A Study of ONO-7475 in Patients With Acute Leukemias

Study Overview
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Brief Summary
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[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.

Official Title
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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

Conditions
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Acute Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: ONO-7475
* Drug: ONO-7475 + venetoclax


Participation Criteria
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Eligibility Criteria
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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: Total bilirubin within 1.5 x upper limit of normal (ULN), except those with Gilberts syndrome for whom this must be ≤3 x ULN AST and ALT ≤2.5 x ULN Calculated creatinine clearance ≥45 mL/min 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): 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 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) 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ONO-7475 (Part A)<br>Successive dose escalation cohorts to determine MTD/OBD | Drug: ONO-7475<br>* ONO-7475 tablets<br>|
| Experimental: ONO-7475 + venetoclax (Part D)<br>Successive dose escalation of ONO-7475 cohorts + venetoclax | Drug: ONO-7475 + venetoclax<br>* ONO-7475 tablets + venetoclax tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, nature, and severity of (serious) Adverse Events (Part A) | To determine the safety and tolerability of ONO-7475 | Up to 12 months | 
| Clinically significant ophthalmology examinations (Part A) | To determine the safety and tolerability of ONO-7475 | Up to 12 months | 
| Clinically significant electrocardiogram (ECG) (Part A) | To determine the safety and tolerability of ONO-7475 | Up to 12 months | 
| Complete response (CR)/complete response with partial hematologic recovery (CRh) rate (Part D) | To assess the preliminary efficacy of ONO-7475 + venetoclax | Up to 12 months | 
| Incidence, nature and severity of (serious) Adverse Events (Part D) | To determine the safety and tolerability of ONO-7475 + venetoclax | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Maximum Tolerated Dose (MTD) (Part A) | As assessed by the incidence, nature, and severity of (serious) Adverse Events | Up to 12 months | 
| Determination of recommended pharmacological dose (Part A) | As assessed by the Plasma inhibitory activity (PIA) | Up to 12 months | 
| Determination of recommended Phase 2 dose (Part D) | As assessed by safety, PK and PD data | Up to 12 months | 
| Pharmacokinetics (Tmax) (Part A) | Assessment of the time to reach maximum observed plasma concentration of ONO-7475. | Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics (Tmax) (Part D) | Assessment of the time to reach maximum observed plasma concentration of ONO-7475. | Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (Cmax) (Part A) | Assessment of the maximum plasma concentration of ONO-7475. | Day 1 and Day 28 of Cycle 1(each cycle is 28 days) | 
| Pharmacokinetics (Cmax) (Part D) | Assessment of the maximum plasma concentration of ONO-7475. | Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (AUC) (Part A) | Assessment of the plasma area under the curve (day 1 and 28) of ONO-7475. | Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics (AUC) (Part D) | Assessment of the plasma area under the curve (day 1 of Cycle 2) of ONO-7475. | Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (T1/2) (Part A) | Assessment of the elimination half life of ONO-7475. | Day 1 and Day 28 of Cycle 1 (each cycle is 28 days) | 
| Pharmacokinetics (T1/2) (Part D) | Assessment of the elimination half life of ONO-7475. | Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (Ctrough) (Part A) | Assessment of the trough concentration of ONO-7475 in the plasma. | 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) | 
| Pharmacokinetics (Ctrough) (Part D) | Assessment of the trough concentration of ONO-7475 in the plasma. | Day 7 and Day 15 of Cycle 1 and Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (Cmax) - Food effect (Part A) | Assessment of the food effect on the maximum plasma concentration of ONO-7475. | Day 57 (Cycle 3 Day 1) (each cycle is 28 days) | 
| Pharmacokinetics (Tmax) - Food effect (Part A) | Assessment of the food effect on the time to reach maximum observed plasma concentration of ONO-7475. | Day 57 (Cycle 3 Day 1) (each cycle is 28 days) | 
| Pharmacokinetics (AUC) - Food effect (Part A) | Assessment of the food effect on the plasma area under the curve of ONO-7475 | Day 57 (Cycle 3 Day 1) (each cycle is 28 days) | 
| Pharmacokinetics (T1/2) - Food effect (Part A) | Assessment of the food effect on the elimination half life of ONO-7475. | Day 57 (Cycle 3 Day 1) (each cycle is 28 days) | 
| Pharmacokinetics (Ctrough) - Food effect (Part A) | Assessment of the food effect on the trough concentration of ONO-7475 in the plasma. | Day 57 (Cycle 3 Day 1) (each cycle is 28 days) | 
| Pharmacokinetics (Tmax) - (Part D) | Assessment of the time to reach maximum observed plasma concentration of venetoclax. | Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (Cmax) - (Part D) | Assessment of the maximum plasma concentration of venetoclax. | Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (AUC) - (Part D) | Assessment of the plasma area under the curve of venetoclax | Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (T1/2) - (Part D) | Assessment of the elimination half life of venetoclax | Day 1 of Cycle 1 and Cycle 2 (each cycle is 28 days) | 
| Pharmacokinetics (Ctrough) - (Part D) | Assessment of the trough concentration of venetoclax in the plasma | Day 15 of Cycle 1 and on Day 1 of Cycle 2 (each cycle is 28 days) | 
| Pharmacodynamics of ONO-7475 (Part A and D) | Assessment of the pharmacodynamic activity of ONO-7475 as assessed by a PIA assay (pAxl/pMer inhibition). | Up to 12 months | 
| Overall response rate (ORR) (Part A and D) | CR/CRh (Part D only)/CRi/MLFS/PR for AML | Up to 12 months | 
| Transfusion independence rate (Part D) | Assessment by the usage of blood transfusions. | Up to 12 months | 
| Duration of response (DOR) (Part A) | Duration in months from CR/CRi/MLFS/PR to disease recurrence for AML. | Up to 12 months | 
| Duration of response (DOR) (Part D) | Duration in months from CR/CRh to disease recurrence for AML. | Up to 12 months | 
| Event-free survival (Part A and D) | Duration in months from date of first study treatment to disease recurrence/treatment failure or death for AML. | Up to 12 months | 
| Complete Response rate (Part D) | Assessment of the number of patients with complete response (CR) | Up to 12 months | 
| Complete response with partial hematologic recovery rate (Part D) | Assessment of the number patients with complete response with partial hematologic recovery (CRh) | Up to 12 months | 
| Complete Response (Part A and D)/ Complete Response with partial hematologic recovery without minimal residual disease (MRD) AML (Part D only) | Assessed by flow cytometry for patients who achieve CR or CRh (Part D only) | Up to 12 months | 
| Overall Survival (Part D) | Duration in months from the date of first study treatment to death from any cause. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, MER, MERTK, TYRO3, AXL, AML, Relapsed/ Refractory AML, TAM, MDS, Myelodysplastic Syndrome, Relapsed/ Refractory MDS