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

NCT ID: NCT04580121

Last Updated: 2024-06-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-04
• Study Completion Date: 2023-08-09

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).

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A: Single Participant Dose Escalation

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.

Group Type: EXPERIMENTAL

RO7283420

Intervention Type: 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.

Tocilizumab

Intervention Type: 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.

Dasatinib

Intervention Type: 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.

Dexamethasone

Intervention Type: 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.

Paracetamol/acetaminophen

Intervention Type: 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.

Diphenhydramine

Intervention Type: 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 B: Multiple Participant Dose Escalation

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.

Group Type: EXPERIMENTAL

RO7283420

Intervention Type: 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.

Tocilizumab

Intervention Type: 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.

Dasatinib

Intervention Type: 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.

Dexamethasone

Intervention Type: 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.

Paracetamol/acetaminophen

Intervention Type: 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.

Diphenhydramine

Intervention Type: 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 C: Dose Expansion

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

Group Type: EXPERIMENTAL

RO7283420

Intervention Type: DRUG

RO7283420 at RP2D will be administered by IV infusion or SC injection as per dosing schedule determined in Part B.

Tocilizumab

Intervention Type: 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.

Dasatinib

Intervention Type: 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.

Dexamethasone

Intervention Type: 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.

Paracetamol/acetaminophen

Intervention Type: 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.

Diphenhydramine

Intervention Type: 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.

Interventions

RO7283420

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.

Intervention Type: DRUG

RO7283420

RO7283420 at RP2D will be administered by IV infusion or SC injection as per dosing schedule determined in Part B.

Intervention Type: DRUG

Tocilizumab

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.

Intervention Type: DRUG

Dasatinib

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.

Intervention Type: DRUG

Dexamethasone

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.

Intervention Type: DRUG

Paracetamol/acetaminophen

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.

Intervention Type: DRUG

Diphenhydramine

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.

Intervention Type: DRUG

Other Intervention Names

Actemra, RoActemra

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

UC Davis Comprehensive Cancer Center

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

ASST PAPA GIOVANNI XXIII; Ematologia

Bergamo, Lombardy, Italy

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

Rozzano, Lombardy, Italy

Ospedale Santa Chiara; Unita Operativa Di Ematologia

Pisa, Tuscany, Italy

Institut Catala d?Oncologia Hospital Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitari Vall d'Hebron; Servicio de Hematologia

Barcelona, , Spain

Hospital Clínic i Provincial; Servicio de Hematología y Oncología

Barcelona, , Spain

Hospital Univ. 12 de Octubre; Servicio de Hematologia

Madrid, , Spain

Hospital Universitario la Fe; Servicio de Hematologia

Valencia, , Spain

China Medical University Hospital; Oncology and Hematology

Taichung, , Taiwan

National Cheng Kung University Hospital; Oncology

Tainan City, , Taiwan

National Taiwan Universtiy Hospital; Division of Hematology

Taipei, , Taiwan

Churchill Hospital

Oxford, , United Kingdom

Royal Marsden NHS Foundation Trust

Sutton, , United Kingdom

Countries

United States; Australia; Canada; Denmark; France; Germany; Italy; Spain; Taiwan; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 40746940 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34280257 (View on PubMed)

Other Identifiers

2020-000216-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

WP42004

Identifier Type: -

Identifier Source: org_study_id