scholarly journals Towards an optimal treatment algorithm for metastatic pancreatic ductal adenocarcinoma (PDA)

2018 ◽  
Vol 25 (1) ◽  
pp. 90 ◽  
Author(s):  
M. Uccello ◽  
M. Moschetta ◽  
G. Mak ◽  
T. Alam ◽  
C. Murias Henriquez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Optimal Algorithm ◽  
Treatment Algorithm ◽  
Ductal Adenocarcinoma ◽  
Line Treatment ◽  
Second Line ◽  
New Paradigm ◽  
First Line ◽  
First Line Treatment

Chemotherapy remains the mainstay of treatment for advanced pancreatic ductal adenocarcinoma (pda). Two randomized trials have demonstrated superiority of the combination regimens folfirinox (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel over gemcitabine monotherapy as a first-line treatment in adequately fit subjects. Selected pda patients progressing to first-line therapy can receive secondline treatment with moderate clinical benefit. Nevertheless, the optimal algorithm and the role of combination therapy in second-line are still unclear. Published second-line pda clinical trials enrolled patients progressing to gemcitabine-based therapies in use before the approval of nab-paclitaxel and folfirinox. The evolving scenario in second-line may affect the choice of the first-line treatment. For example, nanoliposomal irinotecan plus 5-fluouracil and leucovorin is a novel second-line option which will be suitable only for patients progressing to gemcitabinebased therapy. Therefore, clinical judgement and appropriate patient selection remain key elements in treatment decision. In this review, we aim to illustrate currently available options and define a possible algorithm to guide treatment choice. Future clinical trials taking into account sequential treatment as a new paradigm in pda will help define a standard algorithm.

SBP-101, a polyamine metabolic inhibitor, administered in combination with gemcitabine and nab-paclitaxel, shows signals of efficacy as first-line treatment for subjects with metastatic pancreatic ductal adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4127-4127
Author(s):  
Nimit Singhal ◽  
Darren Sigal ◽  
Niall C. Tebbutt ◽  
Aram F Hezel ◽  
Adnan Nagrial ◽  
...  
Keyword(s):  
Adverse Events ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Retinal Toxicity ◽  
Ductal Adenocarcinoma ◽  
Metabolic Inhibitor ◽  
Line Treatment ◽  
Hepatic Toxicity ◽  
First Line ◽  
Phase 1B ◽  
First Line Treatment

4127 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A fourth cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for phase 1b expansion. Interim Results: Fifty patients were enrolled (N=25, phase 1a and N=25, phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N= 6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring dose reduction or discontinuation. There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28 achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Median OS has not been reached. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation. Clinical trial information: NCT03412799.

scholarly journals Efficacy and safety of second-line nab-paclitaxel plus gemcitabine after progression on FOLFIRINOX for unresectable or metastatic pancreatic ductal adenocarcinoma: multicenter retrospective analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592092342 ◽  
Author(s):  
Heejung Chae ◽  
Hyehyun Jeong ◽  
Jaekyung Cheon ◽  
Hong Jae Chon ◽  
Hyewon Ryu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Retrospective Analysis ◽  
Treatment Option ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Grade 3

Background: FOLFIRINOX (fluorouracil, folinic acid, irinotecan plus oxaliplatin) is an effective standard first-line treatment option for advanced pancreatic ductal adenocarcinoma (PDAC). There is no clear consensus on the second-line treatment following progression on FOLFIRINOX. In this multicenter retrospective analysis, we evaluated the efficacy and tolerability of second-line nab-P/Gem (nab-paclitaxel and gemcitabine) after progression on FOLFIRNOX in PDAC. Methods: Patients with unresectable or metastatic PDAC who received nab-P/Gem after progression on FOLFIRINOX between February 2016 and February 2019 were identified from five referral cancer centers in South Korea. Baseline characteristics, treatment history, survival outcomes, and toxicity profile were obtained retrospectively from medical records. Results: A total of 102 patients treated with second-line nab-P/Gem for advanced PDAC after progression on FOLFIRINOX were included. At the time of nab-P/Gem, the median age was 60 years, with males comprising 49.0%, and most (75.5%) had metastatic disease. Patients received a median of three cycles (range 1–12) of nab-P/Gem. The median overall survival (OS) and progression-free survival (PFS) from the start of second-line nab-P/Gem therapy were 9.8 (95% CI, 8.9–10.6) and 4.6 months (3.7–5.5), respectively. A partial response was achieved in 8.5%, and the disease control rate was 73.6%. From the start of first-line FOLFIRIOX, the OS1+2 and PFS1+2 were 20.9 (15.7–26.1) and 13.9 (10.8–17.0) months, respectively, with a 2-year survival rate of 45.1%. There was no treatment-related mortality and grade ⩾3 toxicity was observed in 60.2%. Conclusion: Our results showed that nab-P/Gem was an effective and tolerable second-line treatment option in medically fit patients with advanced PDAC who progressed on first-line FOLFIRNOX. ClinicalTrials.gov identifier: NCT04133155

