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A Study of ONO-7475 in Patients With Acute Leukemias

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03176277
Recruitment Status : Terminated (Protocol defined futility criteria)
First Posted : June 5, 2017
Last Update Posted : March 15, 2023
Sponsor:
Information provided by (Responsible Party):
Ono Pharmaceutical Co. Ltd

Tracking Information
First Submitted Date  ICMJE May 19, 2017
First Posted Date  ICMJE June 5, 2017
Last Update Posted Date March 15, 2023
Actual Study Start Date  ICMJE June 26, 2017
Actual Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
  • Incidence, nature, and severity of (serious) Adverse Events (Part A) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Clinically significant ophthalmology examinations (Part A) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Clinically significant electrocardiogram (ECG) (Part A) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Complete response (CR)/complete response with partial hematologic recovery (CRh) rate (Part D) [ Time Frame: Up to 12 months ]
    To assess the preliminary efficacy of ONO-7475 + venetoclax
  • Incidence, nature and severity of (serious) Adverse Events (Part D) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475 + venetoclax
Original Primary Outcome Measures  ICMJE
 (submitted: June 1, 2017)
  • Incidence, nature, and severity of (serious) Adverse Events [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Clinically significant changes in electroretinogram (ERG) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Clinically significant ophthalmology examinations [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
  • Clinically significant electrocardiogram (ECG) [ Time Frame: Up to 12 months ]
    To determine the safety and tolerability of ONO-7475
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
  • Determination of Maximum Tolerated Dose (MTD) (Part A) [ Time Frame: Up to 12 months ]
    As assessed by the incidence, nature, and severity of (serious) Adverse Events
  • Determination of recommended pharmacological dose (Part A) [ Time Frame: Up to 12 months ]
    As assessed by the Plasma inhibitory activity (PIA)
  • Determination of recommended Phase 2 dose (Part D) [ Time Frame: Up to 12 months ]
    As assessed by safety, PK and PD data
  • Pharmacokinetics (Tmax) (Part A) [ Time Frame: Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) ]
    Assessment of the time to reach maximum observed plasma concentration of ONO-7475.
  • Pharmacokinetics (Tmax) (Part D) [ Time Frame: Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the time to reach maximum observed plasma concentration of ONO-7475.
  • Pharmacokinetics (Cmax) (Part A) [ Time Frame: Day 1 and Day 28 of Cycle 1(each cycle is 28 days) ]
    Assessment of the maximum plasma concentration of ONO-7475.
  • Pharmacokinetics (Cmax) (Part D) [ Time Frame: Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the maximum plasma concentration of ONO-7475.
  • Pharmacokinetics (AUC) (Part A) [ Time Frame: Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) ]
    Assessment of the plasma area under the curve (day 1 and 28) of ONO-7475.
  • Pharmacokinetics (AUC) (Part D) [ Time Frame: Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the plasma area under the curve (day 1 of Cycle 2) of ONO-7475.
  • Pharmacokinetics (T1/2) (Part A) [ Time Frame: Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) ]
    Assessment of the elimination half life of ONO-7475.
  • Pharmacokinetics (T1/2) (Part D) [ Time Frame: Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the elimination half life of ONO-7475.
  • Pharmacokinetics (Ctrough) (Part A) [ Time Frame: Cycle 1 predose Day 7, Day 15 and Day 28/ 7 days after the last dosing of ONO-7475 at investigator's discretion (PK follow-up) (each cycle is 28 days) ]
    Assessment of the trough concentration of ONO-7475 in the plasma.
  • Pharmacokinetics (Ctrough) (Part D) [ Time Frame: Day 7 and Day 15 of Cycle 1 and Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the trough concentration of ONO-7475 in the plasma.
