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).
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
Interventions
Drug | Synonyms | Arms |
---|
RO7283420 | | RO7283420 Part A |
RO7283420 | | RO7283420 Part C |
Tocilizumab | Actemra, RoActemra | RO7283420 Part A |
Dasatinib | | RO7283420 Part A |
Dexamethasone | | RO7283420 Part A |
Paracetamol/acetaminophen | | RO7283420 Part A |
Diphenhydramine | | RO7283420 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, only participants achieving at least partial remission may receive three additional
treatment cycles.
Trial Arms
Name | Type | Description | Interventions |
---|
RO7283420 Part A | Experimental | Participants 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
- Dexamethasone
- Paracetamol/acetaminophen
- Diphenhydramine
|
RO7283420 Part B | Experimental | Multiple-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). If needed, a step-up dosing regimen with more frequent administrations of RO7283420 during cycle 1 will be evaluated. | - RO7283420
- Tocilizumab
- Dasatinib
- Dexamethasone
- Paracetamol/acetaminophen
- Diphenhydramine
|
RO7283420 Part C | Experimental | Participants will receive the respective RP2D for Group I and Group II. | - RO7283420
- Tocilizumab
- Dasatinib
- Dexamethasone
- Paracetamol/acetaminophen
- Diphenhydramine
|
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 -
hematologic relapsed/refractory and Group II - molecular relapsed/refractory) will be
included
- Participants who have received hematopoietic stem cell transplant (HSCT) must have the
HSCT performed ≥ 90 days prior to the first dose of RO7283420 on Cycle 1 Day 1, having
demonstrated hematological engraftment and do not have an active Graft versus Host
Disease, not requiring immunosuppressive treatment (including but not limited to
cyclosporine, tacrolimus, sirolimus, and mycophenolate), which must be stopped at
least 28 days prior to the first dose of RO7283420 on Cycle 1 Day 1
- 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 (a creatinine clearance of >=50 mL/min as calculated according to the
Cockroft-Gault formula) and adequate 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)
- Grade >= 2 glomerular proteinuria at screening or on Cycle 1 Day 1 prior to the first
dosing.
- Another primary malignancy (other than AML) that requires active therapy. Adjuvant
hormonal therapy is allowed
- Clinical evidence or history of central nervous system (CNS) leukemia
- Presence of 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, tocilizumab, or dasatinib
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
August 23, 2021