindy Neuzillet ◽  
Vincent Hautefeuille ◽  
Aurélien Lambert ◽  
Marie-Line Garcia-Larnicol ◽  
Dewi Vernerey
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Vaccine Antigen ◽  
New Combination ◽  
Ductal Adenocarcinoma ◽  
Open Label

TPS4160 Background: FOLFIRINOX (5-fluorouracil [5FU], folinic acid [FA], irinotecan [Iri], and oxaliplatin [Ox]) is a standard 1st-line treatment in fit Pts with aPDAC. Anti-PD-1/PD-L1 as single agents have failed in PDAC so far and new combination immunotherapies are needed. Tedopi (OSE2101) is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts, targeting 5 tumor-associated antigens (CEA, HER2, MAGE2, MAGE3, TP53) that are frequently expressed in PDAC. This study aims to assess the efficacy and safety of Tedopi alone and in combination with anti-PD-1 nivolumab, or FOLFIRI as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction CT. Methods: TEDOPaM - PRODIGE 63 is a 3-arm, Fleming 2-stage, open-label, randomized, non-comparative phase II study. 156 Pts with locally advanced or metastatic, pathologically proven PDAC; ECOG performance status 0-1; HLA-A2 genotype; controlled disease (objective response or stable disease) after 8 cycles of (modified) FOLFIRINOX; and adequate organ functions, are randomized (1:1:1, stratified on center, tumor stage, and best response to FOLFIRINOX) into 3 arms: Clinical trial information: NCT03806309. In Arms B and C, FOLFIRI is reintroduced at disease progression or unacceptable toxicity. Primary endpoint: overall survival rate at M12. Secondary endpoints: progression-free survival (CT-scan Q8W), duration of disease control, safety, objective response rate, RECIST v1.1/iRECIST comparison, HRQoL (EORTC QLQ-C30), Q-TWiST. An interim analysis is planned after inclusion of 20 Pts in each arm. Translational research will be performed on tumor tissue (initial FFPE biopsy and optional re-biopsy at inclusion): RNAseq (cancer and stroma), mutation burden, MMR status, immune infiltrates; and in blood (before and on-treatment): cytokine panel, PBMC phenotyping, vaccine-antigen specific T-cells, TCR repertoire, and extracellular vesicles, to explore biomarkers and pharmacodynamics effects of Tedopi ± nivolumab. Enrollment (12th Feb 2019): 1. ClinicalTrials Registration: NCT03806309.[Table: see text]

Impact of nab-paclitaxel-based second-line chemotherapy on the outcomes of pancreatic cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 483-483
Author(s):  
Neelakanta Dadi ◽  
Safi Shahda ◽  
Bert H. O'Neil ◽  
Amikar Sehdev
Keyword(s):  
Retrospective Study ◽  
Performance Status ◽  
Locally Advanced ◽  
Group Versus ◽  
Ductal Adenocarcinoma ◽  
Cancer Center ◽  
Line Treatment ◽  
Second Line ◽  
Second Line Chemotherapy ◽  
Line Chemotherapy

483 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with no standard second line chemotherapies. We conducted a retrospective study with the primary aim to examine the effect of second line chemotherapy with nab-paclitaxel-based regimen on the overall survival (OS) and progression-free survival (PFS) of locally advanced and metastatic PDAC patients. Methods: Indiana University Simon Cancer Center (IUSCC) Cancer Registry was used to identify patients with locally advanced or metastatic PDAC between 2009 and 2015. Only patients who received second line chemotherapies were included in the study. These patients were divided in to two groups: a) nab-paclitaxel-based treatment and, b) non-nab-paclitaxel-based treatment. Demographic (age, race, gender, year of diagnosis, family history, comorbidity), clinical (histology, CA 19-9, bilirubin, tumor location, performance status, metastatic sites, chemotherapy, surgery or radiation) and outcome (OS, PFS) characteristics were obtained. OS and PFS were estimate by using Kaplan-Meier method and 95% CI. Cox proportional-hazard model was used for multivariate analysis. Results: Forty-seven (39%) and seventy-three (61%) patients received nab-paclitaxel-based and non-nab-paclitaxel-based second line chemotherapy, respectively. In the univariate analyses, nab-paclitaxel-based treatment was only associated with younger age (60.4 vs. 64 years; P = 0.02). The median PFS was 2.8 and 2.1 months (HR 0.62; 95% CI 0.38-1.02; P = 0.06), and the median OS was 7.5 and 4.7 months (HR 0.67; 95% CI 0.45-1.00; P = 0.05) in patients who received nab-paclitaxel based second line treatment versus not, respectively. Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR 0.60, 95% CI 0.36-0.98; P = 0.04) and a suggestion of improved OS (adjusted HR 0.67; 95% CI 0.44-1.01, P = 0.05) in the nab-paclitaxel based second line treatment group versus not, respectively. Conclusions: In a single institution retrospective study, we report significant improvement in the PFS and a suggestion of improvement in the OS with nab-paclitaxel based treatment as compared with non-nab-paclitaxel based treatment in the second line setting.

