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First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome

Primary Purpose

Leukaemia

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

SAR440234

About this trial

This is an interventional treatment trial for Leukaemia

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Confirmed diagnosis of Acute Myeloblastic leukemia (AML) (except acute promyelocytic leukemia), or myelodysplastic syndrome (MDS) with a risk category of intermediate or higher. Participants must had exhausted available treatment options and might not be eligible for any treatment known to provide clinical benefit.
Participants with AML must had relapsed or refractory disease that had been resistant to available therapies.
Participants with B-ALL (B acute lymphoid leukemia) in second or subsequent relapse: should had completed previously greater than or equal to (>=) 1 cycle of a salvage regimen. Participants must had exhausted available treatment options and must not be eligible for any treatment known to provide clinical benefit.
Participants with HR-MDS (high risk myelodysplastic syndrome) must have greater than (>) 10 percentage blasts in the bone marrow at the time of enrollment and fit one of the following categories: Not eligible for induction therapy and having completed >=2 cycles of therapy or not eligible for allogeneic stem cell transplant and had completed >=1 course of induction therapy.
Signed written informed consent.

Exclusion criteria:

Aged less than 16 years old.
Eastern Cooperative Oncology Group (ECOG) performance status >2.
Participants with inadequate biological tests.
White blood cell count > 30,000 per cubic millimeter.
History of active or chronic autoimmune conditions that had required or requires therapy.
Graft-versus-host disease following allogeneic stem cell transplantation required treatment with more than 10 milligrams (mg) of oral prednisone or equivalent daily. The stem cell transplant and/or donor lymphocyte infusion should had been performed more than 3 months before study treatment start.
Second primary malignancy that required active therapy. Adjuvant hormonal therapy was allowed.
Previous treatment with radiotherapy or immunotherapeutic agents in the 4 weeks prior to investigational medicinal product (IMP) administration.
Previous treatment with any other investigational agent in the 4 weeks prior to IMP administration.
Receiving, at the time of first IMP administration, of concurrent steroids >10 mg per day of oral prednisone or the equivalent for >=3 months.
Requirement for tocilizumab for any other diagnosis.
Evidence of active central nervous system leukemia at the time of enrollment.
Acquired immunodeficiency syndrome (AIDS-related illnesses) or human immunodeficiency virus disease requiring antiretroviral treatment or had active Hepatitis B viral infection or Hepatitis C viral infection.
Women of childbearing potential, male with a partner of childbearing potential who did not agree to use effective methods of birth control.
Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the participant or may interfere with compliance or interpretation of the study results.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sites / Locations

Investigational Site Number 8400001
Investigational Site Number 2500004
Investigational Site Number 2500001
Investigational Site Number 2500003

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

SAR440234

Arm Description

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.

Outcomes

Primary Outcome Measures

Dose Escalation Part: Number of Participants With Dose Limiting Toxicities (DLTs)

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).

Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions

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.

Expansion Part: Percentage of Participants With Overall Response (OR) Per International Working Group (IWG) Criteria

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)

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

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 Outcome Measures

Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

An AE was defined as any untoward medical occurrence in a participant 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 hospitalization, 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).

Dose Escalation Part: Percentage of Participants With Objective Response Per IWG Criteria

Objective response was defined as the percentage of participants 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.

Immunogenicity: Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADA) Response

ADA response categories: 1) Treatment-induced ADA: Participants without pre-existing ADA and without pre-treatment samples and who developed ADAs during the TEAE period. 2) Treatment-boosted ADA: Participant 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: Participants 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.

Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234

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.

