Phase I Dose Escalation Study of Intravenously Administered S64315 in Combination With Orally Administered Venetoclax in Patients With Acute Myeloid Leukaemia.

Servier

Status and phase: Completed; Phase 1

Conditions: Acute Myeloid Leukaemia

Treatments: Combination Product: S 64315 (also referred as MIK665) and venetoclax

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03672695

2018-001809-88 (EudraCT Number)

CL1-64315-002

Details and patient eligibility

About

The purpose of this study is to determine the safety profile, tolerability and the Recommended Phase 2 Dose of the combination S64315 with venetoclax in patients with Acute Myeloid Leukaemia.

Enrollment: 37 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Male or female aged ≥ 18 years;

2. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by World Health Organization (WHO) 2016 classification (Arber, 2016), excluding acute promyelocytic leukaemia (APL, French-American British M3 classification):

   • With relapsed or refractory disease without established alternative therapy or
   • Secondary to MDS treated at least by hypomethylating agent and without established alternative therapy or
   • ≥ 65 years not previously treated for AML and who are not candidates for intensive chemotherapy nor candidates for established alternative therapy

3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

4. Able to comply with study procedures

5. Adequate renal function within 7 days before the inclusion of the patient defined as:

   • Serum creatinine ≤ 1.5 x ULN (upper normal limit) or calculated creatinine clearance (determined by MDRD) > 50 mL/min/1.73m2

6. Adequate hepatic function within 7 days before the inclusion of the patient defined as:

   • AST and ALT ≤ 1.5 x ULN
   • Total serum bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert's syndrome, who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN

Exclusion criteria

1. Participant already enrolled and treated in the study
2. Pregnancy, breastfeeding or possibility of becoming pregnant during the study
3. Participation in another interventional study requiring investigational treatment intake at the same time or within 2 weeks or at least 5 halflives (whichever is longer) prior to first dose of IMP (participation in non-interventional registries or epidemiological studies is allowed). In case of biologic agents with a long half life such as CART cells, immune checkpoint antibodies, bispecific antibodies a flat wash-out of 28 days will be acceptable
4. Presence of ≥ CTCAE Grade 2 toxicity (except alopecia of any grade) due to prior cancer therapy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE, version 4.03).
5. Known carriers of HIV antibodies
6. Known history of significant liver disease
7. Uncontrolled hepatitis B or C infection
8. Known active acute or chronic pancreatitis
9. History of myocardial infarction (MI), unstable angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
10. Any factors that could increase the risk of QTc prolongation or risk of arrhythmic events.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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37 participants in 8 patient groups

Initial Schedule - S64315 low dose and venetoclax high dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Initial Schedule - S64315 medium dose and venetoclax low dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Initial Schedule - S64315 medium dose and venetoclax medium dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Initial Schedule - S64315 medium dose and venetoclax high dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Initial Schedule - S64315 high dose and venetoclax medium dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Alternative Schedule - Venetoclax medium dose administered with no S64315

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Alternative Schedule - S64315 medium dose and venetoclax medium dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax

Alternative Schedule - S64315 high dose and venetoclax low dose administered in combination

Experimental group

Treatment:

Combination Product: S 64315 (also referred as MIK665) and venetoclax