Chronic Myeloid Leukemia, Chronic Phase
Conditions
Keywords
Omega-3 Fatty Acid, Eicosapentaenoic Acid, Tyrosine Kinase Inhibitors, TKI, GoldAID Eicosapentaenoic Acid, Fish Oil
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.
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.
Interventions
Eicosapentaenoic Acid once per day orally
DRUGTyrosine kinase inhibitor
Tyrosine kinase inhibitor to be administered at subjects' pre-study dose
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 1. BCR-ABL p210 at stable molecular disease (e.g., MMR stable but not CMR) 2. HR but no MMR. 5. 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. 6. ECOG PS of ≤ 3 7. 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 8. 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. 9. 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. 10. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Countries
United States
Participant flow
Pre-assignment details
One subject was consented but withdrew from participation.
Participants by arm
| Arm | Count |
|---|---|
| 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
Eicosapentaenoic Acid: Eicosapentaenoic Acid once per day orally
Tyrosine kinase inhibitor: Tyrosine kinase inhibitor to be administered at subjects' pre-study dose | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Product issue | 1 |
Baseline characteristics
| Characteristic | Eicosapentaenoic Acid (EPA) |
|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Phase II - Anti-CML Response to Recommended Phase II Dose Eicosapentaenoic Acid
BCR-ABL transcript levels will be assessed every 3 months post initiation of Eicosapentaenoic Acid to assess Anti-CML response.
Time frame: 1 year
Population: data were not collected
Primary
Phase I - Recommended Phase II Dose of EPA
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
Population: data were not collected
Secondary
Induction of Apoptosis in CML Leukemia Stem Cell by Formation of Δ12-PGJ3 and Other Metabolites
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
Population: data were not collected
Secondary
Molecular Responses of CML
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
Population: data were not collected