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Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer (THREAD)

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ClinicalTrials.gov Identifier: NCT03825289
Recruitment Status : Recruiting
First Posted : January 31, 2019
Last Update Posted : January 31, 2019
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
University of Utah

Brief Summary:
This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trametinib together with hydroxychloroquine may work better in treating patients with pancreatic cancer.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Carcinoma Stage II Pancreatic Cancer Stage IIA Pancreatic Cancer Stage IIB Pancreatic Cancer Stage III Pancreatic Cancer Stage IV Pancreatic Cancer Unresectable Pancreatic Carcinoma Drug: Hydroxychloroquine Drug: Trametinib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of escalating doses of hydroxychloroquine (HCQ) in combination with a fixed dose of trametinib in subjects with metastatic or locally advanced, unresectable pancreatic ductal adenocarcinoma and determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of the combination.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: THREAD: A Phase I Trial of Trametinib and Hydroxychloroquine in Patients With Advanced Pancreatic Cancer
Actual Study Start Date : January 18, 2019
Estimated Primary Completion Date : January 18, 2024
Estimated Study Completion Date : January 18, 2025


Arm Intervention/treatment
Experimental: Treatment (trametinib, hydroxychloroquine)
Patients receive trametinib PO QD on days 1-28 and hydroxychloroquine PO QD or BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Hydroxychloroquine
Given PO

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist




Primary Outcome Measures :
  1. Incidence of adverse events (AEs) [ Time Frame: At 28 days ]
    To assess the safety and tolerability of escalating doses of hydroxychloroquine (HCQ) in combination with a fixed dose of trametinib in subjects. Adverse events will be collected for each subject that received study treatment.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject with histologically confirmed metastatic or locally advanced, unresectable pancreatic carcinoma
  • Subject must have available archival tissue OR be willing to provide a baseline biopsy
  • Subject must have progressed during or after first line treatment with either gemcitabine/ nab-paclitaxel or FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin)
  • Subject must have computed tomography (CT) measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Subject must be able and willing to undergo contrast CT while on study and afterwards, if removed for reason other than progression
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelet count >= 100 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 3 x ULN. Patients with liver metastases will be allowed to enroll with AST and ALT levels =< 5 x ULN
  • Estimated creatinine clearance >= 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
  • Negative serum or urine pregnancy test at screening for women of childbearing potential
  • Highly effective contraception for both male and female subjects throughout the study and for at least 4 months after last study treatment administration
  • Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
  • Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

Exclusion Criteria:

  • Subject who have received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy within 2 weeks or within 5 half-lives of the investigational therapy prior to starting study treatment, whichever is longer
  • Subject who have received radiotherapy within 2 weeks prior to the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe
  • Subjects who have undergone major surgery =< 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
  • Patients with multiple primary malignancies may be enrolled if non-pancreatic ductal adenocarcinoma (PDAC) tumor(s) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by treating investigator and do not require active treatment
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
  • Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders:

      • Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
      • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before first dose
    • History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
    • History of seizures
    • Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma creatine kinase (CK) levels should be avoided while on study treatment
    • Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
    • Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the principal investigator [PI] may impair absorption of study drugs)
    • Any other condition that would, in the Investigator?s judgment, contraindicate the patient?s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication.(patients may not receive drug through a feeding tube), social/ psychological issues, etc
  • Screening corrected QT interval by Fridericia (QTcF) > 500 msec
  • Known human immunodeficiency virus (HIV), unless patient is on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is undetectable
  • Known history of hepatitis C virus (HCV) infection, unless treated and cured; for patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
  • Sexually active males who are not willing to use a condom during intercourse while taking the drug and for 4 months after stopping treatment. A condom is also required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid
  • Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer institute [NCI] CTCAE v5.0 grade >= 3)

Information from the National Library of Medicine

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): NCT03825289


Contacts
Contact: Susan Sharry 801-585-3453 susan.sharry@hci.utah.edu

Locations
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Conan G. Kinsey    801-585-0255    Conan.Kinsey@hci.utah.edu   
Principal Investigator: Conan G. Kinsey         
Sponsors and Collaborators
University of Utah
Novartis Pharmaceuticals
Investigators
Principal Investigator: Conan Kinsey, MD Huntsman Cancer Institute/ University of Utah

Responsible Party: University of Utah
ClinicalTrials.gov Identifier: NCT03825289     History of Changes
Other Study ID Numbers: HCI116898
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: January 31, 2019
Last Verified: January 2019

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Pancreatic Diseases
Carcinoma
Digestive System Diseases
Endocrine System Diseases
Trametinib
Hydroxychloroquine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antirheumatic Agents