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

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT04006847
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 8.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• 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.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
• Actual Study Start Date: Sep 14, 2020
• Actual Primary Completion Date: May 21, 2021
• Actual Study Completion Date: May 21, 2021

Arms and Interventions

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 Names: 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

Outcome Measures

Primary Outcome Measures

1. Phase I - Recommended Phase II Dose of EPA [the time of initiation of the study medication to 30 days after last dose of study medication]

   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 [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. Molecular Responses of CML [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

2. Induction of Apoptosis in CML Leukemia Stem Cell by Formation of Δ12-PGJ3 and Other Metabolites [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female ≥18 years of age.

2. Confirmed diagnosis of CML ≥ 18 months from diagnosis.

3. Current concomitant treatment with TKI therapy (Imatinib, Dasatinib, Nilotinib or Bosutinib; excluding Ponatinib). TKI therapy should be stable (same drug and dose) for at least 3 months prior to study enrollment.

4. One of the following confirmed:

5. BCR-ABL p210 at stable molecular disease (e.g., MMR stable but not CMR)

6. HR but no MMR.

7. Stable molecular response defined as 2 sequential BCR-ABL p210 levels done in the same lab with less than ½ log reduction of BCR-ABL (BA) 3-6 months apart.

8. ECOG PS of ≤ 3

9. Adequate organ function, as defined by the following:

ANC ≥ 500 cells/mm3 Platelet count ≥ 50,000 cells/mm3 Serum bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN Alkaline phosphatase ≤ 2.5 x ULN

1. WOCP as defined as defined as not surgically sterile or not one year post-menopausal, must have a negative result for a serum or urine pregnancy test within 7 days of initial receipt of study drug. Surgically sterile is defined as having had a hysterectomy, tubal ligation, or oophorectomy.

2. WOCP 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. Acceptable methods of contraception include abstinence, barrier method with spermicide, intrauterine device (IUD) known to have a failure rate of less than 1% per year, or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method.

3. 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. Acceptable methods of contraception include abstinence, barrier method with spermicide, WOCP partner's use of an IUD known to have a failure rate of less than 1% per year, WOCP partner's use of steroidal contraceptive (oral, implanted or injected) in conjunction with a barrier method, WOCP partner is surgically sterile or 1 year postmenopausal. In addition, male subjects may not donate sperm for the duration of the study and for 30 days after last dose of study drug.

Exclusion Criteria:

1. Has a malignancy or infection requiring active treatment

2. Has a known HIV infection, Hepatitis B , or Hepatitis C infection

3. Has a known symptomatic congestive heart failure (CHF), unstable angina or cardiac arrhythmia

4. Is using Aspirin or NSAID or COX-I

5. Is known to be non-compliant to medications.

6. Has, in the opinion of the physician investigator, an uncontrolled medical or psychiatric disorder.

7. Has active central nervous system (CNS) leukemia.

8. Is preceding allogeneic stem HSCT.

9. Has a known T 315 I mutation.

10. Is taking FISH oil at EPA dose > 500 mg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn State Cancer Institute	Hershey	Pennsylvania	United States	17033

Sponsors and Collaborators

• Milton S. Hershey Medical Center

Investigators

• Principal Investigator: Seema Naik, MD, Penn State Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 19, 2021

More Information

Publications

None provided.

• 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: Jul 5, 2019
• Last Update Posted: Jul 1, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Seema Naik, MD, Assistant Professor, Cancer Institutue, Milton S. Hershey Medical Center: Omega-3 Fatty Acid; Eicosapentaenoic Acid; Tyrosine Kinase Inhibitors; TKI; GoldAID Eicosapentaenoic Acid; Fish Oil
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Dasatinib

Study Results

Participant Flow

Pre-assignment Detail	One subject was consented but withdrew from participation.

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	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 Eicosapentaenoic Acid: Eicosapentaenoic Acid once per day orally Tyrosine kinase inhibitor: Tyrosine kinase inhibitor to be administered at subjects' pre-study dose
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	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 Eicosapentaenoic Acid: Eicosapentaenoic Acid once per day orally Tyrosine kinase inhibitor: Tyrosine kinase inhibitor to be administered at subjects' pre-study dose
Overall Participants	1
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (0)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Phase I - Recommended Phase II Dose of EPA
Description	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.
Time Frame	the time of initiation of the study medication to 30 days after last dose of study medication

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	Phase I: TKI with escalating/de-escalating doses of EPA to determine MTD. Phase I dose level: Dose Level 1 = EPA 1500 mg orally once per day;
Measure Participants	0

2. Primary Outcome

Title	Phase II - Anti-CML Response to Recommended Phase II Dose Eicosapentaenoic Acid
Description	BCR-ABL transcript levels will be assessed every 3 months post initiation of Eicosapentaenoic Acid to assess Anti-CML response.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	Phase I: TKI with escalating/de-escalating doses of EPA to determine MTD. Phase I dose level: Dose Level 1 = EPA 1500 mg orally once per day;
Measure Participants	0

3. Secondary Outcome

Title	Molecular Responses of CML
Description	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
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	Phase I: TKI with escalating/de-escalating doses of EPA to determine MTD. Phase I dose level: Dose Level 1 = EPA 1500 mg orally once per day;
Measure Participants	0

4. Secondary Outcome

Title	Induction of Apoptosis in CML Leukemia Stem Cell by Formation of Δ12-PGJ3 and Other Metabolites
Description	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
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	Phase I: TKI with escalating/de-escalating doses of EPA to determine MTD. Phase I dose level: Dose Level 1 = EPA 1500 mg orally once per day;
Measure Participants	0

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	CTCAE v. 5.0
Arm/Group Title	Eicosapentaenoic Acid (EPA)
Arm/Group Description	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 Eicosapentaenoic Acid: Eicosapentaenoic Acid once per day orally Tyrosine kinase inhibitor: Tyrosine kinase inhibitor to be administered at subjects' pre-study dose
All Cause Mortality
	Eicosapentaenoic Acid (EPA)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Eicosapentaenoic Acid (EPA)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Eicosapentaenoic Acid (EPA)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

Limitations/Caveats

Due to the product issues, the trials was halted.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.