Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma

2003 ◽  
Vol 21 (7) ◽  
pp. 1301-1306 ◽  
Author(s):  
Steven J. Cohen ◽  
Linus Ho ◽  
Sulabha Ranganathan ◽  
James L. Abbruzzese ◽  
R. Katherine Alpaugh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Phase Ii ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Clinical Activity ◽  
Peripheral Blood Mononuclear ◽  
Pancreatic Cell ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Ftase Activity

Purpose: R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21ras and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma. Patients and Methods: Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2. Results: No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean ± SD) decreased by 49.8% ± 9.8% 4 hours after treatment on day 1 and 36.1% ± 24.8% before treatment on day 15. HDJ-2 farnesylation (mean ± SD) decreased by 33.4% ± 19.8% on day 15. Conclusion: Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

A randomized phase II and coagulation study of bevacizumab alone or with docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4556-4556 ◽  
Author(s):  
I. A. Astsaturov ◽  
N. J. Meropol ◽  
R. K. Alpaugh ◽  
J. D. Cheng ◽  
N. L. Lewis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Pancreatic Adenocarcinoma ◽  
Phase Ii ◽  
Stable Disease ◽  
Circulating Endothelial Cells ◽  
Randomized Phase Ii ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Coagulation Study ◽  
Previously Treated

4556 Background: Vascular endothelial growth factor (VEGF) is overexpressed in pancreatic cancer and interacts with coagulation to promote angiogenesis. We performed this randomized phase II study of bevacizumab (BEV) alone or with docetaxel (DOC) in patients (pts) with previously treated metastatic pancreatic adenocarcinoma to investigate their clinical activity and interaction with coagulation. Methods: Eligible pts had one prior gemcitabine regimen, PS 0–1, measurable disease, and no bleeding/thrombosis. BEV was given at 10 mg/kg IV Q 2 weeks alone (Arm A) or with DOC (Arm B) at 35 mg/m2 IV on days 1, 8, and 15 Q 28 days. CT scans were obtained every 2 cycles. The primary endpoint was progression-free survival (PFS), with secondary endpoints response rate and overall survival (OS). Peripheral blood was obtained for coagulation parameters, basic fibroblast growth factor (bFGF), VEGF, and circulating endothelial cells (CEC). A two-stage design with a target median PFS of =4 months in either arm and early stopping for futility was utilized. Results: Thirty pts (15 per arm) received 88 cycles of therapy (44 per arm, median 2, range <1–10). Pt characteristics: median age 61.5 (range 38–81), ECOG 0/1 (11/19). Seven pts in Arm A and 8 in Arm B had grade 3/4 events. Serious adverse events were 5 DVT/PE (3-Arm A; 2-Arm B) and 2 bowel perforations (1 per arm). Best reponse was 4 pts with stable disease in Arm A and 5 pts with stable disease and one unconfirmed PR in Arm B. Median PFS and OS were 43 and 181 days in Arm A and 45 and 123 days in Arm B (p=0.5 for PFS, p=0.8 for OS). The study was stopped after only 2/15 pts per arm had PFS of =4 months. In multivariate analysis, higher bFGF (HR=1.4, p=0.008) and thrombin/antithrombin complex (TAT) levels on treatment (HR=1.75, p<0.001) were associated with worse OS. D-dimer, tissue factor and TAT levels on d15 were associated with increased venous thrombosis and GI perforation (p=0.04). VEGF plasma levels and CEC at all time points were not associated with clinical outcomes. Conclusions: BEV alone or with DOC has minimal antitumor activity in gemcitabine-refractory pancreatic cancer. Increased plasma bFGF and coagulation markers during therapy predict for worse OS and increased perforation and thrombosis. [Table: see text]