Deleterious alterations in DNA-damage repair (daDDR) genes as a predictive biomarker for platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 266-266
Author(s):  
Sofia Palacio ◽  
Hannah Stowe McMurry ◽  
Robert Ali ◽  
Talia Donenberg ◽  
Rachel Silva-Smith ◽  
...  
Keyword(s):  
De Novo ◽  
Parp Inhibitor ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Ductal Adenocarcinoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Platinum Based Chemotherapy

266 Background: Germline genetic testing and somatic genomic profiling using commercial multigene panels are now routine in mPDAC. A subset of these patients have deleterious alterations in genes involved with DDR. Herein we investigate the role of daDDR as a predictive biomarker for response to first-line platinum-based chemotherapy. Methods: Utilizing the IRB-approved pancreas cancer and genetics clinic databases at the University of Miami, we identified all patients with mPDAC who had germline and/or somatic mutation testing. We performed a retrospective chart review to extract demographic and clinical characteristics including treatments received, response and survival. Results: Between 2012 and 2018, 116 patients with mPDAC underwent germline (using Invitae, Ambry Counsyl or Myriad) and/or somatic testing (using FoundationOne CDx). Among these, 40 received first-line therapy with FOLFIRINOX (95%) or gemcitabine/cisplatin (5%). The median age was 59 years and 15 (38%) were female. The majority (70%) were Hispanic and 63% had de-novo mPDAC (treatment-naïve). Germline testing revealed daDDR in 5 patients and somatic NGS found an additional 4 patients with daDDR (total of 9 (23%), including 5 with BRCA2, one each with BRCA1, RAD51C, ATM and MUTYH). The median progression-free survival (PFS) was significantly longer in patients with daDDR than without (17.3 vs 7.8 months, log-rank p = 0.01). The median overall survival (OS) was not statistically different between the two groups. Three patients with daDDR had complete or near-complete radiological and tumor marker responses to FOLFIRINOX and were treated with olaparib (a PARP inhibitor) as maintenance and remain progression-free after 7, 12.4 and 13.6 months respectively. Conclusions: daDDR appears to define a subset of patients with mPDAC who may be more sensitive to platinum agents. There are currently no biomarkers for selection of first-line therapy in patients with mPDAC and we demonstrate that this composite biomarker which is easily done via commercially available assays may be able to inform treatment selection.

Rituximab Plus CHOP Followed by Maintenance Rituximab as Initial Therapy for Advanced Stage Indolent Non-Hodgkin’s Lymphoma (NHL); Initial Results of Induction Therapy in a Phase II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4615-4615 ◽  
Author(s):  
Jane E. Huang ◽  
Lowell Hart ◽  
Jonathon Polikoff ◽  
Virginia Langmuir ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Induction Therapy ◽  
Performance Status ◽  
Stage Iii ◽  
Induction Treatment ◽  
Advanced Stage ◽  
Serious Adverse Events ◽  
Ann Arbor ◽  
Initial Results

