Acute Myeloid Leukaemia
Conditions
Keywords
Acute Myeloid Leukaemia, Oncology, Mcl-1 inhibitor, Azacitidine, Combination, Phase I/II, International, Safety, Maximum tolerated dose
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.
Interventions
DRUGS 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.
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Intensity for Azacitidine (Phase I - Dose Escalation) | Through study completion, an average of 6 months | — |
| Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Day -13 up to 30 calendar days after the patient's last study visit (an average of 6 months) | 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 for S64315 (Phase I - Dose Escalation) | Through study completion, an average of 6 months | — |
| 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. |
| Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | an average of 6 months | Incidence and severity of AEs according to NCI CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | At Cycle 1 Day 2 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 Cycle 1 Day 2 and Cycle 1 Day 9 (each cycle is 28 days) | — |
| Assess Anti-leukemic Activity of S64315 in Combination With Azacitidine (Phase I - Dose Escalation) | Through study completion, an average of 6 months | Overall survival (OS) |
Countries
Australia, France, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine 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. | 5 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine 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. | 7 |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine 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. | 5 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 |
| Overall Study | Physician Decision | 1 | 3 | 0 |
| Overall Study | Progressive Disease | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | 50 mg S64315 (Also Referred as MIK665) With Azacitidine | 100 mg S64315 (Also Referred as MIK665) With Azacitidine | 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Total |
|---|---|---|---|---|
| Age, Continuous | 71.6 years STANDARD_DEVIATION 8.3 | 60.1 years STANDARD_DEVIATION 14.1 | 64.8 years STANDARD_DEVIATION 12.9 | 64.9 years STANDARD_DEVIATION 12.5 |
| Age, Customized 18 to less then 65 | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Age, Customized 65 to less then 85 | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 6 Participants | 3 Participants | 14 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 7 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 5 | 5 / 7 | 2 / 5 |
| other Total, other adverse events | 5 / 5 | 6 / 7 | 5 / 5 |
| serious Total, serious adverse events | 5 / 5 | 7 / 7 | 4 / 5 |
Outcome results
Primary
Dose Intensity for Azacitidine (Phase I - Dose Escalation)
Time frame: Through study completion, an average of 6 months
Population: One participant in the 100 mg arm did not receive azacitidine and therefore was not eligible for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for Azacitidine (Phase I - Dose Escalation) | 23.5 mg/m^2/week | Standard Deviation 17 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for Azacitidine (Phase I - Dose Escalation) | 18.8 mg/m^2/week | Standard Deviation 0.3 |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for Azacitidine (Phase I - Dose Escalation) | 22.9 mg/m^2/week | Standard Deviation 9.1 |
Primary
Dose Intensity for S64315 (Phase I - Dose Escalation)
Time frame: Through study completion, an average of 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for S64315 (Phase I - Dose Escalation) | 41.0 mg/week | Standard Deviation 2.7 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for S64315 (Phase I - Dose Escalation) | 60.3 mg/week | Standard Deviation 19.8 |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Intensity for S64315 (Phase I - Dose Escalation) | 119.6 mg/week | Standard Deviation 19.9 |
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.
Time frame: Day -13 to Cycle 1 Day 28 (each cycle is 28 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Limiting Toxicity (DLT) (Phase I - Dose Escalation) | 0 Participants |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Limiting Toxicity (DLT) (Phase I - Dose Escalation) | 1 Participants |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Dose Limiting Toxicity (DLT) (Phase I - Dose Escalation) | 1 Participants |
Primary
Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation)
Incidence and severity of AEs according to NCI CTCAE v5.0
Time frame: an average of 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Total Number of AEs | 72 Events |
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Number of Severe AEs | 39 Events |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Total Number of AEs | 56 Events |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Number of Severe AEs | 22 Events |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Total Number of AEs | 41 Events |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Adverse Events (AEs) and Severe AEs (Phase I - Dose Escalation) | Number of Severe AEs | 13 Events |
Primary
Number of Participants With Dose Interruptions (Phase I - Dose Escalation)
Time frame: Through study completion, an average of 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose delay | 3 Participants |
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose interruption | 4 Participants |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose delay | 2 Participants |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose interruption | 4 Participants |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose delay | 1 Participants |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Interruptions (Phase I - Dose Escalation) | Dose interruption | 3 Participants |
Primary
Number of Participants With Dose Reductions (Phase I - Dose Escalation)
Time frame: Through study completion, an average of 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Reductions (Phase I - Dose Escalation) | 1 Participants |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Reductions (Phase I - Dose Escalation) | 0 Participants |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Participants With Dose Reductions (Phase I - Dose Escalation) | 0 Participants |
Primary
Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation)
Incidence and severity of SAEs according to NCI CTCAE v5.0
Time frame: Day -13 up to 30 calendar days after the patient's last study visit (an average of 6 months)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Total Number of SAEs | 16 Events |
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Fatal SAEs | 2 Events |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Total Number of SAEs | 14 Events |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Fatal SAEs | 2 Events |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Total Number of SAEs | 5 Events |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Number of Serious Adverse Event (SAEs) and Fatal SAEs (Phase I - Dose Escalation) | Fatal SAEs | 0 Events |
Secondary
Assess Anti-leukemic Activity of S64315 in Combinaison With Azacitidine (Phase I - Dose Escalation)
Disease-free survival (DFS)
Time frame: Through study completion, an average of 6 months
Population: In the context of the premature study discontinuation due to strategic reasons, no statistical analyses for this outcome measure was completed since data was not collected.
Secondary
Assess Anti-leukemic Activity of S64315 in Combinaison With Azacitidine (Phase I - Dose Escalation)
Best overall response (BOR)
Time frame: Through study completion, an average of 6 months
Population: In the context of the premature study discontinuation due to strategic reasons, no statistical analyses for this outcome measure was completed since data was not collected.
Secondary
Assess Anti-leukemic Activity of S64315 in Combinaison With Azacitidine (Phase I - Dose Escalation)
Progression-free survival (PFS)
Time frame: Through study completion, an average of 6 months
Population: In the context of the premature study discontinuation due to strategic reasons, no statistical analyses for this outcome measure was completed since data was not collected.
Secondary
Assess Anti-leukemic Activity of S64315 in Combinaison With Azacitidine (Phase I - Dose Escalation)
Duration of response (DOR)
Time frame: Through study completion, an average of 6 months
Population: In the context of the premature study discontinuation due to strategic reasons, no statistical analyses for this outcome measure was completed since data was not collected.
Secondary
Assess Anti-leukemic Activity of S64315 in Combination With Azacitidine (Phase I - Dose Escalation)
Overall survival (OS)
Time frame: Through study completion, an average of 6 months
Population: In the context of the premature study discontinuation due to strategic reasons, no statistical analyses for this outcome measure was completed since data was not collected.
Secondary
Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation)
Time frame: At Cycle 1 Day 2 and Cycle 1 Day 9 (each cycle is 28 days)
Population: For Cycle 1 Day 9 in the 50 mg S64315 arm, the blood sample was collected from the same site of IV infusion and therefore, no descriptive statistics were derived due to unreliable PK Data. The other cohorts had less patients analyzed due to missing patient data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 1588 ng.h/mL | Geometric Coefficient of Variation 2.9 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 1929 ng.h/mL | Geometric Coefficient of Variation 71 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | Cycle 1 Day 9 | 2235 ng.h/mL | — |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 7393 ng.h/mL | Geometric Coefficient of Variation 38 |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Area Under the Curve (AUC) (Phase I - Dose Escalation) | Cycle 1 Day 9 | 8584 ng.h/mL | — |
Secondary
Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation)
Time frame: At Cycle 1 Day 2 and Cycle 1 Day 9 (each cycle is 28 days)
Population: For Cycle 1 Day 9 in the 50 mg S64315 arm, the blood sample was collected from the same site of IV infusion and therefore, no descriptive statistics were derived due to unreliable PK Data. The other cohorts had less patients analyzed due to missing patient data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 923 ng/mL | Geometric Coefficient of Variation 16 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 1021 ng/mL | Geometric Coefficient of Variation 59 |
| 100 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation) | Cycle 1 Day 9 | 1850 ng/mL | — |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation) | Cycle 1 Day 2 | 3646 ng/mL | Geometric Coefficient of Variation 36 |
| 190 mg S64315 (Also Referred as MIK665) With Azacitidine | Pharmacokinetic Profile of S64315 Administered in Combination With Azacitidine in Plasma: Maximum Concentration (Cmax) (Phase I - Dose Escalation) | Cycle 1 Day 9 | 4520 ng/mL | — |