Phase II study of biweekly administration of CPT-11 and gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer in Japan.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15150-e15150
Author(s):  
Ryoji Takada ◽  
Tatsuya Ioka ◽  
Nobuko Ishida ◽  
Takuo Yamai ◽  
Nobuyasu Fukutake ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Phase Ii Study ◽  
Single Agent ◽  
Progression Free Survival ◽  
Current Standard ◽  
Free Survival ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Grade 3

e15150 Background: The current standard therapies for metastatic pancreatic adenocarcinoma in Japan are the single-agent Gemcitabine (Gem) or S-1 and Gem plus erlotinib. Irinotecan (CPT-11) is one of the promising drugs for Gem-refractory PC pts. Both Irinotecan and Gem have shown activity against these diseases with different mechanisms and are non-cross-resistant with each other. Japanese pts have the different metabolism with Irinotecan rather than pts in western countries. Methods: The aim of this phase II study was to evaluate the efficacy and safety of CPT-11 and Gem in Japanese pancreatic cancer pts. Patients with MPC and PS 0-2 were enrolled in this phase II trial. CPT-11, 100mg/m (2), was administered in 90 min. and Gem, 1000mg/m (2), was administered in 30 min. soon after CPT-11 on day1. Chemotherapy was repeated biweekly. Results: From May 2002 to May 2006 40 pts, with median age of 62 (40-74) years, were enrolled in this study. The overall response rate (RR) was 15% with disease control rate of 50%. The median progression-free survival (PFS) was 4.0 months (range: 1.0-15.0 months), and median overall survival (OS) was 7.5 months (range: 3.0-24.0 months). Grade 3/4 anemia, leucopenia occurred in 26.3, 5.2% of pts. The most common non-hematologic toxities were fatigue, diarrhea, nausea/vomiting and anorexia. Grade 3 diarrhea and nausea occurred in 10.5% of pts. Conclusions: The combination chemotherapy with Gem and CPT-11 showed favorable RR as expected and the treatment was manageable in Japanese pts with MPC. We plan to evaluate this combination chemotherapy for MPC pts after progression of FOLFIRINOX in near the future. Clinical trial information: UMIN000009963.

Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7616-7616 ◽  
Author(s):  
S. S. Farag ◽  
S. Zhang ◽  
M. Miller ◽  
M. Buckner ◽  
E. Kraut ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mononuclear Cells ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
M Protein ◽  
Blood Levels ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Median Proportion

7616 Background: Temsirolimus (TEM) is a novel inhibitor of mTOR, a critical molecule in the PI3K/Akt pathway, which is known to play an important role in transducing mitogenic signals induced by the action of cytokines on MM cells. Methods: We performed a phase II trial to investigate the clinical activity and toxicity of TEM in relapsed/refractory MM patients. Patients had Salmon-Durie stage I-IIIA, failed at least one prior therapy, were ≥18 years, had ANC ≥1.2x109/l, platelets ≥75x109/l, serum Cr ≤1.5 mg/dl, fasting cholesterol ≤350 mg/dl, triglycerides ≤400 mg/dl, and ECOG performance status 0–2. TEM was dosed at 25 mg IV on days 1, 8, 15 and 22 of each 28-day cycle. Treatment was continued until progression. Results: 14 patients are evaluable for response and toxicity. Median age was 62.5 (range, 41–75) years; 8 patients were male. 12 patients had stage IIIA and 1 patient had stage IIA and IA each, respectively. Median β2-mg was 3.3 (range, 2.5–7.9) and CRP was 2.2 (range, 0.5–139). Patients had failed a median of 2 (range, 1–5) prior regimens, and 6 had failed autologous stem cell transplant. Overall, 6 (43%) of 14 patients responded, with 5 achieving minor (26–49% decrease in M-protein) responses, and 1 a partial (>50% decrease in M-protein) response using Bladé criteria. 11 patients progressed on treatment. Overall, median time-to-progression was 4.6 months from start of treatment. Grade 3/4 toxicity included neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), nausea (n=1), stomatitis (n=1) and diarrhea (n=1). Response was associated with a maximal reduction in phosphorylated p70S6K (p-p70S6K) and 4EBP1 (p-4EBP1) in peripheral blood mononuclear cells at 48 hours after TEM dosing. The median proportion of p-p70S6K relative to baseline following treatment was 0.38 (range, 0.26–0.84) in responding patients versus 1.65 (range, 0.74–1.66) in non-responders (P=0.0001). Similarly, the median proportion of p-4EBP1 following treatment in responders was 0.49 (range, 0.12–1.25) versus 1.12 (range, 0.73–2.09) in non-responders (P=0.025). Correlation with blood levels of TEM is ongoing. Conclusions: TEM has anti-myeloma activity, and further investigation of TEM as a single agent and in combination therapy is warranted. No significant financial relationships to disclose.

