Isoquercetin in Preventing Venous Thromboembolic Events in Patients with Metastatic or Unresectable Pancreatic Cancer, Stage III-IV Non-small Cell Lung Cancer, or Stage IV Colorectal Cancer
This partially randomized phase II/III trial studies how well isoquercetin works in preventing blood clots (venous thromboembolic events) in patients with pancreatic cancer that has spread to other places in the body or that cannot be removed by surgery, stage III-IV non-small cell lung cancer, or stage IV colorectal cancer. Isoquercetin may help prevent blood clots by blocking some of the enzymes that are involved in the blood clotting process.
Inclusion Criteria
- Participants must have histologically confirmed malignancy that is metastatic or currently unresectable; eligible malignancies include: * Adenocarcinoma of the pancreas (currently unresectable or metastatic) * Colorectal (stage IV) * Non-small cell lung cancer (currently unresectable stage III or stage IV)
- Receiving or scheduled to receive first or second line chemotherapy (within 30 days of registration)
- Life expectancy of greater than 4 months
- ECOG performance status =< 2
- Patient must be able to swallow capsules (phase III only)
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 90,000/mcL
- Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
- Total bilirubin < 2.0 mg/dl
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
- Creatinine < 2.0 mg/dl
- The effects of isoquercetin on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Participants may not be concurrently receiving any other study agents
- Participants with known brain metastases should be excluded from this clinical trial
- Prior history of documented venous thromboembolic event within the last 2 years (excluding central line associated events whereby patients completed anticoagulation)
- Active bleeding or high risk for bleeding (e.g. known acute gastrointestinal ulcer)
- History of significant hemorrhage (requiring hospitalization or transfusion) outside of a surgical setting within the last 24 months
- Familial bleeding diathesis
- Known diagnosis of disseminated intravascular coagulation (DIC)
- Currently receiving anticoagulant therapy
- Current daily use of aspirin (> 81 mg daily), Clopidogrel (Plavix), cilostazol (Pletal), aspirin-dipyridamole (Aggrenox) (within 10 days) or considered to use regular use of higher doses of non-steroidal anti-inflammatory agents as determined by the treating physician (e.g. ibuprofen > 800 mg daily or equivalent)
- Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Known intolerance of niacin or ascorbic acid (including known glucose-6-phosphate dehydrogenase [G6PD] deficiency)
- Pregnant women are excluded from this study because isoquercetin is a protein disulfide isomerases (PDI) inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with isoquercetin, breastfeeding should be discontinued if the mother is treated with isoquercetin; these potential risks may also apply to other agents used in this study
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02195232.
PRIMARY OBJECTIVES:
I. To evaluate the efficacy of isoquercetin to reduce domain (D)-dimer values. (Phase II)
II. To assess the effectiveness of oral isoquercetin to prevent venous thromboembolic events in cancer patients. (Phase III)
SECONDARY OBJECTIVES:
I. To investigate the cumulative incidence of venous thromboembolism (VTE) according to tissue factor bearing microparticle status (and isoquercetin randomization).
II. To evaluate the cumulative incidence of major hemorrhage between the groups of patients treated with isoquercetin versus placebo.
III. To assess overall survival according to randomization and tissue factor bearing microparticle status.
IV. To investigate the cumulative incidence of total or symptomatic VTE in all treatment arms (and according to tissue factor bearing microparticle status).
V. To study the influence of isoquercetin on tissue factor bearing microparticles (TFMP) levels and change in TFMP levels over time.
VI. To evaluate the cumulative incidence of VTE in patients with elevated TFMP as well as very elevated d-dimer (> 1500 mcg/L) overall and according to randomization.
VII. To assess for correlation between complete blood count, Eastern Cooperative Oncology Group (ECOG), histology, stage, D-dimer, and levels of tissue factor bearing microparticles.
VIII. To investigate the influence of chemotherapy, blood counts, growth factors, ECOG performance status on tissue factor bearing microparticle levels as well as VTE risk.
IX. Influence of VTE and isoquercetin on quality of life (QOL).
X. To investigate the association between isoquercetin plasma concentrations, inhibition of protein disulfide isomerase activity, and reduction in D-dimer.
XI. To evaluate the efficacy of isoquercetin to reduce D-dimer or VTE in cancer patients based on levels of circulating tissue factor bearing microparticles or Khorana risk model.
XII. To compare VTE rates at completion of phase II with historical rates of VTE in similar population.
OUTLINE:
PHASE II: Patients are assigned to 1 of 2 treatment arms.
ARM A: Patients receive standard dose isoquercetin orally (PO) once daily (QD) on days 1-28. (CLOSED)
ARM B: Patients receive higher dose isoquercetin PO QD on days 1-28.
PHASE III: Patients are randomized to 1 of 2 treatment arms.
ARM C: Patients receive isoquercetin PO QD on days 1-28.
ARM D: Patients receive placebo PO QD on days 1-28.
In all arms, treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months.
Trial PhasePhase II/III
Trial Typeprevention
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJeffrey Isaac Zwicker
- Primary ID14-114
- Secondary IDsNCI-2015-01705
- ClinicalTrials.gov IDNCT02195232