Clinical trial
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).
Name
CL1-64315-002
Description
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.
Trial arms
Trial start
2018-11-28
Estimated PCD
2022-11-12
Trial end
2023-05-30
Status
Completed
Phase
Early phase I
Treatment
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.
Arms:
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
Size
37
Primary endpoint
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.
Eligibility 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.
Protocol
{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1'], 'designInfo': {'allocation': 'NON_RANDOMIZED', 'interventionModel': 'SEQUENTIAL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 37, 'type': 'ACTUAL'}}
Updated at
2024-02-05
1 organization
1 product
1 indication
Organization
Institut de Recherches Internationales ServierProduct
S 64315 and VenetoclaxIndication
Acute Myeloid Leukemia