Full Information

NCT ID

NCT03594955

First Posted

July 2, 2018

Last Updated

May 3, 2022

Sponsor

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT03594955

Brief Title

First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Terminated

Why Stopped

Sponsor decision

Study Start Date

October 24, 2018 (Actual)

Primary Completion Date

February 6, 2021 (Actual)

Study Completion Date

February 6, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukaemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

SAR440234

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

SAR440234

Intervention Description

Pharmaceutical form:lyophilisate to be resuspended in solution Route of administration: intravenous

Primary Outcome Measure Information:

Title

Dose Escalation Part: Number of Participants With Dose Limiting Toxicities (DLTs)

Description

Time Frame

Cycle 1 (42 days)

Title

Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions

Description

Time Frame

First IMP administration (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Title

Expansion Part: Percentage of Participants With Overall Response (OR) Per International Working Group (IWG) Criteria

Description

Time Frame

From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)

Title

Expansion Part: Duration of Response (DOR)

Description

Time Frame

From 1st documentation of response to date of first documentation of disease progression or death, whichever came earlier (up to 42 days)

Title

Expansion Part: Number of Participants With Disease-free Survival

Description

Time Frame

First IMP administration to date of first documentation of disease progression or relapse or death, whichever came earlier (up to 42 days)

Secondary Outcome Measure Information:

Title

Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Description

Time Frame

From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Title

Dose Escalation Part: Percentage of Participants With Objective Response Per IWG Criteria

Description

Time Frame

From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)

Title

Immunogenicity: Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADA) Response

Description

Time Frame

From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)

Title

Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234

Description

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Confirmed diagnosis of Acute Myeloblastic leukemia (AML) (except acute promyelocytic leukemia), or myelodysplastic syndrome (MDS) with a risk category of intermediate or higher. Participants must had exhausted available treatment options and might not be eligible for any treatment known to provide clinical benefit. Participants with AML must had relapsed or refractory disease that had been resistant to available therapies. Participants with B-ALL (B acute lymphoid leukemia) in second or subsequent relapse: should had completed previously greater than or equal to (>=) 1 cycle of a salvage regimen. Participants must had exhausted available treatment options and must not be eligible for any treatment known to provide clinical benefit. Participants with HR-MDS (high risk myelodysplastic syndrome) must have greater than (>) 10 percentage blasts in the bone marrow at the time of enrollment and fit one of the following categories: Not eligible for induction therapy and having completed >=2 cycles of therapy or not eligible for allogeneic stem cell transplant and had completed >=1 course of induction therapy. Signed written informed consent. Exclusion criteria: Aged less than 16 years old. Eastern Cooperative Oncology Group (ECOG) performance status >2. Participants with inadequate biological tests. White blood cell count > 30,000 per cubic millimeter. History of active or chronic autoimmune conditions that had required or requires therapy. Graft-versus-host disease following allogeneic stem cell transplantation required treatment with more than 10 milligrams (mg) of oral prednisone or equivalent daily. The stem cell transplant and/or donor lymphocyte infusion should had been performed more than 3 months before study treatment start. Second primary malignancy that required active therapy. Adjuvant hormonal therapy was allowed. Previous treatment with radiotherapy or immunotherapeutic agents in the 4 weeks prior to investigational medicinal product (IMP) administration. Previous treatment with any other investigational agent in the 4 weeks prior to IMP administration. Receiving, at the time of first IMP administration, of concurrent steroids >10 mg per day of oral prednisone or the equivalent for >=3 months. Requirement for tocilizumab for any other diagnosis. Evidence of active central nervous system leukemia at the time of enrollment. Acquired immunodeficiency syndrome (AIDS-related illnesses) or human immunodeficiency virus disease requiring antiretroviral treatment or had active Hepatitis B viral infection or Hepatitis C viral infection. Women of childbearing potential, male with a partner of childbearing potential who did not agree to use effective methods of birth control. Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the participant or may interfere with compliance or interpretation of the study results. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Investigational Site Number 8400001

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Investigational Site Number 2500004

City

Marseille

ZIP/Postal Code

13273

Country

France

Facility Name

Investigational Site Number 2500001

City

Paris Cedex 10

ZIP/Postal Code

75010

Country

France

Facility Name

Investigational Site Number 2500003

City

Villejuif Cedex

ZIP/Postal Code

94805

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Citations:

PubMed Identifier

33527351

Citation

Gerard E, Zohar S, Thai HT, Lorenzato C, Riviere MK, Ursino M. Bayesian dose regimen assessment in early phase oncology incorporating pharmacokinetics and pharmacodynamics. Biometrics. 2022 Mar;78(1):300-312. doi: 10.1111/biom.13433. Epub 2021 Feb 18.

Results Reference

derived

Learn more about this trial

First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome

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