Abstract Background: This study was designed to investigate the activity and safety of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in patients with previously untreated advanced stage indolent NHL. The initial results of R-CHOP induction treatment are reported here. Methods: 102 patients with Ann Arbor Stage III or IV indolent NHL (follicle center/follicular grade I/II or nodal marginal zone B-cell by REAL; Type B or C by IWF) were enrolled into this open-label, multi-center, community-based, Phase II, single-arm trial. Patients received 6 cycles of standard R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 all IV on Day 1; prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle except for cycle 1, when it was administered 2–3 days prior to CHOP chemotherapy. Subjects with an ongoing response (CR/CRu or PR) after induction receive maintenance R (4 weekly infusions) within 28 days after the completion of induction and repeated every 6 months for 2 years for a total of 16 maintenance R doses. The primary endpoints were CR/CRu after 6 cycles of induction and the incidence of R infusion-related toxicity during induction and maintenance therapy. Secondary endpoints included overall response rates (ORR), infusion times, serious adverse events (SAE) in induction and maintenance, and rituximab pharmacokinetics in maintenance therapy. Results: Baseline characteristics were: median age 57y (33.3% ≥60y); 40.2% female; ECOG performance status 0: 70.6%; Ann Arbor stage III: 28.4% and IV: 71.6%. Serum β2-microglobulin and LDH at baseline were above normal in 66.3% and 20.6%, respectively. CR/CRu at the end of induction in 102 patients was 51.0% (ORR 86.3%). 1% had progressive disease (PD) during induction. 2 subjects died during the induction period, both due to SAEs (probable pulmonary embolus, acute respiratory distress). SAEs occurred in 22.5% of subjects during induction with the most common event being febrile neutropenia (7.8%). Grade 3–4 R infusion-related toxicity occurred in 4.9% of patients in cycle 1; this decreased to 1% by cycle 2 of induction. Two subjects discontinued R for infusion-related toxicity. 44% of patients were able to receive their R dose within 3 hrs at cycle 2 and 69.2% of patients at cycle 6. Conclusion: Patients with advanced stage indolent NHL treated in the community setting with R-CHOP induction tolerate therapy well and have an excellent response rate. The outcomes of maintenance therapy and rituximab pharmacokinetics in maintenance await further follow-up.

Combination Antibiotic Treatment of Chemotherapy-Induced Neutropenia in Non-Leukemic Patients

1989 ◽  
Vol 75 (5) ◽  
pp. 443-448
Author(s):  
Giampietro Gasparini ◽  
Salvatore Turnolo ◽  
Giuseppe Toffoli ◽  
Renato Talamini ◽  
Alberto Vaglia ◽  
...  
Keyword(s):  
Median Duration ◽  
Bacterial Infections ◽  
Performance Status ◽  
Unknown Origin ◽  
Complete Response ◽  
Second Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Neutropenic Patients

The use of more aggressive chemotherapies in the treatment of patients with some tumors has caused a higher frequency of neutropenia and subsequent serious infections. To verify the role in these patients of a combination therapy of amikacin (300 mg/m2 i.v. every 12 hours) plus ceftazidime (2 g/m2 i.v. every 8 hours) adminsitered as initial empiric treatment, followed in non-responsive cases by a second-line therapy with clindamycin (300 mg/m2 i.v. every 8 hours), we conducted a prospective study in 45 febrile episodes (temperature ≥38.5 °C) in neutropenic patients (neutrophils ≤500/ml). The patients' median age was 58 (range, 19-80); 29 were women and 16 were men. The median performance status was 50 (range, 30-90), and 71 % of the patients had progressive tumoral disease. Before antibiotic therapy the median duration of fever was 12 hours (range, 4-48 hours). The median granulocyte count was 350/ml (range, 100-500 cells/ml), and the median peak temperature was 38.8 °C (range, 38.5-41 °C). The median time for neutrophils to rise towards 1000/ml was 4 days (range, 2-12), and the median duration of therapy was 8 days (range, 3-12). Documented bacterial infections were present in 28 patients whereas 17 had clinically possible infections or fever of unknown origin. The infection sites in microbiologically documented infections were: septicemia (12), multiple sites (4), tonsillitis (4), urinary tract (4), pneumonia (2) and fistula (2). Complete response to first-line therapy was obtained in 36 out of 45 episodes (80 %; 95 % confidence limits from 65 % to 90 %). Five out of 8 cases responded to second-line therapy with clindamycin for an overall recovery rate of 91 %. The amikacin-ceftazidime combination followed by clindamycin in non-responsive cases is effective, with moderate toxicity in non-leukemic febrile neutropenic patients.

scholarly journals Surgery or Locoregional Approaches for Hepatic Oligometastatic Pancreatic Cancer: Myth, Hope, or Reality?

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1095 ◽  
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Massimiliano Salati ◽  
Shelize Khakoo ◽  
Antonio Varricchio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Irreversible Electroporation ◽  
Multimodality Treatment ◽  
Ductal Adenocarcinoma ◽  
Surgical Approaches ◽  
Tumor Control ◽  
Recommended Treatment ◽  
Metastatic Setting

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a subset of patients with oligometastatic disease, multimodality treatment with surgery and/or locoregional approaches may provide long-term disease control and prolong survival. In fact, in highly selected cases, median overall survival has been reported to extend to 56 months in patients treated with surgery. In particular, liver and extraregional nodal resections may provide long-term tumor control with acceptable morbidity. Current guidelines do not recommend surgery for patients with metastatic PDAC and, in the case of PDAC with oligometastases, there are no published randomized controlled trials regarding locoregional or surgical approaches. Here we review the literature on surgical and locoregional approaches including radiofrequency ablation, irreversible electroporation, and stereotactic body radiation, and focus on patients with hepatic oligometastatic pancreatic cancer. We provide a summary regarding survival outcomes, morbidity and mortality and discuss selection criteria that may be useful to predict the best outcomes for such strategies.

PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA7507-LBA7507 ◽  
Author(s):  
Luis Paz-Ares ◽  
Filippo De Marinis ◽  
Mircea Dediu ◽  
Michael Thomas ◽  
Jean-Louis Pujol ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Performance Status ◽  
Phase Iii ◽  
Controlled Study ◽  
Rank Test ◽  
Induction Treatment ◽  
Double Blind ◽  
Risk Of Death ◽  
Continuation Maintenance

LBA7507 Background: The PARAMOUNT trial showed that pem continuation maintenance therapy significantly reduced the risk of disease progression over plb (HR=0.62; 95% CI: 0.49-0.79; p <0.0001) in patients (pts) with advanced NS NSCLC who had not progressed during pem-cis induction. Here we present the final OS data. Methods: In a double-blind, plb-controlled study, alpha-controlled for OS, 939 pts received induction (4 cycles of pem 500 mg/m2 and cis 75 mg/m2 on d1 of 21d cycles), and 539 pts who had not progressed and had an ECOG performance status (PS) of 0/1 were randomized (2:1) to maintenance pem (500 mg/m2, on day 1 of 21-day cycles) plus BSC or plb plus BSC until disease progression. All received B12, folic acid, and dexamethasone. After 397 deaths, a log-rank test compared OS between arms using anominal α level of 0.0498. Results: Pt characteristics were balanced between arms: median age 61 years; 58% men; 32% PS 0; 95% Caucasian; 86% adenocarcinoma; 45% complete/partial response (CR/PR) to induction. Pem resulted in a statistically significant 22% reduction in risk of death (HR=0.78). The HR was the same when measured from the beginning of induction. Survival improvement was similar for pts with an induction outcome of CR/PR versus stable disease. Conclusions: Pem continuation maintenance therapy offers superior OS compared with plb. These final results confirm that pem-cis induction followed by continuation pem further benefits pts compared with induction therapy alone, offering a change in the treatment paradigm for advanced NS NSCLC. [Table: see text]

Everolimus as second-line therapy for metastatic renal cell carcinoma (mRCC) after one previous VEGF-targeted therapy: Final results of the noninterventional change study.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 469-469 ◽  
Author(s):  
Peter J. Goebell ◽  
Ulrich Kube ◽  
Michael Staehler ◽  
Christian Doehn ◽  
Thomas Steiner ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Targeted Therapy ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Progression Free Survival ◽  
Routine Clinical Practice ◽  
Second Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy

469 Background: The mTOR inhibitor everolimus is approved for the treatment of mRCC following failure of VEGF-targeted therapy. To evaluate the effectiveness and tolerability of everolimus following the first VEGF-targeted therapy in routine clinical practice, we conducted the prospective, noninterventional CHANGE study in Germany. Methods: Patients (pts) with mRCC (any histology) were registered at the time of everolimus initiation, or within 90 days thereof, following treatment with either VEGFR-TKI or bevacizumab. Other previous systemic therapies (e.g., cytokines) were permitted. Pts received everolimus 10 mg/d according to the summary product characteristics until disease progression or intolerable toxicity. Study objectives included assessing treatment duration, time to progression (TTP), progression-free survival (PFS), Karnofsky performance status (KPS), and safety. Results: 334 pts were documented at 116 German sites between August 2009 and January 2012 (median age, 68 years; 75% male; median KPS, 80%; 88% clear cell histology). At the start of first-line therapy, MSKCC risk status was favorable in 35%, intermediate in 56%, and poor in 9%. Effectiveness results are shown in the table. In the safety population (n=318), median time to ≥10% deterioration in KPS was 8.4 months (95% CI, 6.1-10.1 months); the most common AEs (any grade) were dyspnea (17%), anemia (14%), and fatigue (12%). Treatment adherence was high, with <2% of patients per visit showing <50% intake of the expected doses. Conclusions: The CHANGE study demonstrates favorable effectiveness and tolerability for everolimus when given in routine clinical practice to pts with mRCC. Our data confirm the use of everolimus as a standard second-line therapy following VEGF-targeted treatment. [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]

Sign in / Sign up

Export Citation Format

Share Document