A Study of ONO-7475 in Patients With Acute Leukemias

Phase 1

Terminated

Conditions: Acute Leukemia
Myelodysplastic Syndromes

Interventions: Drug: ONO-7475 6mg once daily
Drug: ONO-7475 3mg once daily
Drug: ONO-7475 10mg once daily
Drug: ONO-7475 6mg + Venetoclax (70-400mg)

Registration Number: NCT03176277

Lead Sponsor: Ono Pharmaceutical Co. Ltd

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: Part A is a dose escalation study of ONO-7475 in patients with acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes.

Part D is a dose escalation study of ONO-7475 in combination with venetoclax. ONO-7475 starting dose is selected following safety and tolerability outcome of Part A.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 42

Inclusion Criteria

Patients aged ≥18 years at time of screening.
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.
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).
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.
Life expectancy of at least 3 months
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.
Diagnosis of AML or MDS according to WHO criteria 2016 (Part A only).
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 .
All patients must have received at least one previous line of therapy (Part A only).
Diagnosis of AML according to WHO criteria (2016) (Part D only).
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.
Patients must have measured BM aspirate blast counts at Screening. Where the aspirate is hypo cellular or inaspirable a biopsy would be considered.
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

Patients with active central nervous system leukemia.
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).
Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or severe cirrhosis.
Human immunodeficiency virus (HIV), active hepatitis B (HBV) or C (HCV) infection.
Retinal disease (e.g., retinitis pigmentosa including Mertk mutations), retinal hemorrhage or any disorder which may inhibit follow up for retinal toxicity.
Serious intercurrent medical or psychiatric illness that will prevent participation or compliance with study procedures, including serious active infection (including COVID-19).
Acute promyelocytic leukemia (the French-American-British M3 classification).
Patients not recovered to Grade 1 or stabilized from the effects (excluding alopecia) of any prior therapy for their malignancies.
Concurrent treatment with other investigational drugs.
Daily requirement of ≥10 mg/day of prednisone or equivalent dose of other corticosteroids.
Prior HSCT within 12 weeks of the first dose of study treatment or ongoing immunosuppressive therapy for graft-versus-host disease.
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).
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).
Prior radiotherapy within 21 days of screening, with the exception of localized palliative radiotherapy.
Patients undergoing current treatments for other cancers.
Pregnant or lactating women.
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.
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.
Known hypersensitivity to venetoclax (Part D only).
Calculated creatinine clearance <45 mL/min

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ONO-7475 6mg once daily	ONO-7475 6mg once daily	Part A 2nd dose level
ONO-7475 3mg once daily	ONO-7475 3mg once daily	Part A Initial dose level
ONO-7475 10mg once daily	ONO-7475 10mg once daily	Part A 3rd dose level
ONO-7475 6mg + Venetoclax (70-400mg)	ONO-7475 6mg + Venetoclax (70-400mg)	Part D ONO-7475 + Venetoclax combination

Primary Outcome Measures

Name	Time	Method
Clinically Significant Changes in Ophthalmology Examination Parameters (Part A)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).	Incidence (all participants) of ophthalmological treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA Version 23.1. CTCAE = Common Terminology Criteria for Adverse Event version 4.03.
Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).	Participants with clinically significant changes in 12-lead Electrocardiogram (ECG) parameters.
Incidence of Serious Adverse Events (Part A)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).	Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Incidence of Adverse Events (Part D)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).	Incidence of most common (frequency \> 20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Incidence of Serious Adverse Events (Part D)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).	Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTXAE) Version 4.03.
Incidence of Adverse Events (Part A)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).	Incidence of most common (frequency of \>20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D)	From baseline up to maximum of 21 months	Summary of complete response (CR) and complete response with partial hematologic recovery (CRh) rate.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics (Tmax) of ONO-7475 (Part A)	Day 1 and Day 28	Part A Pharmacokinetics Tmax of ONO-7475 assessed on day 1 and day 28.
Pharmacokinetics (T1/2) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 29	Part D Pharmacokinetics (T1/2) of Venetoclax in treatment group ONO-7475 + venetoclax.
Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 1 and Day 29	Part D Pharmacokinetics (Cmax) of Venetoclax in treatment group ONO-7475 + Venetoclax.
Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A)	28 days	Dose Limiting Toxicities (DLT) Criteria: 1) ONO-7475-related ≥Grade 4 hematologic toxicity, 2) any pre-existing condition that worsens by more than 1 grade or to Grade 4, not caused by AML, 3) any ≥Grade 3 non-hematologic toxicity not caused by AML (exception: alopecia, nausea, vomiting, fatigue, headache, chills, electrolyte disturbances), 4) ≥Grade 2 blurred vision (confirmed by loss of 15 letters or more on Early Treatment Diabetic Retinopathy chart and by ophthalmological and retinal assessments) not caused by AML, 5) ≥Grade 2 clinically significant changes in night blindness not caused by AML, 6) ≥Grade 3 differentiation syndrome, 7) death not caused by AML, and 8) any other event determined by the Safety Review Committee for dosing stop. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was applied for toxicity grading.
Event Free Survival in ONO-7475 Groups (Part A)	From baseline up to maximum of 32 months	Part A analysis of event free survival in ONO-7475 treatment groups
Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax	Day 1 and Day 29	Part D Pharmacokinetics (AUC) of Venetoclax in treatment group ONO-7475 + venetoclax.
Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).	Part D Incidence (frequency ≥ 2 participants) and severity (CTCAE grades) of serious treatment-emergent adverse events in ONO-7475 + Venetoclax Group (Part D), preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Overall Response Rate in ONO-7475 + Venetoclax Group (Part D)	From baseline up to maximum of 21 months	Part D Summary of best overall response in ONO-7475 + Venetoclax group.
Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A)	Day 1 and Day 28	Part A Pharmacokinetics Cmax of ONO-7475 assessed on day 1 and day 28, and Ctrough of ONO-7475 assessed on day 28 (pre-dose).
Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A)	Day 2 and Day 28	Assessment of the pharmacodynamic activity by measurement of Axl and Mer inhibition using a Plasma Inhibitory Activity (PIA) assay. PIA is a flow cytometry assay measuring auto-phosphorylation in Axl-expressing Ba/F3 and Mer-expressing Ba/F3 cells, respectively the percentage of inhibition. Pre-dose samples were collected for the analysis on day 2 and day 28.
Pharmacokinetics (Cmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 29	Part D Pharmacokinetics (Cmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 29	Part D Pharmacokinetics (AUC) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Pharmacokinetics (T1/2) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 29	Part D Pharmacokinetics (T1/2) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Pharmacokinetics (AUC) of ONO-7475 (Part A)	Day 1 and Day 28	Part A Pharmacokinetics (AUC0-10h) of ONO-7475 assessed on day 1 and day 28, (AUC0-24h) of ONO-7475 assessed on day 1.
Pharmacokinetics (T1/2) of ONO-7475 (Part A)	Day 1 and Day 28	Part A Pharmacokinetics T1/2 of ONO-7475 assessed on day 1 and day 28. T1/2 was not calculable due to insufficient evaluable data.
Pharmacokinetics of the Food Effect on ONO-7475 (Part A)	Day 28 and Day 57	Part A Pharmacokinetics (Cmax, Tmax, AUC, T1/2, Ctrough) of the food effect on ONO-7475 assessed as ratio of Day57/Day28 and comparing pharmacokinetic parameters from dosing under fasted and non-fasted conditions assessed in 6mg and 10mg dose groups.
Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A)	From baseline up to maximum of 32 months	Part A analysis of best overall response. Duration of response analysis was not performed as no response of complete remission, Morphologic complete remission with incomplete blood count recovery, morphologic leukemia-free state, or partial remission was observed.
Pharmacokinetics (Tmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 29	Part D Pharmacokinetics (Tmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Day 1 and Day 29	Part D Pharmacokinetics (Tmax) of Venetoclax in treatment group ONO-7475 + venetoclax.
Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D)	From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).	Part D Incidence (frequency \> 20%) and severity (CTCAE grades) of treatment-emergent adverse events in ONO-7475 + Venetoclax Group, in preferred terms coded MedDRA version 23.1. CTCAE = common terminology criteria for adverse events (CTCAE) version 4.03.
Duration of Response in ONO-7475 + Venetoclax Group (Part D)	From baseline up to maximum of 21 months	Part D Duration of response in ONO-7475 6mg + Venetoclax group.
Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D)	From baseline up to maximum of 21 months	Part D analysis of event free survival and overall survival in ONO-7475 6mg + Venetoclax group
Transfusion Independence Rate (Part D)	From baseline up to maximum of 21 months	Part D analysis of transfusion Independence rate. Rate of maintenance of transfusion independence = percentage of patients who were transfusion independent post-baseline based upon the patients who were transfusion independent at baseline. Calculated using the Clopper-Pearson method.

Trial Locations

Locations (16): The Ohio State University (OSU)
🇺🇸
Columbus, Ohio, United States
Augusta University Medical Center
🇺🇸
Augusta, Georgia, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Utah - Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
Medical University of South Carolina - Hollins Cancer Center
🇺🇸
Charleston, South Carolina, United States
Yale University School of Medicine - Yale Cancer Center
🇺🇸
North Haven, Connecticut, United States
University of Florida (UF) - Shands Cancer Center
🇺🇸
Gainesville, Florida, United States
Norton Cancer Institute
🇺🇸
Louisville, Kentucky, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Wake Forest University
🇺🇸
Winston-Salem, North Carolina, United States
University of California
🇺🇸
Los Angeles, California, United States
Mayo Clinic - Jacksonville
🇺🇸
Jacksonville, Florida, United States
The Winship Cancer Institute Emory University
🇺🇸
Atlanta, Georgia, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
Thomas Jefferson University
🇺🇸
Philadelphia, Pennsylvania, United States