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)
Overview
- Phase
- Phase 1
- Intervention
- SAR440234
- Conditions
- Leukaemia
- Sponsor
- Sanofi
- Enrollment
- 7
- Locations
- 4
- Primary Endpoint
- Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
Primary Objective:
- Dose escalation: To determine the maximum tolerated dose (MTD) of SAR440234 administered as a single agent in participants with relapsed or refractory acute myeloid leukemia (R/R AML), high risk myelodysplastic syndrome (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 participants with R/R AML or HR-MDS.
Secondary Objective:
- To characterize the safety profile including cumulative adverse drug reactions.
- To evaluate the potential immunogenicity of SAR440234.
- To assess any preliminary evidence of hematologic response in the Dose Escalation Part.
Detailed Description
The duration of the study for the participants included a period for screening of up to 14 days. The cycle duration was 42 days. Participants continued study treatment as long as clinical benefit was possible or until disease progression, unacceptable adverse reaction, participant's decision to stop treatment, or other reason of discontinuation. After study treatment discontinuation participants returned to the study site 30 days after the last administration of SAR440234 for end of treatment assessments. Participants without documented disease progression at the end of a treatment visit who had not yet started treatment with another anti-cancer therapy would proceed with monthly follow-up visits until initiation of another anti-cancer therapy, disease progression, or study cut-off date, whichever came first.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
SAR440234
SAR440234 was administered as intravenous infusion once weekly for 6 weeks per Cycle. Per plan, participants 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 participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Intervention: SAR440234
Outcomes
Primary Outcomes
Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions
Time Frame: First IMP administration (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
In this outcome measure, number of participants 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 characterized by adverse local/general response from exposure to allergen; graded by NCI CTCAE v4.03.
Dose Escalation Part: Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: Cycle 1 (42 days)
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 or 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 or \<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 or improve to Grade less than or equal to (\<=1).
Expansion Part: Percentage of Participants With Overall Response (OR) Per International Working Group (IWG) Criteria
Time Frame: From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)
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 deciliter), neutrophils 1500 per cubic millimeter (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.
Expansion Part: Duration of Response (DOR)
Time Frame: From 1st documentation of response to date of first documentation of disease progression or death, whichever came earlier (up to 42 days)
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.
Expansion Part: Number of Participants With Disease-free Survival
Time Frame: First IMP administration to date of first documentation of disease progression or relapse or death, whichever came earlier (up to 42 days)
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.
Secondary Outcomes
- Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days))
- Dose Escalation Part: Percentage of Participants With Objective Response Per IWG Criteria(From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days))
- Immunogenicity: Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADA) Response(From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days))
- Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234(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)