A Study of ONO-7475 in Patients With Acute Leukemias

Myelodysplastic Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03176277
• Other study ID #: ONO-7475-01
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: June 26, 2017
• Est. completion date: January 20, 2023

Study information

• Verified date: November 2023
• Source: Ono Pharmaceutical Co. Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: January 20, 2023
• Est. primary completion date: December 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemia
• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• ONO-7475 3mg once daily
Part A initial dose level
• ONO-7475 6mg once daily
Part A 2nd dose level
• ONO-7475 10mg once daily
Part A 3rd dose level
• ONO-7475 6mg + Venetoclax (70-400mg)
Part D ONO-7475 + Venetoclax Combination

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ono Pharmaceutical Co. Ltd

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse Events (Part A)	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.	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).
Primary	Incidence of Serious Adverse Events (Part A)	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.	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).
Primary	Clinically Significant Changes in Ophthalmology Examination Parameters (Part A)	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.	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).
Primary	Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A)	Participants with clinically significant changes in 12-lead Electrocardiogram (ECG) parameters.	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).
Primary	Incidence of Adverse Events (Part D)	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.	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).
Primary	Incidence of Serious Adverse Events (Part D)	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.	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).
Primary	Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D)	Summary of complete response (CR) and complete response with partial hematologic recovery (CRh) rate.	From baseline up to maximum of 21 months
Secondary	Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A)	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.	28 days
Secondary	Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A)	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).	Day 1 and Day 28
Secondary	Pharmacokinetics (Tmax) of ONO-7475 (Part A)	Part A Pharmacokinetics Tmax of ONO-7475 assessed on day 1 and day 28.	Day 1 and Day 28
Secondary	Pharmacokinetics (AUC) of ONO-7475 (Part A)	Part A Pharmacokinetics (AUC0-10h) of ONO-7475 assessed on day 1 and day 28, (AUC0-24h) of ONO-7475 assessed on day 1.	Day 1 and Day 28
Secondary	Pharmacokinetics (T1/2) of ONO-7475 (Part A)	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.	Day 1 and Day 28
Secondary	Pharmacokinetics of the Food Effect on ONO-7475 (Part A)	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.	Day 28 and Day 57
Secondary	Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A)	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.	Day 2 and Day 28
Secondary	Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A)	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.	From baseline up to maximum of 32 months
Secondary	Event Free Survival in ONO-7475 Groups (Part A)	Part A analysis of event free survival in ONO-7475 treatment groups	From baseline up to maximum of 32 months
Secondary	Pharmacokinetics (Cmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (Cmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.	Day 29
Secondary	Pharmacokinetics (Tmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (Tmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.	Day 29
Secondary	Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (AUC) of ONO-7475 in treatment group ONO-7475 + venetoclax.	Day 29
Secondary	Pharmacokinetics (T1/2) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (T1/2) of ONO-7475 in treatment group ONO-7475 + venetoclax.	Day 29
Secondary	Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (Cmax) of Venetoclax in treatment group ONO-7475 + Venetoclax.	Day 1 and Day 29
Secondary	Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (Tmax) of Venetoclax in treatment group ONO-7475 + venetoclax.	Day 1 and Day 29
Secondary	Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax	Part D Pharmacokinetics (AUC) of Venetoclax in treatment group ONO-7475 + venetoclax.	Day 1 and Day 29
Secondary	Pharmacokinetics (T1/2) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)	Part D Pharmacokinetics (T1/2) of Venetoclax in treatment group ONO-7475 + venetoclax.	Day 29
Secondary	Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D)	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.	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).
Secondary	Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D)	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.	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).
Secondary	Overall Response Rate in ONO-7475 + Venetoclax Group (Part D)	Part D Summary of best overall response in ONO-7475 + Venetoclax group.	From baseline up to maximum of 21 months
Secondary	Duration of Response in ONO-7475 + Venetoclax Group (Part D)	Part D Duration of response in ONO-7475 6mg + Venetoclax group.	From baseline up to maximum of 21 months
Secondary	Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D)	Part D analysis of event free survival and overall survival in ONO-7475 6mg + Venetoclax group	From baseline up to maximum of 21 months
Secondary	Transfusion Independence Rate (Part D)	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.	From baseline up to maximum of 21 months