PGPC1: Phase 2 Study to Assess the Efficacy & Safety of Gemcitabine + Nab Paclitaxel With or Without Dociparstat in Metastatic Pancreatic Cancer Patients

Sponsor

Chimerix (Industry)

Overall Status

Terminated

CT.gov ID

NCT01461915

Collaborator

Translational Drug Development (Other)

Enrollment

Locations

Arms

Duration (Months)

3.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized, Phase 2, open label study aims to assess the efficacy and safety of gemcitabine + nab paclitaxel with or without dociparstat (ODSH) as first line treatment of metastatic pancreatic cancer. This study consists of 2 periods: a Run-in Period and a Randomized Period.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Pancreatic Cancer	Drug: Nab paclitaxel Drug: Gemcitabine Drug: Dociparstat	Phase 2

Detailed Description

Dociparstat (ODSH) has demonstrated in vitro and in vivo inhibitory activity on mechanisms that are believed to play important roles in pancreatic cancer invasion, metastasis, and resistance to chemotherapy and radiation. Pancreatic cancer appears to have a dependence on autophagy, a regulated catabolic pathway to degrade and recycle cellular organelles and macromolecules. Autophagy appears to be largely driven by the binding of high mobility group box-1 protein (HMGB1) to the receptor for advanced glycation end-products (RAGE), which is strongly inhibited by dociparstat. Autophagy appears to not only assist pancreatic cancer cells to survive in a hypoxic, relatively avascular environment, but also appears to play an important role in chemotherapy resistance. Other important biological activities promoting pancreatic cancer invasion and metastasis affected by dociparstat include the inhibition of heparanase and the binding of tumor cells to endothelium and platelets mediated by the selectins. It is believed that these biological activities such as the inhibition of RAGE, heparanase, and selectin-mediated metastasis, can be inhibited by dociparstat at dose levels that can safely be administered without clinically significant anticoagulation.

The standard of care of pancreatic cancer is evolving. It appears that 2 combination regimens, the "FOLFIRINOX" regimen (a combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin) and the combination of gemcitabine + nab-paclitaxel, could have more activity than the previous standard treatment of gemcitabine alone.

Patients with advanced metastatic pancreatic cancer who have not received chemotherapy, surgical or radiation treatments and have a good performance status are eligible to participate in this study. This study consists of 2 periods: a Run-in Period and a Randomized Period. In total, 10 patients are planned to be enrolled in a Run-in Period to receive gemcitabine + nab-paclitaxel + dociparstat. Pharmacokinetic sampling and safety assessments are to be conducted to decide on the continuation to the Randomized Period of the study where 50 patients are planned to be randomized at a 1:1 ratio to either of the 2 study arms:

Arm A: Patients will receive gemcitabine + nab-paclitaxel + dociparstat
Arm B: Patients will receive gemcitabine + nab-paclitaxel

The primary endpoint of this study is mean progression free survival. The secondary endpoints of this study are to consist of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, overall survival at the end of the study, and changes from baseline for carbohydrate antigen (CA) 19-9 marker, weight, and plasma albumin.

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase II Open Label Study to Assess the Efficacy & Safety of Gemcitabine + Abraxane® With or Without ODSH (2-0, 3-0 Desulfated Heparin) as First Line Treatment of Metastatic Pancreatic Cancer

Study Start Date :

Nov 1, 2011

Actual Primary Completion Date :

Dec 1, 2012

Actual Study Completion Date :

Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Run-in During the Run-In Period, patients will receive gemcitabine + nab-paclitaxel + dociparstat to assess the compatibility of the combination. • Nab-paclitaxel + gemcitabine + dociparstat: Nab-paclitaxel 125 mg/m2 will be administered intravenously (IV) over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately following the completion of gemcitabine administration. Dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered immediately following the dociparstat IV bolus administration.	Drug: Nab paclitaxel Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Other Names: Abraxane Drug: Gemcitabine Following the completion of nab-paclitaxel administration, gemcitabine IV infusion at 1000 mg/m2 will be administered over 30 minutes. Gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-cycle). Drug: Dociparstat Following the completion of gemcitabine administration, dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately after completion of gemcitabine administration. Immediately following the dociparstat IV bolus administration, dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered. Other Names: ODSH 2-O, 3-O Desulfated Heparin Dociparstat sodium
Experimental: Arm A Patients randomized to Arm A will receive gemcitabine + nab-paclitaxel + dociparstat. • Nab-paclitaxel + gemcitabine + dociparstat: Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately following the completion of gemcitabine administration. Dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered immediately following the dociparstat IV bolus administration.	Drug: Nab paclitaxel Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Other Names: Abraxane Drug: Gemcitabine Following the completion of nab-paclitaxel administration, gemcitabine IV infusion at 1000 mg/m2 will be administered over 30 minutes. Gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-cycle). Drug: Dociparstat Following the completion of gemcitabine administration, dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately after completion of gemcitabine administration. Immediately following the dociparstat IV bolus administration, dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered. Other Names: ODSH 2-O, 3-O Desulfated Heparin Dociparstat sodium
Active Comparator: Arm B Patients randomized to Arm B will receive gemcitabine + nab-paclitaxel. • Nab-paclitaxel + gemcitabine: o Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle).	Drug: Nab paclitaxel Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Other Names: Abraxane Drug: Gemcitabine Following the completion of nab-paclitaxel administration, gemcitabine IV infusion at 1000 mg/m2 will be administered over 30 minutes. Gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-cycle).

Arm

Intervention/Treatment

Experimental: Run-in

During the Run-In Period, patients will receive gemcitabine + nab-paclitaxel + dociparstat to assess the compatibility of the combination. • Nab-paclitaxel + gemcitabine + dociparstat: Nab-paclitaxel 125 mg/m2 will be administered intravenously (IV) over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately following the completion of gemcitabine administration. Dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered immediately following the dociparstat IV bolus administration.

Drug: Nab paclitaxel

Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle).

Other Names:

Abraxane

Drug: Gemcitabine

Following the completion of nab-paclitaxel administration, gemcitabine IV infusion at 1000 mg/m2 will be administered over 30 minutes. Gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-cycle).

Drug: Dociparstat

Following the completion of gemcitabine administration, dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately after completion of gemcitabine administration. Immediately following the dociparstat IV bolus administration, dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered.

Other Names:

ODSH

2-O, 3-O Desulfated Heparin

Dociparstat sodium

Experimental: Arm A

Patients randomized to Arm A will receive gemcitabine + nab-paclitaxel + dociparstat. • Nab-paclitaxel + gemcitabine + dociparstat: Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle). Dociparstat IV bolus at 4 mg/kg will be administered in 5 minutes immediately following the completion of gemcitabine administration. Dociparstat 48-hour IV continuous infusion at 0.375 mg/kg/hr will be administered immediately following the dociparstat IV bolus administration.

Drug: Nab paclitaxel

Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle).

Other Names:

Abraxane

Drug: Gemcitabine

Drug: Dociparstat

Other Names:

ODSH

2-O, 3-O Desulfated Heparin

Dociparstat sodium

Active Comparator: Arm B

Patients randomized to Arm B will receive gemcitabine + nab-paclitaxel. • Nab-paclitaxel + gemcitabine: o Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes followed by the administration of gemcitabine IV infusion at 1000 mg/m2 over 30 minutes. Nab paclitaxel + gemcitabine will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle).

Drug: Nab paclitaxel

Nab-paclitaxel 125 mg/m2 will be administered IV over 30 minutes. Nab-paclitaxel will be administered weekly for 3 weeks followed by 1 week of rest (28-day cycle).

Other Names:

Abraxane

Drug: Gemcitabine

Outcome Measures

Primary Outcome Measures

Number of Patients who Achieved Progression-Free Survival [9 months]
The primary objective of this study is to evaluate progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines Version 1.1. This will be assessed from Baseline to disease progression or death (whichever occurred first), for up to 9 months.

Secondary Outcome Measures

Proportion of Patients who Achieved Overall Survival [9 months]
A secondary objective of this study is to evaluate overall survival at the End of the Study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must meet all the following criteria to be eligible for this study:

Has histologically confirmed adenocarcinoma of the pancreas that is metastatic and for which potential curative measures, such as resection of an isolated metastasis, are not available. Patients with islet cell neoplasms will be excluded.
Has ≥ 1 metastatic tumors measurable by computerized tomography (CT) scan AND a serum carbohydrate antigen (CA) 19-9 measurement >2 times the upper limit of normal. Patients must have measurable disease, defined as at least 1 lesion that could be accurately measured in at least 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
Is male or non-pregnant and non-lactating female and ≥ 18 to ≤ 75 years of age. If a female patient is of child-bearing potential, she must have a negative serum pregnancy test documented within 72 hours prior to the first administration of study drug and on Day 1 of each cycle thereafter. If sexually active, the patient must agree to use contraception prior to study entry and for the duration of study participation.
Must have received no prior radiotherapy or chemotherapy for metastatic disease. Patients who have received radiotherapy or chemotherapy as adjuvant or neo-adjuvant therapy for locally advanced disease 6 months or more prior to enrollment into this study are eligible.
Has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained ≤14 days prior to randomization) and at Baseline-Day 0: Absolute neutrophil count (ANC) ≥1.5 × 109/L; Platelet count ≥ 100,000/mm3 (100 × 109/L); Hemoglobin (Hgb) ≥ 9 g/dL.
Has the following blood chemistry levels at Screening (obtained ≤14 days prior to randomization) and at Baseline-Day 0:

Aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT) ≤ 2.5 × upper limit of normal range (ULN), unless liver metastases are present, then ≤5 × ULN is allowed. Total bilirubin ≤1.5 × ULN.
Serum creatinine (Cr) within normal limits or calculated clearance ≥60 mL/min/1.73 m2 for patients with creatinine (Cr) levels above or below the institutional normal value. If using Cr clearance, actual body weight should be used for calculating Cr clearance (e.g., using the Cockcroft-Gault formula).

Has acceptable coagulation studies at Screening (obtained ≤14 days prior to randomization) as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (±15%).
Has an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1.
Has been informed about the nature of the study, and agrees to participate in the study, and signed the Informed Consent Form (ICF) prior to participation in any study-related activities.

Exclusion Criteria:

If a patient meets any of the following criteria, they are not eligible to participate in this study:

Has brain metastases.
Has only locally advanced disease.
Has experienced an increase of ECOG score to >1 between Screening and Randomization.
Requires continuous treatment with coumadin or other oral or parenteral anticoagulation (heparin, low molecular weight heparin [LMWH], heparinoids) to prevent or treat thromboembolic disease. The use of prophylactic antiplatelet drugs such as clopidogrel and aspirin are allowed before and during the study.
Has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
Has undergone major surgery, other than diagnostic surgery (i.e., surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Randomization in this study.
Has a history of allergy or hypersensitivity to any of the study drugs, their pharmaceutical class, or any of their excipients.
Has a concomitant serious medical or psychiatric illness that, in the opinion of the Investigator, could compromise the patient's safety or the study data integrity.
Is enrolled in any other clinical protocol or investigational trial that involves administration of anti-neoplastic compounds for the treatment of metastatic pancreatic cancer.
Is unwilling or unable to comply with study procedures.
Nab-paclitaxel is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Co-administration of substrates, inhibitors of CYP2C8 and/or CYP3A4 with nab-paclitaxel is not allowed. The following medications and substances are not allowed during the study: ritonavir, saquinavir, indinavir, nelfinavir, rifampicin, carbamazepine, phenytoin, efavirenz, or nevirapine, grapefruit (juice or seeds) or some herbals like St. John's wort.
Has risk factors for or a history of Torsades des Pointes (TdP), or a significant QT prolongation that, in the opinion of the Investigator, may place the patient at risk.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
2	Disney Family Cancer Center	Burbank	California	United States	91505
3	Marin Cancer Care	Greenbrae	California	United States	94904
4	Scripps Clinic Torrey Pines ( Green Hospital)	La Jolla	California	United States	92037
5	Cleveland Clinic Florida	Weston	Florida	United States	33331
6	Loyola University Medical Center/Cardinal Bernardin Cancer Center	Maywood	Illinois	United States	60153
7	Indiana University Health, Goshen Center for Cancer Care	Goshen	Indiana	United States	46526
8	Fesit-Weiller Cancer Center	Shreveport	Louisiana	United States	71130
9	Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
10	Summa Health System - Cooper Cancer Center	Akron	Ohio	United States	44304
11	Thomas Jefferson University [Kimmel Cancer Center]	Philadelphia	Pennsylvania	United States	19107
12	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
13	UPMC Cancer Center	Pittsburgh	Pennsylvania	United States	15232
14	Medical University of South Carolina Hollings Cancer Center	Charleston	South Carolina	United States	29425
15	University of Texas Medical Branch	Galveston	Texas	United States	77555
16	South Texas Oncology & Hematology	San Antonio	Texas	United States	78229

Sponsors and Collaborators

Chimerix
Translational Drug Development

Investigators

Principal Investigator: Mitesh J Borad, MD, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic , Scottsdale Arizona
Study Director: Stephen Marcus, MD, ParinGenix Inc, Weston FL