Use of the Optimata Virtual Patient (OVP) to predict effects of sunitinib malate in advanced pancreatic cancer.

341 Background: Pancreatic cancer is considered to be incurable by available treatment modalities, with 5-year survival rate <4%. Sunitinib malate (Sutent) significantly increased progression-free survival in patients with advanced islet cell tumors (pancreatic); however, it demonstrated only modest single-agent effect in a phase II study in patients with metastatic pancreatic adenocarcinoma (PaC) that progressed after first-line therapy with gemcitabine. To improve the response of PaC patients to drugs, the interplay between biologic, pathologic, and pharmacologic processes underlying drug-patient interactions have been mathematically modeled, predicting efficacy responses, different toxicities, and long-term tolerability in clinical trials, allowing for improved dosing regimens and patient selection (OVP engine) (Agur Z., 2010). The OVP engine was used to predict Sunitinib malate single-agent activity in advanced PaC. Methods: OVP replicated the observed growth patterns of human PaC. Pharmacokinetics (PK) and pharmacodynamics (PD) of sunitinib malate were modeled based on literature (NDA 21-938). Effects of sunitinib malate on human PaC xenografts were scaled to model PK/PD in human. To evaluate drug efficacy in advanced PaC patient-population, a Virtual PaC Patient- Population was created by replacing the population averaged parameter values in the model by their distribution in the population. Using this procedure, a large set of virtual patients was generated. Model simulations with sunitinib malate therapy (50 mg QD/28 days; 14 days rest [1 cycle]) enabled the prediction and classification of patients' response according to RECIST criteria and compared with the actual clinical response (O'Reilly et al, 2008). Results: Simulations of the FDA-approved schedule, predicted a stable disease in 81% of the patients following one treatment cycle and 54% following two treatment cycles. Stable disease was predicted to be the best observed response, which was confirmed in the clinical study. Conclusions: Our model predictions are compatible with clinical results of a recent phase II trial with the same treatment regimen of sunitinib malate (O'Reilly et al, 2008) and further suggest the use of mathematical model during drug development. [Table: see text]

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A phase II trial of capecitabine and docetaxel in patients with previously treated pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14111 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14111-14111

Author(s):

G. Lopes ◽

B. Bastos ◽

E. Ahn ◽

J. A. Quesada ◽

M. Allison ◽

...

Keyword(s):

Pancreatic Cancer ◽

Median Survival ◽

Phase Ii ◽

Stable Disease ◽

Phase Ii Trial ◽

Single Agent ◽

Advanced Pancreatic Cancer ◽

Sequential Design ◽

Ca 19.9 ◽

Ecog Ps

14111 Background: There is no accepted standard treatment for patients with advanced pancreatic cancer who progress after gemcitabine-based therapy. Capecitabine and docetaxel have single-agent activity in pancreatic cancer and have documented synergy in both pre-clinical models and in the treatment of other solid tumors. Methods: A phase II trial with a 3-stage sequential design was planned to assess the efficacy (primary end-point: response rate) and toxicity of capecitabine 800 mg/m2 PO bid on days 1–14 in combination with docetaxel 30 mg/m2 IV on days 1 and 8 of each 21-day cycle in patients with advanced pancreatic cancer who failed first-line gemcitabine-based chemotherapy. If no responses are observed after 13 patients or less than 3 responses are seen after 26 patients, accrual will stop and the combination deemed ineffective. Results: Eight patients have been enrolled (5 women, 3 men). Median age was 67 years. ECOG PS was as follows: PS 1, three patients; PS 2, five patients. All patients had adequate organ function. A total of 26 cycles have been administered (median: 2 cycles, range 1 to 8). Four patients had stable disease (median duration 9 weeks, range 6 to 24), and 3 had progressed at the time of first evaluation (2 cycles). One patient has not yet completed 2 cycles and is therefore not assessable for radiologic response. Out of 7 patients with an elevated CA 19–9, four had a decrease of 50% or greater while on chemotherapy. Grade 1 or 2 toxicity was seen in 3 patients (diarrhea, 1 patient; fatigue, 2 patients). Grade 3 or 4 toxicity was as follows: fatigue, 2 patients; dehydration, 1 patient; neuropathy, 1 patient. There were no treatment related deaths. Enrollment continues. Efficacy data fulfilling the first stage sequential design should be available at the time of the meeting. Median survival for all patients is currently 13 weeks (range 7–23 weeks) Conclusions: Capecitabine in combination with docetaxel is a well-tolerated regimen in the treatment of patients with pancreatic cancer who have failed prior gemcitabine-based therapy. Four out of 8 patients have had stable disease. Four of 7 patients have had a decrease of 50% or greater in CA 19.9 levels. Enrollment continues. Median survival of 13 weeks underscores the poor prognosis of this patient population. [Table: see text]

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Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15111 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15111-15111 ◽

Cited By ~ 1

Author(s):

Y. Park ◽

S. Yi ◽

H. Kim ◽

S. Lee ◽

I. Hwang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stable Disease ◽

Single Agent ◽

Advanced Pancreatic Cancer ◽

Median Number ◽

Line Treatment ◽

Second Line ◽

Best Response ◽

Grade 3 ◽

Number Of Cycles

15111 Background: The aim of this phase II study was to determine whether second line therapy with single agent irinotecan could provide any clinical benefit in patients with gemcitabine- pretreated advanced pancreatic cancer. Methods: From January 2004 to October 2006, patients with advanced pancreatic cancer previously treated with gemcitabine alone or combination were treated with single agent irinotecan(150 mg/m2, biweekly), until unacceptable toxicity or disease progression. Primary endpoint was response rate with single stage design. Results: Twenty-eight patients were enrolled(22 male, 6 female, median age : 54.5 years (39–76)). Nine patients are still alive and 3 remain on therapy with stable disease. The median number of cycles was 3.5(1–12). Twenty-four patients were assessable for toxicity and 21 for response. The most common toxicities was diarrhea (grade 3, 12.5%). Grade 3 neutropenia in 1 patient was observed. Other hematological and non-hematological toxicities were mild and manageable. Partial responses were observed in 3 patients (3/21, 14%). An additional 9 patients (9/21, 43%) had stable disease as their best response. 12 patients have progressed with a median time-to-progression of 4.0 months. Conclusions: Single-agent irinotecan was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced pancreatic cancer, refractory to gemcitabine. No significant financial relationships to disclose.

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Activity of RX-3117, an oral antimetabolite nucleoside, in patients with pancreatic cancer: Preliminary results of stage 1 of the phase 1a/2b.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.445 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 445-445 ◽

Cited By ~ 1

Author(s):

Drew W. Rasco ◽

Christine Peterson ◽

Ely Benaim ◽

Jaime R. Merchan

Keyword(s):

Pancreatic Cancer ◽

Primary Endpoint ◽

Stable Disease ◽

Performance Status ◽

Single Agent ◽

Advanced Pancreatic Cancer ◽

Metastatic Pancreatic Cancer ◽

Cancer Data ◽

Phase 1B ◽

Stage 1

445 Background: RX-3117 is an oral smallmolecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 1 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 1 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage Simon design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% (2 out of 10 subjects) rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% (1 of 10 subjects) with a partial response rate or better. Results: As of Sep 2016, 8 out of 10 subjects have been enrolled (4 females, 4 males), the mean age was 70 years, ECOG performance status was 1 and 5 subjects had received more than 4 prior therapies. Two subjects met the primary endpoint of stable disease with a duration of 140-168 days at the time of this submission. The most frequent adverse events were moderate to severe anemia, mild to moderate fatigue, abdominal pain and diarrhea. Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. As the primary endpoint has been achieved, the study will now move to stage 2 where an additional 40 subjects with advanced pancreatic cancer will be enrolled. Clinical trial information: NCT02030067.

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RXÂ 3117: Activity of an oral antimetabolite nucleoside in subjects with pancreatic cancerâ€“Preliminary results of stage II of the phase Ia/IIb study.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.396 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 396-396

Author(s):

Vincent M. Chung ◽

Jaime R. Merchan ◽

Allyson J. Ocean ◽

Drew W. Rasco ◽

Hani M. Babiker ◽

...

Keyword(s):

Pancreatic Cancer ◽

Partial Response ◽

Primary Endpoint ◽

Stable Disease ◽

Single Agent ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Metastatic Pancreatic Cancer ◽

Cancer Data ◽

Phase 1B

396 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started. Clinical trial information: NCT02030067.

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Phase II study of regorafenib (Reg) in patients with previously treated advanced pancreatic cancer (APC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15751 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15751-e15751 ◽

Cited By ~ 3

Author(s):

John Stuart Salmon ◽

Jimmy J. Hwang ◽

Myra M. Robinson ◽

James Thomas Symanowski ◽

Lloye M Dillon ◽

...

