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

NCT04580121 | Completed Phase 1 FDA Drug

• 2 other identifiers: WP420042020-000216-30
• Study Type: interventional
• Target: 59
• Locations: 10 countries
• Sites: 23

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).

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants with Adverse Events (AEs)

  From baseline up to 9 months

• Percentage of Participants with Dose-Limiting Toxicities (DLTs)

  From baseline up to 28 days

• Recommended Phase II Dose (RP2D)

  From baseline up to 7 months

Secondary Outcomes (16)

• Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow (Group I Dose Escalation Cohorts only)

  From baseline up to 7 months

• Percentage of Participants who Achieve a Response

  From baseline up to approximately 4 years

• Transfusion Independence

  From baseline up to 7 months

• Event-free Survival (EFS)

  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)

  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)

Study Arms (3)

Part A: Single Participant Dose Escalation

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.

Drug: RO7283420; Drug: Tocilizumab; Drug: Dasatinib; Drug: Dexamethasone; Drug: Paracetamol/acetaminophen; Drug: Diphenhydramine

Part B: Multiple Participant Dose Escalation

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. 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 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Additionally, step-up dosing regimens with more frequent administrations of RO7283420 during cycle 1 will be evaluated.

Drug: RO7283420; Drug: Tocilizumab; Drug: Dasatinib; Drug: Dexamethasone; Drug: Paracetamol/acetaminophen; Drug: Diphenhydramine

Part C: Dose Expansion

EXPERIMENTAL

Participants will receive the respective RP2D for Group I and Group II.

Drug: RO7283420; Drug: Tocilizumab; Drug: Dasatinib; Drug: Dexamethasone; Drug: Paracetamol/acetaminophen; Drug: Diphenhydramine

Interventions

RO7283420 DRUG

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.

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation

Tocilizumab DRUG

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.

Also known as: Actemra, RoActemra

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation; Part C: Dose Expansion

Dasatinib DRUG

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.

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation; Part C: Dose Expansion

Dexamethasone DRUG

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.

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation; Part C: Dose Expansion

Paracetamol/acetaminophen DRUG

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.

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation; Part C: Dose Expansion

Diphenhydramine DRUG

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.

Part A: Single Participant Dose Escalation; Part B: Multiple Participant Dose Escalation; Part C: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (23)

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Peter MacCallum Cancer Centre; Medical Oncology

Melbourne, Victoria, 3000, Australia

Location

The Alfred

Melbourne, Victoria, 3124, Australia

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT

København Ø, 2100, Denmark

Location

Institut Paoli Calmettes; Departement D' Onco-Hematologie

Marseille, 13273, France

Location

Hopital De Haut Leveque; Hematologie Clinique

Pessac, 33604, France

Location

Uniklinikum "Carl Gustav Carus"; Med. Klinik 1; Hämatologie, Zelltherapie und Medizinische Onkologie

Dresden, 01307, Germany

Location

Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III

München, 81377, Germany

Location

ASST PAPA GIOVANNI XXIII; Ematologia

Bergamo, Lombardy, 24127, Italy

Location

Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia

Rozzano, Lombardy, 20089, Italy

Location

Ospedale Santa Chiara; Unita Operativa Di Ematologia

Pisa, Tuscany, 56100, Italy

Location

Institut Catala d?Oncologia Hospital Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitari Vall d'Hebron; Servicio de Hematologia

Barcelona, 08035, Spain

Location

Hospital Clínic i Provincial; Servicio de Hematología y Oncología

Barcelona, 08036, Spain

Location

Hospital Univ. 12 de Octubre; Servicio de Hematologia

Madrid, 28041, Spain

Location

Hospital Universitario la Fe; Servicio de Hematologia

Valencia, 46026, Spain

Location

China Medical University Hospital; Oncology and Hematology

Taichung, 404, Taiwan

Location

National Cheng Kung University Hospital; Oncology

Tainan, 00704, Taiwan

Location

National Taiwan Universtiy Hospital; Division of Hematology

Taipei, 100, Taiwan

Location

Churchill Hospital

Oxford, OX3 7LJ, United Kingdom

Location

Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (2)

• Hutchings M, Korfi K, Montesinos P, Santoro A, Hou HA, Martinez-Sanchez P, Vives S, Galimberti S, Chen TY, Frigeni M, Garciaz S, Salamero Garcia O, Yeh SP, Yee K, Esteve J, Bajel A, Fleming S, Bretz AC, Attig J, Sun M, Nassiri S, Rutishauser T, Klein C, Ma YM, Schnetzler G, Vauleon S, Yu H, Barata T, Richard M, Simon S, Hinton H, Keshelava N, Subklewe M. Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia. Blood Neoplasia. 2025 May 11;2(3):100110. doi: 10.1016/j.bneo.2025.100110. eCollection 2025 Aug.

  PMID: 40746940 DERIVED

• 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.

  PMID: 34280257 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

tocilizumab; Dasatinib; Dexamethasone; Acetaminophen; Diphenhydramine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Ethylamines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2020
• First Posted: October 8, 2020
• Study Start: November 4, 2020
• Primary Completion: August 9, 2023
• Study Completion: August 9, 2023
• Last Updated: June 3, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2); IT (3); AU (2); DK (1); TW (3); FR (2); DE (2); CA (1); ES (5); GB (2)