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

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Recruiting

CT.gov ID

NCT04629443

Collaborator

ADIR, a Servier Group company (Industry)

180

Enrollment

Locations

Arm

36.4

Anticipated Duration (Months)

25.7

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukaemia	Drug: S 64315 (also referred as MIK665) and azacitidine	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Feb 17, 2021

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: S64315 (also referred as MIK665) with azacitidine	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.

Arm

Intervention/Treatment

Experimental: S64315 (also referred as MIK665) with azacitidine

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.

Outcome Measures

Primary Outcome Measures

Dose Limiting Toxicity (DLT) (Phase I - dose escalation) [Day -13 to Cycle 1 Day 28 (each cycle is 28 days)]
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.
Incidence and severity of Adverse Events (AEs) (Phase I - dose escalation) [an average of 6 months]
Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0
Incidence and severity of Serious Adverse Event (SAEs) (Phase I - dose escalation) [Day -13 up to 30 calendar days after the patient's last study visit]
Incidence and severity of SAEs according to NCI CTCAE v5.0
Number of participants with dose interruptions (Phase I - dose escalation) [Through study completion, an average of 6 months]
Number of participants with dose reductions (Phase I - dose escalation) [Through study completion, an average of 6 months]
Dose intensity (Phase I - dose escalation) [Through study completion, an average of 6 months]

Secondary Outcome Measures

Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) [Through study completion, an average of 6 months]
Overall survival (OS)
Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) [Through study completion, an average of 6 months]
Duration of response (DOR)
Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) [Through study completion, an average of 6 months]
Best overall response (BOR)
Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) [Through study completion, an average of 6 months]
Progression-free survival (PFS)
Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) [Through study completion, an average of 6 months]
Disease-free survival (DFS)
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)]
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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged ≥ 18 years
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.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
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:

Previous myeloproliferative syndrome (MPS).
Patients previously treated with any Mcl-1 inhibitor.
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.
Severe or uncontrolled active acute or chronic infection.
Uncontrolled hepatitis B or C infection.
Known carriers of HIV antibodies, history of significant liver disease, active acute or chronic pancreatitis, active central nervous system disease.
Troponin > ULN (Upper Limit of reference range) or Troponin T > ULN if Troponin I cannot be assessed.
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).
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.
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.
Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center Department of Leukemia, Division of Cancer Medicine	Houston	Texas	United States	77030
2	Victorian Comprehensive Cancer Centre	Melbourne		Australia	3002
3	The Alfred Hospital Malignant Haematology & Stem Cell Transplantation Services	Melbourne		Australia	3004
4	Institut Paoli-Calmettes	Marseille		France
5	Hôpital Saint Antoine	Paris		France	75012
6	H. Universitario Valle de Hebrón Servicio de Hematología	Barcelona		Spain	08035
7	H. Universitario La Fe Servicio de Hematologia	Valencia		Spain	46026