Clinical trial NCT04580121: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-10-08
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 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).

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

Primary outcomes:
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: From baseline up to 9 months
measure: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: From baseline up to 28 days
measure: Recommended Phase II Dose (RP2D)
timeFrame: From baseline up to 7 months
Secondary outcomes:
measure: Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow (Group I Dose Escalation Cohorts only)
timeFrame: From baseline up to 7 months
measure: Percentage of Participants who Achieve a Response
timeFrame: From baseline up to approximately 4 years
measure: Transfusion Independence
timeFrame: From baseline up to 7 months
measure: Event-free Survival (EFS)
timeFrame: From baseline to the time to progression, relapse, death from any cause, or start of a new treatment (up to approximately 4 years)
measure: Duration of Response (DoR)
timeFrame: 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)
measure: Time to Hematological Relapse (Group II Only)
timeFrame: From baseline until the time of documented hematological relapse
measure: Early Mortality Rate
timeFrame: From baseline to Day 30, and to Day 60
measure: Progression-free Survival (PFS)
timeFrame: 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)
measure: Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment
timeFrame: From baseline up to 7 months
measure: Area Under the Curve (AUC) of RO7283420
timeFrame: 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.
measure: Maximum Concentration (Cmax) of RO7283420
timeFrame: 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.
measure: Minimum Concentration (Cmin) of RO7283420
timeFrame: 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.
measure: Clearance (Cl) of RO7283420
timeFrame: 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.
measure: Volume (V) of RO7283420
timeFrame: 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.
measure: Half-life (T1/2) of RO7283420
timeFrame: 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.
measure: Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420
timeFrame: 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
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre; Medical Oncology
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT
city: Marseille
country: France
facility: Institut Paoli Calmettes; Departement D' Onco-Hematologie
city: Pessac
country: France
facility: Hopital De Haut Leveque; Hematologie Clinique
city: Dresden
country: Germany
facility: Uniklinikum "Carl Gustav Carus"; Med. Klinik 1; Hämatologie, Zelltherapie und Medizinische Onkologie
city: München
country: Germany
facility: Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III
city: Bergamo
country: Italy
facility: ASST PAPA GIOVANNI XXIII; Ematologia
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia
state: Lombardia
city: Pisa
country: Italy
facility: Ospedale Santa Chiara; Unita Operativa Di Ematologia
state: Toscana
city: Badalona
country: Spain
facility: Institut Catala d?Oncologia Hospital Germans Trias i Pujol
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Servicio de Hematologia
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Hematología y Oncología
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre; Servicio de Hematologia
city: Valencia
country: Spain
facility: Hospital Universitario la Fe; Servicio de Hematologia
city: Taichung
country: Taiwan
facility: China Medical University Hospital; Oncology and Hematology
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital; Oncology
city: Taipei
country: Taiwan
facility: National Taiwan Universtiy Hospital; Division of Hematology
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Augsberger C, Hanel G, Xu W, Pulko V, Hanisch LJ, Augustin A, Challier J, Hunt K, Vick B, Rovatti PE, Krupka C, Rothe M, Schonle A, Sam J, Lezan E, Ducret A, Ortiz-Franyuti D, Walz AC, Benz J, Bujotzek A, Lichtenegger FS, Gassner C, Carpy A, Lyamichev V, Patel J, Konstandin N, Tunger A, Schmitz M, von Bergwelt-Baildon M, Spiekermann K, Vago L, Jeremias I, Marrer-Berger E, Umana P, Klein C, Subklewe M. Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody. Blood. 2021 Dec 23;138(25):2655-2669. doi: 10.1182/blood.2020010477.