  • Pharmacokinetics (Cmax) - Food effect (Part A) [ Time Frame: Day 57 (Cycle 3 Day 1) (each cycle is 28 days) ]
    Assessment of the food effect on the maximum plasma concentration of ONO-7475.
  • Pharmacokinetics (Tmax) - Food effect (Part A) [ Time Frame: Day 57 (Cycle 3 Day 1) (each cycle is 28 days) ]
    Assessment of the food effect on the time to reach maximum observed plasma concentration of ONO-7475.
  • Pharmacokinetics (AUC) - Food effect (Part A) [ Time Frame: Day 57 (Cycle 3 Day 1) (each cycle is 28 days) ]
    Assessment of the food effect on the plasma area under the curve of ONO-7475
  • Pharmacokinetics (T1/2) - Food effect (Part A) [ Time Frame: Day 57 (Cycle 3 Day 1) (each cycle is 28 days) ]
    Assessment of the food effect on the elimination half life of ONO-7475.
  • Pharmacokinetics (Ctrough) - Food effect (Part A) [ Time Frame: Day 57 (Cycle 3 Day 1) (each cycle is 28 days) ]
    Assessment of the food effect on the trough concentration of ONO-7475 in the plasma.
  • Pharmacokinetics (Tmax) - (Part D) [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Assessment of the time to reach maximum observed plasma concentration of venetoclax.
  • Pharmacokinetics (Cmax) - (Part D) [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Assessment of the maximum plasma concentration of venetoclax.
  • Pharmacokinetics (AUC) - (Part D) [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Assessment of the plasma area under the curve of venetoclax
  • Pharmacokinetics (T1/2) - (Part D) [ Time Frame: Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) ]
    Assessment of the elimination half life of venetoclax
  • Pharmacokinetics (Ctrough) - (Part D) [ Time Frame: Day 15 of Cycle 1 and on Day 1 of Cycle 2 (each cycle is 28 days) ]
    Assessment of the trough concentration of venetoclax in the plasma
  • Pharmacodynamics of ONO-7475 (Part A and D) [ Time Frame: Up to 12 months ]
    Assessment of the pharmacodynamic activity of ONO-7475 as assessed by a PIA assay (pAxl/pMer inhibition).
  • Overall response rate (ORR) (Part A and D) [ Time Frame: Up to 12 months ]
    CR/CRh (Part D only)/CRi/MLFS/PR for AML
  • Transfusion independence rate (Part D) [ Time Frame: Up to 12 months ]
    Assessment by the usage of blood transfusions.
  • Duration of response (DOR) (Part A) [ Time Frame: Up to 12 months ]
    Duration in months from CR/CRi/MLFS/PR to disease recurrence for AML.
  • Duration of response (DOR) (Part D) [ Time Frame: Up to 12 months ]
    Duration in months from CR/CRh to disease recurrence for AML.
  • Event-free survival (Part A and D) [ Time Frame: Up to 12 months ]
    Duration in months from date of first study treatment to disease recurrence/treatment failure or death for AML.
  • Complete Response rate (Part D) [ Time Frame: Up to 12 months ]
    Assessment of the number of patients with complete response (CR)
  • Complete response with partial hematologic recovery rate (Part D) [ Time Frame: Up to 12 months ]
    Assessment of the number patients with complete response with partial hematologic recovery (CRh)
  • Complete Response (Part A and D)/ Complete Response with partial hematologic recovery without minimal residual disease (MRD) AML (Part D only) [ Time Frame: Up to 12 months ]
    Assessed by flow cytometry for patients who achieve CR or CRh (Part D only)
  • Overall Survival (Part D) [ Time Frame: Up to 12 months ]
    Duration in months from the date of first study treatment to death from any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2017)
  • Determination of Maximum Tolerated Dose (MTD) [ Time Frame: Up to 12 months ]
    As assessed by the incidence, nature, and severity of (serious) Adverse Events
  • Determination of recommended pharmacological dose [ Time Frame: Up to 12 months ]
    As assessed by the Plasma inhibitory activity (PIA)
  • Pharmacokinetics (Tmax) [ Time Frame: Day 1 and Day 28 of Cycle 1 ]
    Assessment of the time to reach maximum observed plasma concentration of ONO-7475.
