scholarly journals Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hemant M. Kocher ◽  
Bristi Basu ◽  
Fieke E. M. Froeling ◽  
Debashis Sarker ◽  
Sarah Slater ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Retinoic Acid ◽  
Controlled Trial ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Assessment Method ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome.

1993 ◽  
Vol 11 (8) ◽  
pp. 1489-1495 ◽  
Author(s):  
R Kurzrock ◽  
E Estey ◽  
M Talpaz
Keyword(s):  
Retinoic Acid ◽  
Side Effects ◽  
Myelodysplastic Syndrome ◽  
Acid Tolerance ◽  
Maximum Tolerated Dose ◽  
Significant Activity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Biologic Effects ◽  
Dose Levels

PURPOSE We conducted a study to evaluate the tolerance to and biologic effects of all-trans retinoic acid in patients with myelodysplastic syndrome. PATIENTS AND METHODS Thirty-nine patients with myelodysplastic syndrome were treated with oral all-trans retinoic acid for 6 weeks. Dose levels were 10, 25, 50, 100, 150, 200, and 250 mg/m2/d. At least three patients were treated on each dose level. RESULTS The most common side effects were mucocutaneous dryness and erythema, and hypertriglyceridemia. Dose-limiting side effects were diverse and included dermatitic problems, sensorineural hearing loss, headaches, nausea and vomiting, myalgias, and dyspnea. The maximum-tolerated dose was 150 mg/m2/d. Only one response was seen among 29 patients considered assessable for response. CONCLUSION All-trans retinoic acid can be safely administered to patients at doses up to 150 mg/m2/d for 6 weeks. However, as administered in this study, this compound does not appear to have significant activity in myelodysplastic syndromes.

A phase Ⅰ open-label dose-escalation study of AL2846 in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16210-e16210
Author(s):  
Rui Liu ◽  
Ting Deng ◽  
Ming Bai ◽  
Le Zhang ◽  
Tao Ning ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Level ◽  
Standard Dose ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Efficacy Evaluation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels

e16210 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 10%. Overexpression of c-Met is associated with the poor prognosis in patients with PDAC and it was noted that phosphorylation of c-Met is increased in gemcitabine-resistant PDAC. AL2846 is an oral c-Met inhibitor, which targets multiple receptor tyrosine kinases (RTK’s) primarily including c-Met, VEGFR1, KIT, Axl and RET. The combination of AL2846 with chemotherapy may improve the clinical efficacy of PDAC. Based on these consideration, a phase Ⅰ clinical trial was initiated to determine the maximum tolerated dose (MTD) of AL2846 in combination with gemcitabine in patients with advanced PDAC and to clarify the potential anti-tumor activity. Methods: Patients with untreated locally advanced or metastatic PDAC were enrolled to receive oral AL2846 once daily in a fasted state in combination with gemcitabine intravenous infusion over 30 min on days 1, 8, and 15 every 28 days. The starting dose level is AL2846 40 mg and gemcitabine 1000 mg/m2. Primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose level at which ≤33 % of patients incurred a dose-limiting toxicity (DLT), and RP2D. Secondary endpoints included response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of January 1, 2021, a total of 15 patients with PDAC were enrolled and received 4 dose-levels of AL2846 (40 mg: n = 1; 60 mg: n = 6; 90 mg: n = 3; 120 mg: n = 5) treatment. DLTs occurred in 1 patient who experienced grade 3 abnormal liver function. The most common grade 3 or above drug-related adverse events were neutropenia (n = 7, 46.7%), thrombocytopenia (n = 5, 33.3%), leukopenia (n = 4, 26.7%), GGT increased (n = 4, 26.7%), hyperbilirubinemia (n = 3, 20.0%) and alkaline phosphatase increased (n = 3, 20.0%). Among the 15 patients available for efficacy evaluation, 1 patient (6.6%) achieved partial response who was at the dose levels of 90mg. There were 4 patients whose PFS was more than 5 months. Although there were no more than 2 DLT events, we chose 90 and 120 mg as the target dose for RP2D according to the dose reduction and proportion of gemcitabine. Conclusions: The RP2D of AL2846 in combination with standard dose of gemcitabine were 90 and 120 mg QD continuously. The results demonstrated that AL2846 in combination with gemcitabine was well tolerated at doses up to 120 mg. Further clinical studies about the efficacy of AL2846 in pancreatic cancer are in progress. Clinical trial information: CTR20201021.

scholarly journals Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia

Cancer ◽  
2005 ◽  
Vol 104 (12) ◽  
pp. 2717-2725 ◽  
Author(s):  
Gesine Bug ◽  
Markus Ritter ◽  
Barbara Wassmann ◽  
Claudia Schoch ◽  
Thorsten Heinzel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Valproic Acid ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Poor Risk ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

1997 ◽  
Vol 39 (4) ◽  
pp. 291-299 ◽  
Author(s):  
B. A. Conley ◽  
Merrill J. Egorin ◽  
Rajeshwari Sridhara ◽  
Rebecca Finley ◽  
Ramzi Hemady ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Retinoic Acid ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michelle R. Goulart ◽  
Jennifer Watt ◽  
Imran Siddiqui ◽  
Rita T. Lawlor ◽  
Ahmet Imrali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Diagnostic Biomarkers ◽  
All Trans Retinoic Acid ◽  
Desmoplastic Stroma ◽  
Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

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