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Omega -3 Fatty Acid in Combination With Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04006847
Recruitment Status : Not yet recruiting
First Posted : July 5, 2019
Last Update Posted : February 20, 2020
Sponsor:
Information provided by (Responsible Party):
Seema Naik, MD, Milton S. Hershey Medical Center

Brief Summary:
This is a Phase I/II single site, open label clinical trial. The purpose of the Phase I portion is to determine the safety, tolerability, and recommended Phase II dose of Eicosapentaenoic Acid (EPA) when given daily in combination with a Tyrosine Kinase Inhibitor (TKI) in subjects with Chronic Myeloid Leukemia (CML) in chronic stable phase. The recommended Phase II dose will be the maximum tolerated dose (MTD) of EPA as determined by the evaluation of dose-limiting toxicities (DLTs). The Phase II portion will subsequently examine the Anti-CML effects of EPA when administered with a TKI at the recommended Phase II dose. This efficacy objective will be done by evaluating BCR-ABL p210 quantitative PCR blood levels every 3 months to 1 year.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia, Chronic Phase Drug: Eicosapentaenoic Acid Drug: Tyrosine kinase inhibitor Phase 1 Phase 2

Detailed Description:
Targeting CML leukemia stem cells is of paramount importance in successfully preventing cancer relapse. EPA metabolite, Δ12-PGJ3 may represent a new chemotherapeutic agent for leukemia that targets leukemia stem cells. Selective targeting of cancer stem cells may be potentially a highly effective treatment for cancer. As most CML patients treated with a TKI will reach a complete cytogenetic response, quantification of residual BCR-ABL transcripts by quantitative reverse transcription PCR (RT-qPCR) is a critical tool to further monitor response kinetics. Addition of EPA to TKI may help decrease residual BCR-ABL positive (Ph+) leukemia stem cells.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Phase I/II, open-label, single site study using a standard 3 + 3 statistical design to determine the MTD and the recommended Phase 2 dose for oral EPA when administered to subjects receiving on a TKI pre-study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Omega-3 Fatty Acid, Eicosapentaenoic Acid, and Its Metabolites in Combination With Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia in Stable Chronic Phase
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : August 1, 2023


Arm Intervention/treatment
Experimental: Eicosapentaenoic Acid (EPA)

Phase I: TKI with escalating/de-escalating doses of EPA to determine MTD.

Phase I dose levels: Dose Level 1 = EPA 1500 mg orally once per day; Dose Level 2 = EPA 2000 mg orally once per day; Dose Level 3 = EPA 3000 mg orally once per day; Dose Level -1 = EPA 1000 mg orally once per day; Dose Level -2 = EPA 500 mg orally once per day.

Phase II: TKI administered in combination with the recommended Phase II dose of EPA

Drug: Eicosapentaenoic Acid
Eicosapentaenoic Acid once per day orally
Other Name: Omega-3 fatty acid

Drug: Tyrosine kinase inhibitor
Tyrosine kinase inhibitor to be administered at subjects' pre-study dose
Other Names:
  • TKI
  • Imatinib
  • Dasatinib
  • Nilotinib
  • Bosutinib




Primary Outcome Measures :
  1. Phase I - Recommended Phase II dose of EPA [ Time Frame: 1 month ]
    Recommended Phase II dose of EPA will be established by using a standard 3 + 3 statistical design to determine the MTD as assessed by DLTs when administered orally in combination with a TKI in subjects with CML in stable chronic phase. Toxicity will be evaluated using the NCI Common Toxicity Criteria (CTC) version 5.0.

  2. Phase II - Anti-CML response to recommended Phase II dose Eicosapentaenoic Acid [ Time Frame: 1 year ]
    BCR-ABL transcript levels will be assessed every 3 months post initiation of Eicosapentaenoic Acid to assess Anti-CML response.