  • Pharmacokinetics (Cmax) [ Time Frame: Day 1 and Day 28 of Cycle 1 ]
    Assessment of the maximum plasma concentration of ONO-7475.
  • Pharmacokinetics (AUC) [ Time Frame: Day 1 and Day 28 of Cycle 1 ]
    Assessment of the plasma area under the curve (day 1 and 28) of ONO-7475.
  • Pharmacokinetics (T1/2) [ Time Frame: Day 1 and Day 28 of Cycle 1 ]
    Assessment of the plasma decay half life of ONO-7475.
  • Pharmacokinetics (Ctrough) [ Time Frame: Cycle 1 predose Day 7 and Day 15 ]
    Assessment of the trough concentration of ONO-7475 in the plasma.
  • Pharmacokinetics (Cmax) - Food effect [ Time Frame: Day 57 (Cycle 3 Day 1) ]
    Assessment of the food effect on the maximum plasma concentration of ONO-7475.
  • Pharmacokinetics (Tmax) - - Food effect [ Time Frame: Day 57 (Cycle 3 Day 1) ]
    Assessment of the food effect on the time to reach maximum observed plasma concentration of ONO-7475.
  • Pharmacokinetics (AUC) - Food effect [ Time Frame: Day 57 (Cycle 3 Day 1) ]
    Assessment of the food effect on the plasma area under the curve of ONO-7475
  • Pharmacokinetics (T1/2) - Food effect [ Time Frame: Day 57 (Cycle 3 Day 1) ]
    Assessment of the food effect on the plasma decay half life of ONO-7475.
  • Pharmacokinetics (Ctrough) - Food effect [ Time Frame: Day 57 (Cycle 3 Day 1) ]
    Assessment of the food effect on the trough concentration of ONO-7475 in the plasma.
  • Pharmacodynamics of ONO-7475 [ Time Frame: Up to 12 months ]
    Assessment of the pharmacodynamic activity of ONO-7475 as assessed by a PIA assay (pAxl/pMer inhibition).
  • Overall response rate (ORR) [ Time Frame: Up to 12 months ]
    CR + CRi + PR
  • Duration of response (DOR) [ Time Frame: Up to 12 months ]
    Duration in months from PR, CRi and CR
  • Progression free survival (PFS) [ Time Frame: Up to 12 months ]
    Duration in months from first study treatment to disease progression or death
  • Relapse free survival [ Time Frame: Up to 12 months ]
    Time of disease relapse or patient death from any cause
  • Event-free survival [ Time Frame: Up to 12 months ]
    Time of treatment failure, disease relapse or patient death from any cause
  • Remission duration [ Time Frame: Up to 12 months ]
    Disease relapse (measured at CR)
  • Minimal residual disease (MRD) [ Time Frame: Up to 12 months ]
    Assessed by flow cytometry for patients who achieve CR
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of ONO-7475 in Patients With Acute Leukemias
Official Title  ICMJE A Phase I/II Open Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Efficacy of ONO-7475 in Patients With Acute Leukemias or Myelodysplastic Syndromes
Brief Summary [Updated]: To assess the safety and tolerability of ONO-7475 monotherapy in patients with relapsed or refractory acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes and to assess: i) safety and tolerability and ii) preliminary efficacy of the combination of ONO-7475 and venetoclax in patients with relapsed or refractory acute myeloid leukemia.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Leukemia
  • Myelodysplastic Syndromes
Intervention  ICMJE
  • Drug: ONO-7475
    ONO-7475 tablets
  • Drug: ONO-7475 + venetoclax
    ONO-7475 tablets + venetoclax tablets
Study Arms  ICMJE
  • Experimental: ONO-7475 (Part A)
    Successive dose escalation cohorts to determine MTD/OBD
    Intervention: Drug: ONO-7475
  • Experimental: ONO-7475 + venetoclax (Part D)
    Successive dose escalation of ONO-7475 cohorts + venetoclax
    Intervention: Drug: ONO-7475 + venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 1, 2017)		 42
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 20, 2023
Actual Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients aged ≥18 years at time of screening.
  2. Written informed consent by the patient (or their legal representative) prior to admission to this study. In addition, any locally required authorization (Health Insurance Portability and Accountability Act in the US), must be obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.

