Clinical Trial Results:
An Open-label, First-in-human, Dose Escalation Study of SAR440234 Administered as Single Agent by Intravenous Infusion in Patients with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), or High Risk Myelodysplasia (HR-MDS)
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Summary
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EudraCT number |
2017-004148-39 |
Trial protocol |
FR |
Global end of trial date |
06 Apr 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Apr 2022
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First version publication date |
22 Apr 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TED15138
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03594955 | ||
WHO universal trial number (UTN) |
U1111-1197-8041 | ||
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Sponsors
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Sponsor organisation name |
Sanofi aventis recherche & développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 May 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Apr 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Dose Escalation Part: To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of SAR440234 administered as a single agent in subjects with relapsed or refractory acute myeloid leukemia (R/R AML), high risk myelodysplasia (HR-MDS), or B-cell acute lymphoblastic leukemia (B-ALL) and determine the recommended Phase 2 dose (RP2D) for the subsequent Expansion Part. Expansion Part: To assess the activity of single agent SAR440234 at the RP2D in subjects with R/R AML or HR-MDS.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Oct 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 2
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Country: Number of subjects enrolled |
France: 5
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Worldwide total number of subjects |
7
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EEA total number of subjects |
5
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
2
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted at 4 sites in France and the United States. A total of 12 subjects were screened, of whom 5 subjects were screen failures, mainly due to not meeting inclusion criteria. A total of 7 subjects were enrolled and treated in Dose Escalation Part before termination of study. | ||||||||||||||
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Pre-assignment
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Screening details |
Study consisted of 2 parts: Dose Escalation and Expansion. Enrollment of subjects in Dose Expansion Part was planned to start after completion of Dose Escalation Part. Due to early termination of study, Dose Expansion Part was not conducted. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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SAR440234 | ||||||||||||||
Arm description |
SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, subjects were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all subjects received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
SAR440234
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Investigational medicinal product code |
SAR440234
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
SAR440234 IV infusion weekly for 6 weeks in Cycle 1. Dose escalation scheme was followed for first 3 weeks in Cycle 1 and then fixed doses were given from Week 4 to Week 6 unless the dose needed to be decreased for safety reasons.
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Baseline characteristics reporting groups
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Reporting group title |
SAR440234
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Reporting group description |
SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, subjects were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all subjects received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SAR440234
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Reporting group description |
SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, subjects were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all subjects received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly. | ||
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End point title |
Dose Escalation Part: Number of Subjects With Dose Limiting Toxicities (DLTs) [1] | ||||||
End point description |
DLTs: occurrence of any of following related to investigational medicinal product (IMP): Any grade (G) greater than or equal to (>=) 3 nonhematological adverse events (AE); G4 hematological toxicities (bone marrow hypocellularity, decreased neutrophils, febrile neutropenia, decreased platelet count and anemia) as defined in national cancer institute common terminology criteria for adverse events (NCI-CTCAE, v4.03); G3/G4 cytokine release syndrome (CRS) (G1: fever, nausea, fatigue, headache, myalgias and malaise; G2: oxygen requirement less than[<] 40 percent (%); G3: oxygen requirement greater than[>] 40% ; G4: life-threatening symptoms, requirement for mechanical ventilation, organ toxicity, G5:death) graded by NCI Consensus Guidelines; Grade 2 CRS for >48 hours/<48 hours before IMP; any treatment-emergent AE of potential significance and IMP-related adverse reaction lasted >2 weeks with failure to recover to baseline/improve to G less than or equal to(<=1). DLT evaluable population.
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End point type |
Primary
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End point timeframe |
Cycle 1 (42 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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End point title |
Dose Escalation Part: Number of Subjects With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions [2] | ||||||
End point description |
In this endpoint, number of subjects with allergic reactions or hypersensitivity and CRS or acute infusion reactions is reported. CRS is a nonantigen specific toxicity that occurs as result of potent immune activation mediated by large, rapid release of cytokines into blood from immune cells affected by IMP. Grading and management of CRS was based on National Cancer Institute (NCI) Consensus Guidelines 2014. Allergic/Hypersensitivity reactions or acute infusion reactions are defined as disorder characterised by adverse local/general response from exposure to allergen; graded by NCI CTCAE v4.03. Analysis was performed on safety population which included all registered subjects who had given their informed consent and had received at least 1 dose of SAR440234. Analysis was performed on safety population which included all registered subjects who had given their informed consent and had received at least 1 dose of SAR440234.
