Clinical Trials /

A Dose Escalation and Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7283420.

NCT04580121

Description:

This open-label, entry-into-human (EIH) study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of RO7283420. Escalating doses of RO7283420 will be administered to participants with Acute Myeloid Leukemia (AML) in order to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Dose Escalation and Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7283420.
  • Official Title: An Open-Label, Multi-Center, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7283420 as a Single Agent in Hematologic and Molecular Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: WP42004
  • SECONDARY ID: 2020-000216-30
  • NCT ID: NCT04580121

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
RO7283420RO7283420 Part A
RO7283420RO7283420 Part C
TocilizumabActemra, RoActemraRO7283420 Part A
DasatinibRO7283420 Part A

Purpose

This open-label, entry-into-human (EIH) study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of RO7283420. Escalating doses of RO7283420 will be administered to participants with Acute Myeloid Leukemia (AML) in order to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D).

Detailed Description

      The study will include AML participants with measurable disease, for whom standard-of-care
      (SOC) is not available. Two Groups of AML participants will be included in this study:

        -  Group I participants will have hematologic relapse/refractory disease (participants not
           in CR or CRi i.e. with >=5% blast cells in the bone marrow (BM) or presence of
           circulating blast)

        -  Group II participants will have molecular relapse/persistent disease (participants with
           a CR or CRi, and a positive MRD based on local multi-parameter flow cytometry (MFC)
           assessment).

      The study consists of three parts:

        -  Part A (single-participant dose escalation cohorts) - single participants from Group I
           will receive increment-based escalating doses until a Grade >=2 AE related to RO7283420
           or a clear pharmacodynamic effect

        -  Part B (multiple-participant dose escalation cohorts) - multiple-participant cohorts of
           >=3 participants will be enrolled for dose escalation for Group I and Group II
           independently.

        -  Part C (dose expansion) - participants will receive the respective identified RP2D for
           that group.

      Each participant will receive up to 6 cycles of treatment with RO7283420. At the end of Cycle
      6, at the discretion of the Investigator (based on the assessment of clinical benefit), the
      participant could receive up to 3 additional treatment cycles.
    

Trial Arms

NameTypeDescriptionInterventions
RO7283420 Part AExperimentalParticipants from Group I will receive escalating doses of RO7283420, once every 3 weeks (Q3W) starting on Cycle 1, Day 1 (C1D1) for up to 6 cycles with a starting dose of 0.15mg.
  • RO7283420
  • Tocilizumab
  • Dasatinib
RO7283420 Part BExperimentalMultiple-participant cohorts of >= 3 participants will be enrolled for dose escalation for Group I and Group II independently. Participants will be administered a starting dose of 0.15 mg or highest dose administered in Part A of RO7283420 once Q3W starting on C1D1 up to Cycle 6 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).
  • RO7283420
  • Tocilizumab
  • Dasatinib
RO7283420 Part CExperimentalParticipants will receive the respective RP2D for Group I and Group II.
  • RO7283420
  • Tocilizumab
  • Dasatinib

Eligibility Criteria

        Inclusion Criteria:

          -  With confirmed diagnosis of primary or secondary AML according to WHO classification
             2016, with measurable disease. Eligible participants need to have received
             standard-of-care (SOC) and have no other SOC options available. Participants who are
             not willing to receive SOC will be not eligible. Two groups of participants (Group I
             and Group II) will be included.

          -  Participants who have received hematopoietic stem cell transplant (HSCT) must have the
             HSCT performed ≥ 28 days prior to screening, having demonstrated hematological
             engraftment and do not have an active Graft versus Host disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Peripheral blast counts =< 20,000/mm3 on Cycle 1 Day 1 prior to the first dosing

          -  Confirmed genotype of HLA-A*02

          -  Adequate renal and liver test results

          -  Male or female participants agree to use contraception and the abstinence requirements
             to prevent exposure of an embryo to the study treatment

        Exclusion Criteria:

          -  Acute promyelocytic leukemia (APL)

          -  Core Binding Factor (CBF)-AML Note: participants with r/r CBF-AML after at least 2
             salvage attempts can be enrolled into the study

          -  Group II only: participants with normal karyotype and a favorable molecular profile
             according to ELN guideline 2017

          -  Participants with active bacterial, fungal or viral infection considered by the
             Investigator to be clinically uncontrolled or of unacceptable risk upon the induction
             of neutropenia (i.e. participants who are or should be on antimicrobial agents for the
             treatment of active infection)

          -  Glomerular proteinuria (Grade >= 2) with presence of transferrin and/or IgG in the
             urine

          -  Another primary malignancy (other than AML) that requires active therapy. Adjuvant
             hormonal therapy is allowed

          -  History of autoimmune disease

          -  Clinical evidence or history of central nervous system (CNS) leukemia

          -  Presence of isolated extramedullary disease at screening

          -  Current or past history of CNS disease, such as stroke, CNS inflammation, epilepsy,
             CNS vasculitis, or neurodegenerative disease

          -  Participants who have a history of clinically significant liver disease, including
             liver cirrhosis (e.g. Child-Pugh class B and C) or participants who have a history of
             active or chronic infectious hepatitis unless serology demonstrates clearance of
             infection

          -  Participants who might refuse to receive blood products and/or have known
             hypersensitivity to any of the components of RO7283420
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Adverse Events (AEs)
Time Frame:From baseline up to 9 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow
Time Frame:From baseline up to 7 months
Safety Issue:
Description:
Measure:Percentage of Participants with >= 50% Reduction from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow
Time Frame:From baseline up to 7 months
Safety Issue:
Description:
Measure:Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment
Time Frame:From baseline up to 7 months
Safety Issue:
Description:
Measure:Area Under the Curve (AUC) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Maximum Concentration (Cmax) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Minimum Concentration (Cmin) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Clearance (Cl) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Volume (V) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Half-life (T1/2) of RO7283420
Time Frame:Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:
Measure:Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420
Time Frame:Day 1, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 and 8 of Cycle 2, Day 1 of Cycle 3-9, at end of treatment visit (28 days after the last dose of RO7283420)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

November 4, 2020