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

• ClinicalTrials.gov Identifier: NCT03672695
• Recruitment Status: Terminated
• First Posted: September 14, 2018
• Last Update Posted: December 22, 2022
• Sponsor: Institut de Recherches Internationales Servier
• Collaborator: ADIR, a Servier Group company
• Information provided by (Responsible Party): Servier ( Institut de Recherches Internationales Servier )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukaemia	Combination Product: S 64315 (also referred as MIK665) and venetoclax	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An International Phase Ib Multicentre Study to Characterize the Safety and Tolerability of Intravenously Administered S64315, a Selective Mcl-1 Inhibitor, in Combination With Orally Administered Venetoclax, a Selective Bcl-2 Inhibitor in Patients With Acute Myeloid Leukaemia (AML).
• Actual Study Start Date: November 28, 2018
• Actual Primary Completion Date: November 12, 2022
• Actual Study Completion Date: November 12, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: S64315 and venetoclax administered in combination

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

Outcome Measures

Primary Outcome Measures :

1. Incidence of Dose Limiting Toxicity (DLTs) [ Time Frame: At the end of cycle 1 (each cycle is 21 or 28 days). ]
2. Incidence and severity of AEs [ Time Frame: Through study completion, an average of 6 months. ]
3. Incidence and severity of SAEs [ Time Frame: Through study completion, an average of 6 months. ]
4. Number of participants with dose interruptions "will be measured and reported in the Outcome Measure results data table. [ Time Frame: Through study completion, an average of 6 months. ]
5. Number of participants with dose reductions "will be measured and reported in the Outcome Measure results data table. [ Time Frame: Through study completion, an average of 6 months. ]
6. Dose intensity [ Time Frame: Through study completion, an average of 6 months. ]

Secondary Outcome Measures :

1. Anti-leukemic activity [ Time Frame: Through study completion, an average of 6 months. ]
   Using blood, bone marrow aspirate and medullary biopsy if available according to ELN 2017 criteria
2. Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Area Under the Curve (AUC) [ Time Frame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days). ]
3. Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Concentration at the end of infusion (Cinf) [ Time Frame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days). ]
4. Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: terminal half-life (t½z) [ Time Frame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days). ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Connecticut

Smilow Cancer Hospital at Yale

New Haven, Connecticut, United States, 06511

United States, Texas

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

Houston, Texas, United States, 77030

Australia

Peter MacCallum cancer centrer

Melbourne, Australia

The Alfred Hospital Department of Haematology

Victoria Park, Australia

France

Institut Paoli-Calmettes

Marseille, France

Hopital Saint-Antoine

Paris, France

Institut Universitaire du Cancer Toulouse - Oncopole

Toulouse, France

Sponsors and Collaborators

Institut de Recherches Internationales Servier

ADIR, a Servier Group company

Investigators

• Principal Investigator: Andrew WEI; The Alfred Hospital, Melbourne, Victoria

More Information

Additional Information:

Find Results on Servier Clinical Trial Data website 

Study Data/Documents: Individual Participant Data Set 

Study Protocol 

Statistical Analysis Plan 

Informed Consent Form 

Clinical Study Report 

• Responsible Party: Institut de Recherches Internationales Servier
• ClinicalTrials.gov Identifier: NCT03672695
• Other Study ID Numbers: CL1-64315-002; 2018-001809-88 ( EudraCT Number )
• First Posted: September 14, 2018
• Last Update Posted: December 22, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://clinicaltrials.servier.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Venetoclax; Antineoplastic Agents