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).
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 defined as participants not in complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). * 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) or molecular 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. The treatment period for each participant will be up to 7 months with a maximum number of cycles depending on the dosing frequency the participant receives. Each participant will receive up to 6, 9, and 18 cycles of treatment with RO7283420, when treated with Q3W, every-2-weeks (Q2W), or once-a-week (QW) dosing regimens, respectively. Additional 3, 5, or 9 cycles may be administered for the Q3W, Q2W, and QW dosing regimens, respectively, in case the participants have achieved at least partial remission (PR).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
59
RO7283420 will be administered to participants by intravenous (IV) infusion Q3W at a starting dose of 0.15mg. Starting dose levels (double step-up regimen, Q3W) for SC injections was the same as the highest dose levels that have been cleared in the IV double step-up cohorts at that timepoint. Each participant will receive up to 6, 9, and 18 cycles of treatment with RO7283420, when treated with Q3W, Q2W, or QW dosing regimens, respectively.
RO7283420 at RP2D will be administered by IV infusion or SC injection as per dosing schedule determined in Part B.
Tocilizumab will be administered as an IV infusion 8 mg/kg (for participants with a weight of 30 kg and above) and 12 mg/kg (for participants with a weight of less than 30 kg). Tocilizumab will be given as rescue medication.
UC Davis Comprehensive Cancer Center
Percentage of Participants with Adverse Events (AEs)
Time frame: From baseline up to 9 months
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
Time frame: From baseline up to 28 days
Recommended Phase II Dose (RP2D)
Time frame: From baseline up to 7 months
Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow (Group I Dose Escalation Cohorts only)
Time frame: From baseline up to 7 months
Percentage of Participants who Achieve a Response
Defined by ELN 2017 recommendations, i.e., complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with absence of measurable residual disease (CRMRD-), and partial remission (PR).
Time frame: From baseline up to approximately 4 years
Transfusion Independence
Time frame: From baseline up to 7 months
Event-free Survival (EFS)
Time frame: From baseline to the time to progression, relapse, death from any cause, or start of a new treatment (up to approximately 4 years)
Duration of Response (DoR)
Time frame: From first occurrence of a documented response until the time of documented relapse, disease progression or death from any cause, whichever occurs first (up to approximately 4 years)
Time to Hematological Relapse (Group II Only)
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Dasatinib 100 mg film-coated tablets will be administered daily until symptom resolution (up to 100 mg twice daily \[BID\] for a maximum 3 days); orally. Dasatinib will be given as rescue medication.
20 mg IV of dexamethasone will be administered as pre-medication at least 60 minutes prior to the all RO7283420 infusions or injections during cycle 1.
500 or 1000 mg of paracetamol/acetaminophen will be administered orally or by IV as pre-medication at least 30 minutes prior to each RO7283420 infusion or injection.
25 mg or 50 mg of diphenhydramine will be administered orally or by IV as pre-medication at least 30 minutes prior to each RO7283420 infusion or injection.
Sacramento, California, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Peter MacCallum Cancer Centre; Medical Oncology
Melbourne, Victoria, Australia
The Alfred
Melbourne, Victoria, Australia
Princess Margaret Cancer Center
Toronto, Ontario, Canada
Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT
København Ø, Denmark
Institut Paoli Calmettes; Departement D' Onco-Hematologie
Marseille, France
Hopital De Haut Leveque; Hematologie Clinique
Pessac, France
Uniklinikum "Carl Gustav Carus"; Med. Klinik 1; Hämatologie, Zelltherapie und Medizinische Onkologie
Dresden, Germany
Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III
München, Germany
...and 13 more locations
Time frame: From baseline until the time of documented hematological relapse
Early Mortality Rate
Time frame: From baseline to Day 30, and to Day 60
Progression-free Survival (PFS)
Time frame: From Cycle 1 Day 1 to the first occurrence of documented disease progression, or death from any cause, whichever occurs first (up to approximately 4 years)
Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment
Time frame: From baseline up to 7 months
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, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
Maximum Concentration (Cmax) of RO7283420
Time frame: Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
Minimum Concentration (Cmin) of RO7283420
Time frame: Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
Clearance (Cl) of RO7283420
Time frame: Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
Volume (V) of RO7283420
Time frame: Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
Half-life (T1/2) of RO7283420
Time frame: Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1, 2, 3, 8 of Cycle 2 only in case of triple step-up dosing; Day 1 of Cycle 2-9 (Q3W), 2-14 (Q2W), 2-27 (QW); end of treatment visit.
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 (Q3W), 3-14 (Q2W), 3-27 (QW); at end of treatment visit