5-fluorouracil, oxaliplatin and dasatinib (FOLFOX-D) for previously untreated metastatic pancreatic adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS517-TPS517
Author(s):  
Thomas J. George ◽  
Long H. Dang ◽  
Karen Colleen Daily ◽  
Jason Scott Starr ◽  
Hiral D. Parekh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Target Lesion ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Investigation Methods ◽  
Cancer Phenotype

TPS517 Background: Systemic chemotherapy for pancreatic adenocarcinoma improves survival and cancer related symptoms. Most targeted agents combined with gemcitabine have consistently failed to demonstrate clinical benefits. Src is overexpressed in pancreatic cancer and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the pancreatic cancer phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This is a multicenter phase II trial to determine activity and toxicity of FOLFOX + D in previously untreated metastatic pancreatic adenocarcinoma. Eligible pts must have at least 1 measurable target lesion by RECIST, ECOG PS 0-2, normal QTc and adequate organ function. Pts received standard cycles of mFOLFOX6 repeated q14d with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints included progression-free survival (primary; PFS), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those demonstrating durable disease control or exceptional response. Sample size was based on a 50% improved median PFS from 4 (historical) to 6 months. NCT01652976. Results: Enrollment continues on this prospective phase II study with 38 of 42 evaluable patients. There are no unexpected toxicities noted thus far. Clinical trial information: NCT01652976. [Table: see text]

Effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2005-2005 ◽  
Author(s):  
S. Goel ◽  
G. Goldberg ◽  
L. C. Iacono ◽  
M. Cohen ◽  
T. Griffin ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Geometric Mean ◽  
Single Agent ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Peripheral Blood Mononuclear

2005 Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m2. The maximum tolerated dose of Ixa with K was 20 mg/m2. Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose. [Table: see text]

A phase II trial of 13-cis retinoic acid, interferon, docetaxel, and estramustine (RITE) for the treatment of hormone refractory prostate cancer (HRPC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15542-15542
Author(s):  
A. Mehta ◽  
M. N. Stein ◽  
S. Goodin ◽  
S. Doyle-Lindrud ◽  
M. Todd ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase Ii ◽  
Mononuclear Cells ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Term Treatment ◽  
Clinical Activity ◽  
Peripheral Blood Mononuclear ◽  
Vein Thrombosis ◽  
Long Term Treatment

15542 Background: Efficacy of chemotherapy for the treatment of HRPC is limited secondary to the development of multiple mechanisms of resistance. In our prior studies, we demonstrated the safety and activity of docetaxel (T) 40 mg/m2 given with 13-cis retinoic acid (R), interferon alpha (I) and estramustine (E), along with a decrease in the expression of the anti-apoptotic protein Bcl-2. To test whether this regimen had clinical activity in HRPC, we conducted a phase II trial with the combination of these drugs. Methods: Eligible patients (pts) received 13-cis retinoic acid 1 mg/kg on days 1 to 4, interferon alfa 6 million units/m2 on days 1 to 4, estramustine 280 mg three times a day on days 1 to 5, and docetaxel 40 mg/m2 on day 2, all repeated every 21 days. Pts had peripheral blood mononuclear cells (PBMCs) obtained prior to therapy and on days 2 through 4 of the first cycle to assess the effect of therapy on the expression of Bcl-2. Results: Nineteen of 20 registered pts (mean age 66) have been treated in this trial. The median pre-treatment PSA was 33.3 ng/mL. A PSA decrease was seen in 13/19 pts (68%) with a mean decrease of 50.3%. A PSA decrease ≥ 50% was seen in 7/19 pts (37%), with an average PSA decrease of 70.4% in these pts. One patient had an objective response (partial remission). The median time to progression (TTP) was 16.3 weeks (range: 3.1 - 132.6 weeks). Three pts remain on study with a median TTP of 25.1 weeks (range: 6.1 - 132.6 weeks). Grade 3 toxicities included 2 pts with hypophosphatemia, 1 patient with neutropenia, and 1 patient with flu-like symptoms. One patient experienced a pulmonary embolism and one patient had a portal vein thrombosis. Common Grade 2 toxicities included fatigue (21%), cytopenias (21%) and GI side effects (16%). There was no treatment-related mortality. Conclusions: These data support the efficacy of the RITE regimen, and the possibility of using alternative Bcl-2 modulating agents in combination with docetaxel in future studies. In addition, long term treatment with low dose docetaxel may be feasible. The assessment of an effect on PBMC Bcl-2 expression is ongoing. No significant financial relationships to disclose.