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End point type |
Primary
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End point timeframe |
First IMP administration (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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End point title |
Expansion Part: Percentage of Subjects With Overall Response (OR) Per International Working Group (IWG) Criteria [3] | ||||||||
End point description |
Response: assessed by IWG 2003 recommendations for acute myeloid leukemia (AML) and revised 2000 criteria for myelodysplastic syndrome (MDS). MDS - OR: complete remission (CR)/marrow CR/partial remission (PR), CR: repeat bone marrow show <5% myeloblasts and peripheral blood evaluations lasting >=2 months hemoglobin (>11 grams per decilitre), neutrophils 1500 per cubic millimetre (mm^3), platelets >=100000/mm^3, blasts 0% and no dysplasia, PR: all CR criteria except blasts decreased by >=50% over pretreatment or less advanced than pretreatment. AML - OR:CR/CR with incomplete hematological recovery(CRi)/PR, CR:absolute neutrophil count (ANC) >=1000 per microliter (mcL), platelets >=100000/mcL, <5% blast cells in bone marrow; auer rods should not be detectable; no platelet/whole blood transfusions for 7 days prior hematology test. CRi:all criteria of CR except platelets and/or ANC. PR:all CR criteria except blasts decreased by >=50% over pretreatment or less advanced than pretreatment.
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End point type |
Primary
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End point timeframe |
From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| Notes [4] - Due to the early termination of the study, data for this endpoint was not collected and analysed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Duration of Response (DOR) [5] | ||||||||
End point description |
DOR: time from first tumor assessment at which the overall response was recorded as CR, marrow CR, or PR (MDS) and CR/CRi (AML) until documented progressive disease (PD) determined by IWG criteria, or death from any cause, whichever occurred first. Per IWG criteria, relapse was defined as reappearance of blasts in blood or bone marrow (>5%) or in any extramedullary site after a CR. CR:<= 5% myeloblasts in bone marrow with no evidence of persistent dysplasia; peripheral blood showing hemoglobin>=11g/dL. Marrow CR: no circulating blasts, <5% blast, absolute neutrophil count >1000/mcL, platelets >100000/mcL, no recurrence for 4 weeks. CRi: meet all criteria for CR except platelet count and/or ANC. PR: all CR criteria except blasts decreased by >=50% over pretreatment or less advanced than pretreatment. Progression: at least 50% decrease from maximum remission/response in granulocytes/platelets; reduction in Hgb by >=2 g/dL; transfusion dependence.
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End point type |
Primary
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End point timeframe |
From 1st documentation of response to date of first documentation of disease progression or death, whichever came earlier (up to 42 days)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| Notes [6] - Due to the early termination of the study, data for this endpoint was not collected and analysed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Expansion Part: Number of Subjects With Disease-free Survival [7] | ||||||
End point description |
Disease-free survival was defined as the time from date of first administration of study intervention until the earliest of any of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response whichever occurred first.
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End point type |
Primary
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End point timeframe |
First IMP administration to date of first documentation of disease progression or relapse or death, whichever came earlier (up to 42 days)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| Notes [8] - Due to the early termination of the study, data for this endpoint was not collected and analysed. |
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| No statistical analyses for this end point | |||||||
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End point title |
Dose Escalation Part: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | ||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious AEs (SAEs) were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalisation, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as the AEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
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End point type |
Secondary
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End point timeframe |
From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
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| No statistical analyses for this end point | |||||||||||
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End point title |
Dose Escalation Part: Percentage of Subjects With Objective Response Per IWG Criteria | ||||||||
End point description |
Objective response was defined as the percentage of subjects who had a marrow CR, or PR (MDS) and CR/CRi (AML) per IWG criteria. For MDS, CR: repeat bone marrow show <5% myeloblasts and peripheral blood evaluations lasting >=2 months of hemoglobin (>11 g/dL), neutrophils 1500/mm^3, platelets >=100000/mm^3, blasts 0% and no dysplasia, PR: all CR criteria except blasts decreased by >=50% over pretreatment or less advanced than pretreatment. For AML, CR: ANC >=1000/mcL, platelet count >=100000/mcL, bone marrow should contain <5% blast cells; auer rods should not be detectable; no platelet/whole blood transfusions for 7 days prior to date of hematology assessment. CRi: morphologic complete remission but ANC count might be <1000/mcL or platelet <100000/mcL.
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End point type |
Secondary
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End point timeframe |
From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)
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| Notes [9] - Due to the early termination of the study, data for this endpoint was not collected and analysed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Immunogenicity: Number of Subjects With Treatment-Emergent Anti-drug Antibodies (ADA) Response | ||||||
End point description |
ADA response categories: 1) Treatment-induced ADA: subjects without pre-existing ADA and without pretreatment samples and who developed ADAs during the TEAE period. 2) Treatment-boosted ADA: subjects with pre-existing ADAs that was increased at least a 4-fold in titer compared to Baseline during the TEAE period. 2) Treatment-emergent ADA: subjects with at least one treatment-induced/boosted ADA sample. TEAE period was defined as the time from the first dose of the IMP to the last dose of the IMP + 30 days. Analysis was performed on ADA population which included all subjects who had given their informed consent, had received at least 1 dose (even incomplete) of SAR440234 and had at least 1 available ADA result after IMP administration.
