Phase I/II Trial of S64315 Plus Azacitidine in Acute Myeloid Leukaemia

Acute Myeloid Leukaemia Clinical Trial

Official title:

Phase I/II, International, Multicentre, Open-label, Non-randomised, Non-comparative, Study Evaluating the Safety, Tolerability and Clinical Activity of Intravenously Administered S64315, a Selective Mcl-1 Inhibitor, in Combination With Azacitidine in Patients With Acute Myeloid Leukaemia (AML)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04629443
• Other study ID #: CL1-64315-004
• Secondary ID: 2019-004896-38
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: February 17, 2021
• Est. completion date: March 1, 2024

Study information

• Verified date: July 2023
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety, tolerability and clinical activity of the combination S64315 with azacitidine in patients with acute myeloid leukaemia.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 17
• Est. completion date: March 1, 2024
• Est. primary completion date: March 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients aged = 18 years

2. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by World Health Organization 2016 classification (Arber, 2016) excluding acute promyelocytic leukaemia (APL, French American-British M3 classification) with: relapsed or refractory disease and without established alternative therapy, or secondary to MyeloDysplastic Syndrome and without established alternative therapy or, newly diagnosed AML, not previously treated for AML and who are not candidate for intensive chemotherapy due to age or comorbidities.

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

4. Adequate haematological, renal and hepatic functions based on the last assessment performed within 7 days prior to the first Investigational Medicinal Product administration.

Exclusion Criteria:

1. Previous myeloproliferative syndrome (MPS).

2. Patients previously treated with any Mcl-1 inhibitor.

3. Patients who have not recovered from toxicity of previous anticancer therapy, including Grade = 2 toxicity (except alopecia of any grade) according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 5.0, prior to the first IMP administration.

4. Severe or uncontrolled active acute or chronic infection.

5. Uncontrolled hepatitis B or C infection.

6. Known carriers of HIV antibodies, history of significant liver disease, active acute or chronic pancreatitis, active central nervous system disease.

7. Troponin > ULN (Upper Limit of reference range) or Troponin T > ULN if Troponin I cannot be assessed.

8. Clinically significant cardiac dysfunction (including New York Heart Association class =II heart failure, Left Ventricular Ejection Fraction (LVEF) < 50% as assessed by echocardiography (ECHO) or Multi-Gated Acquisition (MUGA) scan).

9. QT prolongation defined as QTc (QT interval corrected for heart rate) interval (corrected with Fridericia's formula) > 450 ms for males and > 470 ms for females, obtained from triplicate 12-lead ECG.

10. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.

11. Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg).

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• S 64315 (also referred as MIK665) and azacitidine
The combination treatment at the planned doses may be preceded by a 2-week Lead-In Dose period of S64315 (fixed dose) administered via intravenous (IV) infusion over at least 2 hours. During the combination treatment period S64315 will be administered according to a dose escalation scheme starting at 50 mg up to 250 mg might be explored. The schedule will be a 21-day cycle with a weekly regimen for S64315 and a daily regimen of azacitidine administered at 75 mg/m² via subcutaneous (SC) injection for 7 days from D1 to D7 of each cycle followed by a rest period of 21 days.

Locations

Country	Name	City	State
Australia	The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services	Melbourne
Australia	Victorian Comprehensive Cancer Centre	Melbourne
France	Institut Paoli-Calmettes	Marseille
France	Hôpital Saint Antoine	Paris
Spain	H. Universitario Valle de Hebrón Servicio de Hematología	Barcelona
Spain	H. Universitario La Fe Servicio de Hematologia	Valencia
United States	University of Texas MD Anderson Cancer Center Department of Leukemia, Division of Cancer Medicine	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	ADIR, a Servier Group company

Countries where clinical trial is conducted

United States,  Australia,  France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicity (DLT) (Phase I - dose escalation)	Incidence of DLTs starting from the Lead-In Dose period to the end of the first cycle of treatment of S64315 in combination with azacitidine.	Day -13 to Cycle 1 Day 28 (each cycle is 28 days)
Primary	Incidence and severity of Adverse Events (AEs) (Phase I - dose escalation)	Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0	an average of 6 months
Primary	Incidence and severity of Serious Adverse Event (SAEs) (Phase I - dose escalation)	Incidence and severity of SAEs according to NCI CTCAE v5.0	Day -13 up to 30 calendar days after the patient's last study visit
Primary	Number of participants with dose interruptions (Phase I - dose escalation)		Through study completion, an average of 6 months
Primary	Number of participants with dose reductions (Phase I - dose escalation)		Through study completion, an average of 6 months
Primary	Dose intensity (Phase I - dose escalation)		Through study completion, an average of 6 months
Secondary	Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation)	Overall survival (OS)	Through study completion, an average of 6 months
Secondary	Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation)	Duration of response (DOR)	Through study completion, an average of 6 months
Secondary	Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation)	Best overall response (BOR)	Through study completion, an average of 6 months
Secondary	Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation)	Progression-free survival (PFS)	Through study completion, an average of 6 months
Secondary	Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation)	Disease-free survival (DFS)	Through study completion, an average of 6 months
Secondary	Pharmacokinetic profile of S64315 administered in combination with Azacitidine in plasma: Area Under the Curve (AUC) (Phase I - dose escalation)		At Day -13, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 5, Cycle 1 Day 7 and Cycle 1 Day 9 (each cycle is 28 days)
Secondary	Pharmacokinetic profile of S64315 administered in combination with Azacitidine in plasma: maximum Concentration (Cmax) (Phase I - dose escalation)		At Day -13, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 5, Cycle 1 Day 7 and Cycle 1 Day 9 (each cycle is 28 days)

External Links

•   Find Results on Servier Clinical Trial Data website