A phase II study of capecitabine-gemcitabine(CapGem) as a first line therapy in Bangladeshi patients with locally advanced or metastatic pancreatic adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15100-15100
Author(s):  
M. S. Reza ◽  
M. A. Hai ◽  
Q. Chowdhury
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Locally Advanced ◽  
Ecog Performance Status ◽  
Pain Status ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Ca 19.9

15100 Background: Pancreatic cancer is one of the cancers with very poor prognosis because of its diagnosis at an advanced or metastatic stages. There is no consensus on the optimal management of locally advanced or metastatic pancreatic cancer. This phase II study was designed to evaluate the efficacy and safety of CapGem in patients (Pts.) with pancreatic adenocarcinoma. Methods: From January 2001 to December 2004, 30 pts with; histologically / cytologically proven, bidimensionally measurable locally advanced or metastatic pancreatic adenocarcinoma, age 18∼75 years with ECOG performance status 0∼3, no prior chemotherapy, life expectancy >3 months, adequate bone marrow, renal, hepatic and haematological values were enrolled. It was an open - labeled, non-randomized, single - centered and prospective study. The pts received Capecitabine 750mg/m2 twice dailly,days 1–14,orally and Gemcitabine 1000mg/m2 days 1 & 8, intravenous infusion at an interval of 21 days.The efficacy was measured by response rates, CA-19.9 & pain status and safety was measured by adverse events and laboratory blood values. Results: This study consisted of 16 (53.33%) male and 14 (46.67%) female pts. Median age was 52 years. 18 (60%) pts were inoperable locally advanced and the remaining 12 (40%) were metastatic diseases where 8 hepatic and 4 pulmonary. In total, 152 cycles chemotherapy were administered with a median of 5.06 cycles per pt and 28/30 pts were evaluated for responses. The overall response was 9 ( 32.14%) with 2 complete and 7 partial responses. 14 pts (50%) had stable diseases and 5 (17.86%) had progressive diseases. There was 55% decrease in CA-19.9 and pain reduction was 60%. Overall survival was10 months. Grade 3 haematological toxicities were observed as follows: neutropenia 30% and anaemia 18%. Some non- haematological toxicities including nausea & vomiting 30%, diarrhoea 20% and hand foot syndrome 10% were observed. Conclusions: This phase II study supports the use of CapGem combination in chemo naive locally advanced or metastatic pancreatic adenocarcinoma due to its promising anti-tumor activity with well-tolerated toxicities in Bangladeshi pts. No significant financial relationships to disclose.

scholarly journals A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma

Sarcoma ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Robert G. Maki ◽  
Achim A. Jungbluth ◽  
Sacha Gnjatic ◽  
Gary K. Schwartz ◽  
David R. D’Adamo ◽  
...  
Keyword(s):  
Synovial Sarcoma ◽  
Mononuclear Cells ◽  
Response Rate ◽  
Single Agent ◽  
Delayed Type Hypersensitivity ◽  
Clinical Activity ◽  
Peripheral Blood Mononuclear ◽  
Ct Antigen ◽  
Synovial Sarcomas ◽  
Ct Antigens

Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma.Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity.Results. Six patients were enrolled and received 1–3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy.Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.

Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4168-TPS4168
Author(s):  
Laith I. Abushahin ◽  
Anne M. Noonan ◽  
John L. Hays ◽  
Pannaga G. Malalur ◽  
Ashish Manne ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Pancreatic Adenocarcinoma ◽  
Cell Lines ◽  
Dose Intensity ◽  
Standard Of Care ◽  
Significance Level ◽  
Pancreatic Cancer Cells ◽  
Metastatic Pancreatic Adenocarcinoma

TPS4168 Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.

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