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End point type |
Secondary
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End point timeframe |
From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
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| No statistical analyses for this end point | |||||||
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End point title |
Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234 | ||||||||||||||||||||
End point description |
Cmax was the maximum observed plasma concentration. Cmax was obtained by a non-compartmental analysis. Here in the time frame, Day = D, start of infusion = SOI, mid of infusion = MOI, end of infusion = EOI and hours = H. Analysed on PK population which included subjects who had given their informed consent and had received at least one dose (even incomplete) of SAR440234 with at least 1 evaluable drug concentration after IMP administration. Here, 'n' = subjects with available data for each specified category, '99999' indicates that mean and standard deviation (SD) were not estimable as no subject had plasma concentration greater than lower limit of quantification and '9999' indicates that SD was not estimable because only 1 subject was available for the analysis at the specified time point.
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End point type |
Secondary
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End point timeframe |
Cycle 1: D 1: SOI, EOI, 1, 2, 5, 7, 24, 48, 72 H post EOI; D 8: SOI, MOI, EOI, 2, 5, 168 H post EOI; D 15: MOI, EOI, 2, 5, 24 H post EOI; D 22: SOI, MOI, EOI, 2, 5, 24, 48, 72, 96, 168 H post EOI; D 29: EOI, 2 H post EOI; D 36: SOI, EOI, 2 H post EOI
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of IMP up to 30 days after the last dose of IMP (i.e., up to 72 days)
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Adverse event reporting additional description |
Reported AEs and deaths were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of IMP + 30 days). Analysis was performed on safety population.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
SAR440234
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Reporting group description |
SAR440234 was administered as intravenous (IV) infusion once weekly for 6 weeks per Cycle. Per plan, subjects were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all subjects received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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29 May 2018 |
Following changes were made: Clarify some discontinuation criteria; Modify some Inclusion/Exclusion criteria; Define overdose for oral intake; Update premedication prior to infusion. Additional premedication is now required: dexamethasone 20 mg IV and montelukast 10 mg oral (PO) 4 hours prior to the start of SAR440234; Update dose modification rules for Grade 3 and 4 CRS; Add specific guidelines for the risk stratification, diagnosis, prevention, and treatment of tumor lysis syndrome; Add magnesium to blood chemistry. |
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15 Feb 2019 |
The following changes were made:
- Updated exclusion criteria - Modify allowed chemotherapy to permit use of hydroxyurea, if needed, to control the white blood count during Cycle 1.
- Clarified wording in the dose delay/reduction section to avoid misinterpretations.
- Clarified wording of DLT definitions.
- Updated flow charts section with below details.
- Require performance of Day 42 assessment on the day that the subject discontinues therapy with SAR440234.
- Require performance of end of treatment (EOT) assessment within 30 days of last SAR440234 administration.
- Require follow up via telephone call and record review if a subject was unable to return to clinic for monthly study visits after discontinuing SAR440234.
- Clarified enrollment schedule and some discontinuation criteria.
- Modified some Inclusion/Exclusion criteria.
- Defined overdose of oral intake.
- Updated premedication prior to infusion: Additional premedication is now required: dexamethasone 20 mg IV and monteleukast 10 mg oral (PO) 4 hours prior to the start of SAR440234.
- Updated dose modification rules for Grade 3 and 4 CRS.
- Added specific guidelines for the risk stratification, diagnosis, prevention, and treatment of tumor lysis syndrome. - Added magnesium to blood chemistry. |
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29 Aug 2019 |
The following changes were made: - Text was added to clarify that the first 3 subjects treated during the Dose Escalation Part were replaced because abnormalities were detected in their PK profiles. These findings suggested that these subjects might had received unintentional overdoses of SAR440234 on some occasions. Data from these subjects would be used as part of the safety database but would not be used for dose escalation decision. - Clarified to be consistent with Clinical Trial Summary. - To improve the ability to detect safety signals accurately, the Dose Escalation Part will now follow a 3+3 trial design, rather than an accelerated design. - Text was added to draw attention to the importance of referring to the Pharmacy Manual regarding details of SAR440234 preparation and administration. - Correction of formatting, typographical errors and standardisation of wording to increase clarity. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| Sponsor decided to prioritise development of other novel therapies with more innovative mechanisms of action for R/R AML and other cancers. Thus, decided to terminate the study and stopped enrollment in Dose Expansion Part. | |||||||