Keyword(s):

Pancreatic Cancer ◽

Disease Control ◽

Phase Ii ◽

Phase Ii Study ◽

Single Agent ◽

Advanced Pancreatic Cancer ◽

Radiographic Evaluation ◽

Treatment Approaches ◽

Dismal Prognosis ◽

Line Of Therapy

e15751 Background: APC that has progressed after treatment with gemcitabine has a dismal prognosis and novel treatment approaches are needed. Reg is a potent oral inhibitor of VEGFR 1-3, PDGFR, TIE-2, FGFR-1, KIT, and the RAF kinases, and has activity in pancreatic xenograft models. We tested the activity of Reg in patients (pts) with refractory APC. Methods: This single arm, single center phase II study evaluated Reg (120mg/d, for 21 days, followed by 7-day break, with escalation to 160mg after the 1st cycle if tolerated) in pts with metastatic pancreatic cancer whose disease had progressed after at least one prior line of therapy and treatment with gemcitabine. Pts underwent radiographic evaluation every 2 cycles. The primary endpoint was 16-wk PFS. Kaplan Meier techniques were used to estimate PFS and OS. Serum tumor MUC1 antigen (tMUC1) concentrations were measured at baseline, end of cycle 1, and off-treatment using the TAB 004 antibody (Agkura Personal Score blood test, OncoTAb, Inc). Relative change of tMUC1 from baseline to end of cycle 1 was compared between those with and without 16-wk disease control. Results: 20 pts were enrolled into the study. Median age = 65 (47-79), and 80% (16/20) had 2 or more prior lines of therapy for advanced disease. Landmark 16 wk PFS = 10% (2/20), crossing a predefined futility boundary to demonstrate 20% improvement over historical controls with BSC. ORR was 5% (1/20), and DCR at 8 wks was 20% (4/20). Median PFS was 6.1 wks (95% CI: 2.9 – 7.1), and median OS was 9.4 wks (95% CI: 8.1 – 17.0). 10% of pts (2/20) had protocol defined Reg dose escalation to 160mg, and 30% (6/20) had dose reduction to 80mg. The most frequent grade 3-4 adverse events included hyponatremia (35%), fatigue (20%), and hypoalbuminemia (20%). Baseline tMUC1 varied substantially, mean 69.6ug/mL, median 51.3ug/mL (10.8 – 310.5). Serum tMUC1 decreased by a mean of 20.8% in the pts with disease control at 16 wks (n = 2), but increased by 65% (mean) in pts with disease progression or death within 16 wks (n = 13, p = 0.048). Conclusions: Reg has minimal activity as a single agent in pts with heavily treated APC. Serum tMUC1 levels measured by TAB 004 antibody may be a novel tumor marker in this disease. Different treatment approaches are needed. Clinical trial information: NCT02080260.

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Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for patients with advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16257 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16257-e16257

Author(s):

Huayun Zhu ◽

Xiaofeng Sun ◽

Xuan Pan ◽

Pingping Wu ◽

Jia Chen

Keyword(s):

Pancreatic Cancer ◽

Primary Endpoint ◽

Stable Disease ◽

Single Agent ◽

Objective Response ◽

Advanced Pancreatic Cancer ◽

Combined Chemotherapy ◽

Line Treatment ◽

First Line ◽

First Line Treatment

e16257 Background: This study aimed to evaluate the efficacy and safety of Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for advanced pancreatic cancer. Methods: This was a single-arm, simple-center, exploratory trial, which included advanced pancreatic cancer pts. Patients received Sindilimab combined with nab-paclitaxel plus gemcitabine. Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take Sindilimab as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: 16 eligible patients were enrolled and 14 pts were evaluable for efficacy analysis. Baseline characteristics are shown in Table 2. Conclusions: This study has showed high anti-tumor efficacy and tolerant toxicity in first-line regimen for advanced pancreatic cancer. Furthermore, it is needed to be proved in update results and large scale studies. Efficacy As shown in Table 3, among 14 evaluable pts, unconfirmed ORR was 57.1% and DCR was 92.8%. 8 pts got partial response (PR), 5 pts stable disease (SD) and 1 pts progressive disease(PD) at best. PFS: The primary endpoint 6-month PFS rate was 2%(95% CI 50.4%-72.4%). Which indicated that the primary endpoint of the study was reached. And mPFS was 7.3 months(95% CI 5.9-8.1). OS: Median OS was not reached and 6m-OS rate was 85.7% (95%CI 5%-91.3%). Safety. All 16 pts were included in the safety analysis (Table 4). The overall AE incidence rate was 93.75% .≥Grade 3 irAE included GGT increased (37.5%) and peripheral neuropathy (6.25%). No TRAE led to death.[Table: see text][Table: see text][Table: see text][Table: see text]

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