Efficacy & Safety of ODSH (2-0, 3-0 Desulfated Heparin) in Patients With Metastatic Pancreatic Cancer Treated With Gemcitabine & Abraxane (PGPC1)
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| ClinicalTrials.gov Identifier: NCT01461915 |
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Recruitment Status :
Completed
First Posted : October 28, 2011
Last Update Posted : August 29, 2016
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| 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 |
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 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 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Run-in
10 Subjects to be enrolled in the study to receive : gemcitabine + nab-paclitaxel + ODSH
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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 |
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Experimental: Arm A
25 patients to be enrolled to receive gemcitabine + nab-paclitaxel + ODSH
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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 |
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Active Comparator: Arm B
25 patients will be enrolled in the study to receive gemcitabine + nab-paclitaxel
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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 |
- 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
- 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.
- 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.
- 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.
- 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
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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.
- 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.
- 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.
- 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.
- 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.
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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).
- 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%).
- Patient has ECOG performance status ≤ 1.
Exclusion Criteria:
- Patient has brain metastases.
- Patient has only locally advanced disease.
- Patient has experienced an increase of ECOG to > 1 between Screening and Randomization.
- 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.
- Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
- 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.
- Patient has a history of allergy or hypersensitivity to any of the study drugs, their pharmaceutical class or any of their excipients.
- 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.
- Patient is enrolled in any other clinical protocol or investigational trial involving administration of antineoplastic compounds for the treatment of metastatic pancreatic cancer.
- Patient is unwilling or unable to comply with study procedures.
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01461915
| 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 | |
| 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 |
Publications:
| Responsible Party: | Cantex Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT01461915 |
| Other Study ID Numbers: |
PGX-ODSH-2011-PC1 |
| First Posted: | October 28, 2011 Key Record Dates |
| Last Update Posted: | August 29, 2016 |
| Last Verified: | August 2016 |
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Pancreatic Cancer |
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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 |