Efficacy of SBP-101, in combination with gemcitabine and nab-paclitaxel, in first-line treatment of metastatic pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 710-710
Author(s):  
Dusan Kotasek ◽  
Adnan Nagrial ◽  
Sumit Lumba ◽  
Niall C. Tebbutt ◽  
Thomas J. George ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Ductal Adenocarcinoma ◽  
Metabolic Inhibitor ◽  
Line Treatment ◽  
First Line ◽  
Enzyme Elevation ◽  
First Line Treatment

710 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens, N=4) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the safety, tolerability, PK, and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. Safety and tolerability were evaluated by clinical and laboratory assessments. PK was evaluated on day 1 of cycle 1. Efficacy was assessed by CA19-9 levels, objective response as assessed by RECIST criteria, progression-free survival (PFS) and overall survival (OS). Results: Fifteen patients have been enrolled in 3 cohorts (1: N=4, 2: N=7, 3: N=4) and received up to 6 cycles of treatment (7 subjects are ongoing in cohorts 2 and 3). The most common adverse events related to SBP-101 are fatigue (N=4), nausea (N=2) and injection site pain (N=2). There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. One patient in cohort 2 developed grade 3-4 reversible liver enzyme elevation. PK parameters in cohort 1 were below the limits of detection at most time points, but plasma Cmax and AUC0-t were measurable in cohorts 2 and 3. In those cohorts, CA19-9 levels decreased 76-95% in 7 of 8 evaluable subjects (1 additional subject TBD), with 5 patients achieving partial responses (4 ongoing) and 1 achieving stable disease. Median PFS and OS have not yet been reached. Conclusions: Preliminary results suggest SBP-101 is well tolerated when administered with G and A. Signals of efficacy support continued development of SBP-101 in combination first-line treatment for PDA. Clinical trial information: NCT03412799.

scholarly journals Physicians' Behavior, Diagnostics and Treatment Patterns in Multiple Myeloma Management in Belarus: Nation-Wide Survey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5853-5853
Author(s):  
Ihar Iskrou ◽  
Anatoly Uss ◽  
Sergey Golubev ◽  
Vitali Papok
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Plasma Cells ◽  
Treatment Patterns ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Advisory Committees ◽  
First Line Treatment

Abstract Background: Although multiple myeloma (MM) remains an incurable disease, its management progressed during the last decade owing to novelties in diagnostics and new therapeutic options. There is a general belief in heterogeneity of the novel technologies penetration among countries and regions, such differences should be studied. Information on physicians' knowledge, preferences and satisfaction is limited worldwide and may provide important insights for explanation of differences in clinical decision making in routine practice. Moreover, data on typical diagnostic and treatment patterns in real-world clinical setting are particular scarce in the Eastern European and Eurasian region. Methods: A cross-sectional national survey of physicians treating MM in Belarus was performed from October 2017 till January 2018. Among 51 hematologists registered in the country 43 physicians involved in MM management in real clinical settings were approached. Printed forms of 21-item questionnaire containing multiple choice questions were used. We anonymously collected physicians' opinions on typical diagnostics and treatment patterns as well as their clinical reasoning, preferences and satisfaction. We assessed whether practice place and type, practical experience (length of service and average number of MM patients seen per year) and attitude to participation in clinical trials influence answers. Univariate analysis was conducted with Fisher's exact test. Results: All approached physicians completed the survey. Among respondents 17 (40%) belonged to republican specialized centers, 37 (86%) were hospital-based physicians, 23 (53%) had more than 10 years of service, 28 (65%) seen more than 20 MM patients per year. 10 (23%) declared their experience in clinical trials and 20 (46%) had no experience but expressed readiness to be involved in. The clinical uptake of revised ISS for MM was 33%, among adopters physicians with more than 10 years in practice and who sees more than 20 patients per year dominated. The proportions of ISS users which believed that median survival for low-risk, standard-risk and high-risk MM patients to be > 12 months were 100%, 100% and 36%, respectively. For primary MM diagnosis 40% of respondents used MRI and 49% - CT-imaging. Physicians used the next criteria for treatment response : < 5% plasma cells (PCs) in bone marrow (88%), Ig level normalization (74%), absence of clonal PCs in BM (60%), and absence of new lesions (37%). The possibility to perform autologous stem-cells transplantation (ASCT) was revealed as a key factor for first-line treatment choice. Various bortezomib-based regimens were predominant treatment options for first-line treatment of patients eligible for ASCT. Melphalan-containing regimens were more widely spread as first-line treatment of ASCT-ineligible patients. The majority of respondents (52%) practiced first-line treatment of more than 4 months of duration, while 41% of clinicians used second-line therapy of short duration (less than 6 months). In the relapse setting after ASCT the most common regimens were still bortezomib-based as well as schemes with bendamustine. In the second-line setting in patients who did not receive ASCT monotherapy was more commonly reported. In absence of high dose dexamethasone for oral use Belarusian physicians preferred treatment schemes with combination of drugs for IV and per os routes of administration. The predominant factors of drug choice were efficacy (91%) and cost (97%). The respondents reported satisfaction with current situation in diagnostics and treatment in 74% and 65% of cases, respectively. The factors influencing readiness for disease management change were clinical experience, hospital-based practice position and positive attitude to/participation in clinical trials. Conclusions: The study covers the gaps of information about real-world MM management in Belarus. The Belarusian physicians are aware about the modern place of ASCT in MM. Targeted education in specific aspects of MM management (disease biology understanding, clinical guidelines updates, risk evaluation and stratification) may result in wider adoption of innovative diagnostic approaches and treatment technologies. MM management should be further concentrated in large specialized clinical centers for plasma cells disorders. The survey results make possible and warranted further intercountry comparisons. Disclosures Iskrou: Takeda Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Belarus: Consultancy, Honoraria, Speakers Bureau; Novartis Belarus: Consultancy, Honoraria, Speakers Bureau; Nativita Belarus: Consultancy, Honoraria, Speakers Bureau; Octapharma Belarus: Consultancy, Honoraria, Speakers Bureau. Uss:Roche Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Belarus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Golubev:Medical department of Takeda Belarus: Employment. Papok:Medical department of Takeda Belarus: Employment.

Efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4138-4138
Author(s):  
Gang Jin ◽  
Shiwei Guo ◽  
Yanqiao Zhang ◽  
Yue Ma ◽  
Xiaodong Guo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Therapy ◽  
Locally Advanced ◽  
Tumour Response ◽  
Ductal Adenocarcinoma ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
First Line Treatment

4138 Background: Pancreatic ductal adenocarcinoma（PDAC）is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Nab-paclitaxel plus gemcitabine has been recommended by international guidelines for first-line treatment of advanced PDAC but chemoresistance is difficult to avoid. Combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated substantial promise for the treatment of several advanced malignancies. A few recent studies have begun to explore the effect of ICIs monotherapy or co in advanced PDAC with few meaningful results. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. The purpose of this study is to evaluate the efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC. Methods: This ongoing phase II trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and never received systemic anti-tumor therapy for advanced or metastatic diseases. KN046 (5mpk, Q2W) plus nab-paclitaxel (125mg/m2, D1, 8, 15, Q4W) and gemcitabine (1000mg/m2, D1, 8, 15, Q4W) were administered 4-6 cycles followed by KN046 (5mpk) maintenance therapy every 2 weeks. Tumour response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed ORR. Secondary endpoints are DCR, DOR, TTP, PFS, OS and safety. Results: As of December 15, 2020, 17 pts were enrolled, median (range) age was 56 (36-75) years, 9 pts ECOG 1, and 7 pts had liver metastases. Median KN046 exposure time was 9.5 wks. 9 pts were included in the efficacy analysis and 17 pts in the safety analysis. In best overall response assessment, there were 55.6% PR (5/9) and 33.3% SD (3/9). ORR was 55.6% (95% CI: 21.2̃86.3), and DCR was 88.9% (95% CI: 51.8̃99.7). The overall incidence of KN046 related treatment-emergent adverse events was 64.7%, with 29.4% were grade 3 TRAE. The most common KN046 related treatment-emergent adverse events (≥10%) were alanine aminotransferase increased (n = 5, 29.4%), nausea (n = 3, 17.6%), rash (n = 3, 17.6%), aspartate aminotransferase increased (n = 2, 11.8%), diarrhoea (n = 2, 11.8%), hyperphosphataemia (n = 2, 11.8%), pyrexia (n = 2, 11.8%), vomiting (n = 2, 11.8%). Conclusions: Combining KN046 with nab-paclitaxel and gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC patients is safe and feasible, and lays the foundation for subsequent clinical trials. Clinical trial information: NCT04324307.

scholarly journals Immediate hypersensitivity reaction followed by successful oral desensitization to ursodiol

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Erika Yue Lee ◽  
Christine Song
Keyword(s):  
Hypersensitivity Reaction ◽  
Primary Biliary Cholangitis ◽  
Line Treatment ◽  
Second Line ◽  
Immediate Hypersensitivity ◽  
First Line ◽  
Case Presentation ◽  
Desensitization Protocol ◽  
First Line Treatment ◽  
Oral Desensitization

Abstract Background Immediate hypersensitivity reaction to ursodiol is rare and there is no previously published protocol on ursodiol desensitization. Case presentation A 59-year-old woman with primary biliary cholangitis (PBC) developed an immediate hypersensitivity reaction to ursodiol—the first-line treatment for PBC. When she switched to a second-line treatment, her PBC continued to progress. As such, she completed a novel 12-step desensitization protocol to oral ursodiol. She experienced recurrent pruritus after each dose following desensitization, which subsided after a month of being on daily ursodiol. Conclusion Immediate hypersensitivity reaction to ursodiol is uncommon. Our case demonstrated that this novel desensitization protocol to ursodiol could be safely implemented when alternative options are not available or have proven inferior in efficacy.

scholarly journals Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

2021 ◽  
Author(s):  
B. González Astorga ◽  
F. Salvà Ballabrera ◽  
E. Aranda Aguilar ◽  
E. Élez Fernández ◽  
P. García-Alfonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Option ◽  
Scientific Evidence ◽  
Treatment Options ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Effective Therapeutic Option ◽  
Line Setting ◽  
First Line Treatment

AbstractColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

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