Clinical trial NCT03594955: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Leukaemia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-07-20
Enrollment: 7
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Dose Escalation Part: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (42 days)
measure: Dose Escalation Part: Number of Participants With Allergic Reactions/Hypersensitivity and Cytokine Release Syndrome/Acute Infusion Reactions
timeFrame: First IMP administration (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
measure: Expansion Part: Percentage of Participants With Overall Response (OR) Per International Working Group (IWG) Criteria
timeFrame: From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)
measure: Expansion Part: Duration of Response (DOR)
timeFrame: From 1st documentation of response to date of first documentation of disease progression or death, whichever came earlier (up to 42 days)
measure: Expansion Part: Number of Participants With Disease-free Survival
timeFrame: First IMP administration to date of first documentation of disease progression or relapse or death, whichever came earlier (up to 42 days)
Secondary outcomes:
measure: Dose Escalation Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
measure: Dose Escalation Part: Percentage of Participants With Objective Response Per IWG Criteria
timeFrame: From the date of first IMP administration until disease progression or death, whichever came earlier (up to 42 days)
measure: Immunogenicity: Number of Participants With Treatment-Emergent Anti-drug Antibodies (ADA) Response
timeFrame: From Baseline (Day 1) up to last dose of IMP + 30 days (i.e., up to 72 days)
measure: Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of SAR440234
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
Other outcomes:
Locations:
city: Houston
country: United States
facility: Investigational Site Number 8400001
state: Texas
city: Marseille
country: France
facility: Investigational Site Number 2500004
city: Paris Cedex 10
country: France
facility: Investigational Site Number 2500001
city: Villejuif Cedex
country: France
facility: Investigational Site Number 2500003
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
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.