Secondary Outcome Measures :
  1. Number of subjects who experience treatment related Adverse Events (AEs) [ Time Frame: 2 years ]
    Using the NCI CTC Version 5.0, AEs will be assessed from the time of initiation of investigational medication

  2. Severity of AEs experienced by study subjects [ Time Frame: 2 years ]
    Using the NCI CTC Version 5.0, the highest grade of all treatment related AEs collected will be used to determine severity

  3. Study subject compliance with investigational regimen [ Time Frame: 2 years ]
    Proportion of protocol prescribed doses taken by subjects

  4. Molecular responses of CML [ Time Frame: 1 year ]
    Log reduction from stable molecular response with bcr-abl PCR at MR 3 or more to bcr-abl to major molecular response (MR 4.5) or complete molecular response

  5. Induction of apoptosis in CML leukemia stem cell by formation of Δ12-PGJ3 and other metabolites [ Time Frame: 2 years ]
    Apoptosis will be analyzed by in vitro correlative studies using subject's plasma with effect on known leukemia cell line with CML leukemic stem cells. EPA metabolite will be examined by flow cytometry using Annexin V staining and adding serum from treated study subject to murine CML cells grown in vitro culture. The evaluation will be done at baseline, Month 1, and every 3 months up to year 2



Information from the National Library of Medicine

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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:

  • Male or female at least 18 years of age.
  • Confirmed diagnosis of CML
  • Is at least 18 months from CML diagnosis.
  • Current concomitant treatment with TKI therapy (Imatinib, Dasatinib, Nilotinib or Bosutinib; excluding Ponatinib).
  • One of the following confirmed:
  • break point cluster ( BCR)-ABL Polymerase chain reaction (PCR) at stable molecular disease (e.g., Major Molecular Response (MMR) stable but not Complete Molecular Response (CMR) or;
  • HR but no MMR.
  • Stable molecular response defined as 2 sequential BCR-ABL levels done in the same lab with less than one-half log reduction of BCR-ABL (BA)
  • Eastern Cooperative Oncology Group (ECOG) Performance Score of less than 3
  • Absolute neutrophil count greater than or equal to 500 cells/mm^3
  • Platelet count greater than or equal to 50,000 cells/mm^3
  • Serum bilirubin less than or equal to 1.5 times the upper limit of normal
  • Alanine transaminase (ALT) and Aspartate transaminase (AST) less than or equal to 2.5 times the upper limit of normal
  • Alkaline phosphatase less than or equal to 2.5 times the upper limit of normal
  • Not pregnant. Females of child bearing potential must use a medically accepted method of contraception and must agree to continued use of this method for the duration of the study and for 30 days after last dose of study drug.
  • Male subjects capable of producing offspring, must use a medically accepted method of birth control and agree to continued use of this method for the duration of the study and for 30 days after last dose of study drug because of the possible effects on spermatogenesis.

Exclusion Criteria:

  • Known additional malignancy requiring active treatment
  • Active infection requiring antibiotic treatment.
  • Known i.e. previously documented HIV, Hepatitis B, or Hepatitis C infection.
  • Known symptomatic congestive heart failure, unstable angina or cardiac arrhythmia.
  • Current concomitant use of non NSAIDs (including Aspirin) or cyclooxygenase-1 (COX-1); a washout period of 4 weeks prior to enrollment is permitted.
  • Known non-compliance with medications.
  • In the opinion of a PI or Sub-I, an uncontrolled medical or psychiatric disorder.
  • Active central nervous system leukemia.
  • Preceding allogeneic stem hematopoietic stem cell transplant.
  • Known T315I mutation.
  • Current concomitant use of fish oil at EPA dose greater than 500 mg; a washout period of 4 weeks prior to enrollment is permitted.
  • Known hypersensitivity to EPA.
  • Pregnant or breastfeeding

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): NCT04006847


Contacts
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Contact: Seema Naik, MD (717) 531-6585 snaik@pennstatehealth.psu.edu
Contact: Clinical Research Nurse Hematological Malignancies (717) 531-6585

Sponsors and Collaborators
Milton S. Hershey Medical Center
Investigators
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Principal Investigator: Seema Naik, MD Penn State Cancer Institute

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Responsible Party: Seema Naik, MD, Assistant Professor, Cancer Institutue, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT04006847    
Other Study ID Numbers: 17-085
First Posted: July 5, 2019    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seema Naik, MD, Milton S. Hershey Medical Center:
Omega-3 Fatty Acid
Eicosapentaenoic Acid
Tyrosine Kinase Inhibitors
TKI
GoldAID Eicosapentaenoic Acid
Fish Oil
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases