Efficacy & Safety of ODSH (2-0, 3-0 Desulfated Heparin) in Patients With Metastatic Pancreatic Cancer Treated With Gemcitabine & Abraxane (PGPC1)

• ClinicalTrials.gov Identifier: NCT01461915
• Recruitment Status: Completed
• First Posted: October 28, 2011
• Last Update Posted: August 29, 2016
• Sponsor: Cantex Pharmaceuticals
• Collaborator: Translational Drug Development
• Information provided by (Responsible Party): Cantex Pharmaceuticals

Study Description

Brief Summary:

The purpose of the study is to determine whether ODSH (2-0,3-0 desulfated heparin), a low anticoagulant heparin derivate with preserved anti-inflammatory and anti-neoplastic characteristics is efficacious in patients with metastatic pancreatic cancer with gemcitabine and nab-paclitaxel ( Abraxane) as first line therapy.

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Cancer	Drug: Abraxane ( Nab-paclitaxel); Drug: Gemcitabine; Drug: ODSH ( 2-O, 3-O Desulfated Heparin); Drug: Abraxane ( nab-paclitaxel)	Phase 2

Detailed Description:

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 ODSH. 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 ODSH 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 ODSH at dose levels that can safely be administered without clinically significant anticoagulation.

The standard of care of pancreatic cancer is evolving. It appears that two 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.

Subjects with advanced metastatic pancreatic cancer that have not received chemotherapy, surgical or radiation treatments and have a good performance status will be eligible to participate in this study. 10 patients will be enrolled in a Run-in Period to receive gemcitabine + nab-paclitaxel +ODSH. PK sampling and safety assessments will be conducted to decide on the continuation to the Controlled Period of the study where 50 patients will be randomized at a 1:1 ratio to either of the two study arms: Arm A will receive gemcitabine + nab-paclitaxel + ODSH and Arm B will receive gemcitabine + nab-paclitaxel.

The primary endpoint of the study is mean progression free survival. The secondary endpoints consist of tumor response by RECIST criteria, overall survival at the end of the study and changes from baseline for CA19-9 marker, weight and plasma albumin.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 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: November 2011
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: June 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Run-in; 10 Subjects to be enrolled in the study to receive : gemcitabine + nab-paclitaxel + ODSH	Drug: Abraxane ( Nab-paclitaxel); Nab-paclitaxel 125 mg/m2 administered IV over 30 minutes. Given weekly for 3 weeks followed by one week of rest.; Other Name: Nab-paclitaxel = Abraxane; Drug: Gemcitabine; Gemcitabine at 1000 mg/m2 administered IV over 30 minutes (after the nab-paclitaxel IV administration is complete). Gemcitabine to be administered weekly for 3 weeks followed by one week of rest.; Drug: ODSH ( 2-O, 3-O Desulfated Heparin); ODSH IV bolus at 4 mg/kg to be administered in 5 minutes immediately after completion of gemcitabine administration. ODSH 48-h IV continuous infusion at 0.375 mg/kg/h should be started immediately after the ODSH IV bolus has been administered.; Other Name: ODSH = 2-O, 3-O Desulfated Heparin
Experimental: Arm A; 25 patients to be enrolled to receive gemcitabine + nab-paclitaxel + ODSH	Drug: Abraxane ( Nab-paclitaxel); Nab-paclitaxel 125 mg/m2 administered IV over 30 minutes. Nab-paclitaxel to be given weekly for 3 weeks followed by one week of rest.; Other Name: Abraxane = nab-paclitaxel; Drug: Gemcitabine; Gemcitabine at 1000 mg/m2 over 30 minutes to be administered after the completion of Abraxane administration. Gemcitabine will be given weekly for 3 weeks followed by one week of rest.; Drug: ODSH ( 2-O, 3-O Desulfated Heparin); ODSH IV bolus at 4 mg/kg will be administered in 5 minutes immediately after completion of gemcitabine administration. ODSH 48-h IV continuous infusion at 0.375 mg/kg/h should be started immediately after the ODSH IV bolus has been administered.; Other Name: ODSH = 2-O, 3-O desulfated heparin
Active Comparator: Arm B; 25 patients will be enrolled in the study to receive gemcitabine + nab-paclitaxel	Drug: Abraxane ( nab-paclitaxel); Nab-paclitaxel 125 mg/m2 administered IV over 30 minutes will be given weekly for 3 weeks followed by one week of rest.; Other Name: Abraxane = nab-paclitaxel; Drug: Gemcitabine; Gemcitabine to be administered IV at 1000 mg/m2 over 30 minutes given weekly for 3 weeks followed by one week of rest

Outcome Measures

Primary Outcome Measures :

1. Progression-Free Survival (PFS) according to RECIST Guidelines. [ Time Frame: From Baseline to disease progression or death (whichever occurs first), assessed up to 9 months. ]
   Median Progression-Free Survival according to RECIST Guidelines Version 4.03

Secondary Outcome Measures :

1. Incidence of Adverse Events & Toxicity [CTCAE Version 4.03] [ Time Frame: From Baseline to disease progression, assessed up to 9 months ]
   Incidence of Adverse Events, laboratory test abnormalities and chemotherapy toxicity.
2. Overall survival (OS). [ Time Frame: From Baseline to Death, assessed up to 9 months. ]
   Comparative OS among study arms at the end of the study.
3. Objective Tumor Response [ Time Frame: From Baseline to disease progression or death (whichever occurs first), assessed up to 9 months. ]
   Overall Response Rate (Complete / Partial Responses), Duration of Response and Disease Control Rate will be assessed.
4. ODSH Area Under Curve (AUC) [ Time Frame: Time Frame: 0, 15, 30, 45 and 60 minutes after the ODSH IV bolus and at 48 hours (steady state) during the ODSH IV continuous infusion. ]
   PK assessment of ODSH plasma concentration during ODSH IV bolus (4 time-points) and at the end of the ODSH 48-hour IV continuous infusion in 6 patients

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients must have 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 are excluded.
2. Patient has one or more metastatic tumors measurable by CT scan AND a serum CA19-9 measurement > 2 times the upper limit of normal. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one 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.
3. 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.
4. Patients must have received no prior radiotherapy or chemotherapy for metastatic disease. Patients who have received radiotherapy or chemotherapy as adjuvant o neo-adjuvant therapy for locally advanced disease six months or more prior to enrollment into this study are eligible.
5. Patient 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.

6. Patient has the following blood chemistry levels at Screening (obtained ≤ 14 days prior to randomization) and at Baseline-Day 0:

   • AST (SGOT), 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).
7. Patient 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%).
8. Patient has ECOG performance status ≤ 1.

Exclusion Criteria:

1. Patient has brain metastases.
2. Patient has only locally advanced disease.
3. Patient has experienced an increase of ECOG to > 1 between Screening and Randomization.
4. Patient requires continuous treatment with coumadin or other oral or parenteral anticoagulation (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.
5. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
6. Patient 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.
7. Patient has a history of allergy or hypersensitivity to any of the study drugs, their pharmaceutical class or any of their excipients.
8. Patient 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.
9. Patient is enrolled in any other clinical protocol or investigational trial involving administration of antineoplastic compounds for the treatment of metastatic pancreatic cancer.
10. Patient is unwilling or unable to comply with study procedures.
11. Nab-paclitaxel is metabolized by CYP2C8 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.
12. Subjects with 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 study subject at risk.

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Arizona

Scottsdale, Arizona, United States, 85259

United States, California

Disney Family Cancer Center

Burbank, California, United States, 91505

Marin Cancer Care

Greenbrae, California, United States, 94904

Scripps Clinic Torrey Pines ( Green Hospital)

La Jolla, California, United States, 92037

United States, Florida

Cleveland Clinic Florida

Weston, Florida, United States, 33331

United States, Illinois

Loyola University Medical Center/Cardinal Bernardin Cancer Center

Maywood, Illinois, United States, 60153

United States, Indiana

Indiana University Health, Goshen Center for Cancer Care

Goshen, Indiana, United States, 46526

United States, Louisiana

Fesit-Weiller Cancer Center

Shreveport, Louisiana, United States, 71130

United States, Michigan

Saint Mary's Health Care

Grand Rapids, Michigan, United States, 49503

United States, Ohio

Summa Health System - Cooper Cancer Center

Akron, Ohio, United States, 44304

United States, Pennsylvania

Thomas Jefferson University [Kimmel Cancer Center]

Philadelphia, Pennsylvania, United States, 19107

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

UPMC Cancer Center

Pittsburgh, Pennsylvania, United States, 15232

United States, South Carolina

Medical University of South Carolina Hollings Cancer Center

Charleston, South Carolina, United States, 29425

United States, Texas

University of Texas Medical Branch

Galveston, Texas, United States, 77555

South Texas Oncology & Hematology

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Cantex Pharmaceuticals

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

More Information

Additional Information:

Gemcitabine Plus nab-Paclitaxel Treatment in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial. Daniel D. Von Hoff et. al: JCO December 1, 2011 vol. 29 no. 34 4548-4554. 

Publications:

Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548-54. doi: 10.1200/JCO.2011.36.5742. Epub 2011 Oct 3.

• Responsible Party: Cantex Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01461915
• Other Study ID Numbers: PGX-ODSH-2011-PC1
• First Posted: October 28, 2011
• Last Update Posted: August 29, 2016
• Last Verified: August 2016

Keywords provided by Cantex Pharmaceuticals:

Pancreatic Cancer

Additional relevant MeSH terms:

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Gemcitabine; Paclitaxel; Albumin-Bound Paclitaxel; Heparin; Calcium heparin; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anticoagulants; Fibrinolytic Agents; Fibrin Modulating Agents