  3. Adequate renal and hepatic function defined as:

    1. Total bilirubin within 1.5 x upper limit of normal (ULN), except those with Gilberts syndrome for whom this must be ≤3 x ULN
    2. AST and ALT ≤2.5 x ULN
    3. Calculated creatinine clearance ≥45 mL/min
    4. Serum albumin ≥2.5 g/dL For any patient with laboratory values outside the ranges outlined above that are considered due to the patient's underlying disease (AML or MDS), the patient may be enrolled into the study following consultation between the Investigator and the Sponsor's Medical Officer, if the patient is likely to benefit from receiving ONO-7475 (based on the Investigator's assessment).
  4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 as assessed during the screening period and then again anytime during the 2-day period immediately preceding the start of dosing in Parts A and D.
  5. Life expectancy of at least 3 months
  6. Sexually active female patients of childbearing potential and sexually active male patients must agree to use an effective method of birth control (e.g., barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 4 months after final administration of study drug. Note that sterility in female patients must be confirmed in the patients' medical records and be defined as any of the following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses >1 year ago, radiation-induced oophorectomy with last menses >1 year ago, chemotherapy-induced menopause with last menses >1 year ago.
  7. Diagnosis of AML or MDS according to WHO criteria 2016 (Part A only).

  8. Either criterion is met (Part A only):

    1. Patients with R/R AML with at least 5% blasts by BM biopsy or aspirate, or at least 1% blasts in peripheral blood, not likely to benefit from standard salvage chemotherapy
    2. Patients with R/R MDS who are either not eligible for (or unlikely to benefit from) other forms of therapy, including HSCT, according to the treating Physician/Investigator .
  9. All patients must have received at least one previous line of therapy (Part A only).
  10. Diagnosis of AML according to WHO criteria (2016) (Part D only).

  11. Patients with R/R AML who have no standard-of-care options known to provide clinical benefit in patients with R/R AML (Part D only)

    1. Refractory AML: Patients who have not achieved complete remission after two cycles of induction chemotherapy (i.e., anthracycline containing regimen), four cycles of hypomethylating agents, or two cycles of other AML therapy
    2. Relapsed AML: Patients who have ≥5% BM blasts in BM, or reappearance of blasts in the peripheral blood not attributable to another cause (e.g., recovery of normal cells following chemotherapy-induced aplasia) or (re)appearance of extramedullary disease after CR of prior AML therapy.
  12. Patients must have measured BM aspirate blast counts at Screening. Where the aspirate is hypo cellular or inaspirable a biopsy would be considered.
  13. Patients who were refractory to or relapsed after their 1st line treatment for AML must have received 2 or less additional lines of intensive / aggressive chemotherapy, which also includes a venetoclax-based regimen, as per the latest National Comprehensive Cancer Network (NCCN) Guidelines.

Exclusion Criteria:

  1. Patients with active central nervous system leukemia.
  2. QT interval corrected according to Fredericia's formula (QTcF) prolongation defined as a QTcF interval >470 msec or other significant ECG abnormalities including second degree (type II) or third degree atrioventricular block or bradycardia (ventricular rate <50 beats/min).
  3. Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or severe cirrhosis.
  4. Human immunodeficiency virus (HIV), active hepatitis B (HBV) or C (HCV) infection.
  5. Retinal disease (e.g., retinitis pigmentosa including Mertk mutations), retinal hemorrhage or any disorder which may inhibit follow up for retinal toxicity.
  6. Serious intercurrent medical or psychiatric illness that will prevent participation or compliance with study procedures, including serious active infection (including COVID-19).
  7. Acute promyelocytic leukemia (the French-American-British M3 classification).
  8. Patients not recovered to Grade 1 or stabilized from the effects (excluding alopecia) of any prior therapy for their malignancies.
  9. Concurrent treatment with other investigational drugs.
  10. Daily requirement of ≥10 mg/day of prednisone or equivalent dose of other corticosteroids.
  11. Prior HSCT within 12 weeks of the first dose of study treatment or ongoing immunosuppressive therapy for graft-versus-host disease.
  12. Participation in another clinical trial with any investigational drug within 14 days or with any licensed drug within five half-lives, prior to the first ONO-7475 dosing (for Part A) or prior to the first venetoclax dosing (for Part D).
  13. Prior AML or MDS therapy (non-experimental) within 14 days or 5 half-lives, whichever is longer, prior to the first dose of ONO-7475 (for Part A) or prior to the first venetoclax dosing (for Part D) (except those permitted in Section 7.1) and no residual toxicity from the prior therapy hindering of the ONO-7475 dosing (for Part A) or ONO-7475 plus venetoclax dosing (for Part D).
  14. Prior radiotherapy within 21 days of screening, with the exception of localized palliative radiotherapy.
  15. Patients undergoing current treatments for other cancers.
  16. Pregnant or lactating women.
  17. Proliferative disease (white blood cell [WBC] counts >30 x 10e9/L) confirmed prior to the first dose of ONO-7475 (for Part A) or WBC >25 x 10e9/L in Part D.
  18. Active malignancy, other than AML (Parts A and D) or MDS (Part A), requiring systemic therapy except for those patients who have been diagnosed with either prostate or breast cancer and who have received a stable dose of hormone therapy for a minimum of 6 months prior to entering this study.
  19. Known hypersensitivity to venetoclax (Part D only).
  20. Calculated creatinine clearance <45 mL/min
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03176277
Other Study ID Numbers  ICMJE ONO-7475-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
URL: https://www.ono-pharma.com/en/company/policies/clinical_trial_data_transparency_policy.html
Current Responsible Party Ono Pharmaceutical Co. Ltd
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Ono Pharmaceutical Co. Ltd
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Project Leader Ono Pharmaceutical Co. Ltd
PRS Account Ono Pharmaceutical Co. Ltd
Verification Date March 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP