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

NCT03672695 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: CL1-64315-0022018-001809-88
• Study Type: interventional
• Target: 37
• Locations: 3 countries
• Sites: 7

Brief Summary

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.

Conditions

Acute Myeloid Leukaemia

Outcome Measures

Primary Outcomes (6)

• Incidence of Dose Limiting Toxicity (DLTs)

  At the end of cycle 1 (each cycle is 21 or 28 days).

• Incidence and severity of AEs

  Through study completion, an average of 6 months.

• Incidence and severity of SAEs

  Through study completion, an average of 6 months.

• Number of participants with dose interruptions "will be measured and reported in the Outcome Measure results data table.

  Through study completion, an average of 6 months.

• Number of participants with dose reductions "will be measured and reported in the Outcome Measure results data table.

  Through study completion, an average of 6 months.

• Dose intensity

  Through study completion, an average of 6 months.

Secondary Outcomes (4)

• Anti-leukemic activity

  Through study completion, an average of 6 months.

• Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Area Under the Curve (AUC)

  From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).

• Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Concentration at the end of infusion (Cinf)

  From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).

• Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: terminal half-life (t½z)

  From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).

Study Arms (8)

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Alternative Schedule - Venetoclax medium dose administered with no S64315

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Interventions

S 64315 (also referred as MIK665) and venetoclax COMBINATION_PRODUCT

The treatment combination period can only begin after the planned dose of venetoclax is reached. Depending on the administration dosing schedule, the combination treatment at the planned doses may be preceded by a 2-week Lead-In Dose period of S64315 (fixed dose) during which the patient continues to receive venetoclax daily. Once the planned dose of both drugs is reached the schedule will be a 21-day cycle with a weekly regimen for S64315 and a daily regimen for venetoclax. S64315 should be administered 2 to 4 hours after venetoclax intake, via IV infusion. The dose escalation will start at 50 mg once a week and doses up to 250 mg once a week might be explored. Venetoclax will be administered orally once a day. The dose escalation will start at 100 mg daily and doses up to 600 mg daily might be explored. Venetoclax must be taken with a meal (ideally during breakfast) in order to avoid reduced efficacy.

Alternative Schedule - S64315 high dose and venetoclax low dose administered in combination; Alternative Schedule - S64315 medium dose and venetoclax medium dose administered in combination; Alternative Schedule - Venetoclax medium dose administered with no S64315; Initial Schedule - S64315 high dose and venetoclax medium dose administered in combination; Initial Schedule - S64315 low dose and venetoclax high dose administered in combination; Initial Schedule - S64315 medium dose and venetoclax high dose administered in combination; Initial Schedule - S64315 medium dose and venetoclax low dose administered in combination; Initial Schedule - S64315 medium dose and venetoclax medium dose administered in combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged ≥ 18 years;
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Able to comply with study procedures
• Serum creatinine ≤ 1.5 x ULN (upper normal limit) or calculated creatinine clearance (determined by MDRD) \> 50 mL/min/1.73m2
• 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

You may not qualify if:

• Participant already enrolled and treated in the study
• Pregnancy, breastfeeding or possibility of becoming pregnant during the study
• 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
• 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).
• Known carriers of HIV antibodies
• Known history of significant liver disease
• Uncontrolled hepatitis B or C infection
• Known active acute or chronic pancreatitis
• History of myocardial infarction (MI), unstable angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
• Any factors that could increase the risk of QTc prolongation or risk of arrhythmic events.

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead
• ADIR, a Servier Group company: collaborator

Study Sites (7)

Smilow Cancer Hospital at Yale

New Haven, Connecticut, 06511, United States

Location

The University of Texas MD Anderson Cancer Center, Houston, TX

Houston, Texas, 77030, United States

Location

Peter MacCallum cancer centrer

Melbourne, Australia

Location

The Alfred Hospital Department of Haematology

Victoria Park, Australia

Location

Institut Paoli-Calmettes

Marseille, France

Location

Hopital Saint-Antoine

Paris, France

Location

Institut Universitaire du Cancer Toulouse - Oncopole

Toulouse, France

Location

Related Links

• Find Results on Servier Clinical Trial Data website
• Link to Lay Summary and Results Summary

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Andrew WEI

  The Alfred Hospital, Melbourne, Victoria

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2018
• First Posted: September 14, 2018
• Study Start: November 28, 2018
• Primary Completion: November 12, 2022
• Study Completion: May 30, 2023
• Last Updated: February 5, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.

Locations

FR (3); US (2); AU (2)