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

Primary Purpose

Acute Myeloid Leukemia

Status

Recruiting

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

RO7283420

Tocilizumab

Dasatinib

Dexamethasone

Paracetamol/acetaminophen

Diphenhydramine

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

City of Hope
UC Davis Comprehensive Cancer Center
Washington University; Wash Uni. Sch. Of Med
The University of Texas MD Anderson Cancer Center
Peter MacCallum Cancer Centre; Medical Oncology
The Alfred
Princess Margaret Cancer Center
Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KATRecruiting
Institut Paoli Calmettes; Departement D' Onco-HematologieRecruiting
Hopital De Haut Leveque; Hematologie Clinique
Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I
Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik IIIRecruiting
ASST PAPA GIOVANNI XXIII; Ematologia
Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia
Ospedale Santa Chiara; Unita Operativa Di Ematologia
Institut Catala d?Oncologia Hospital Germans Trias i Pujol
Hospital Universitari Vall d'Hebron; Servicio de Hematologia
Hospital Clínic i Provincial; Servicio de Hematología y Oncología
Hospital Univ. 12 de Octubre; Servicio de Hematologia
Hospital Universitario la Fe; Servicio de Hematologia
China Medical University Hospital; Oncology and HematologyRecruiting
National Cheng Kung University Hospital; OncologyRecruiting
National Taiwan Universtiy Hospital; Division of Hematology
Churchill HospitalRecruiting
Royal Marsden NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Part A: Single Participant Dose Escalation

Part B: Multiple Participant Dose Escalation

Part C: Dose Expansion

Arm Description

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.

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.

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

Outcomes

Primary Outcome Measures

Percentage of Participants with Adverse Events (AEs)

Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Recommended Phase II Dose (RP2D)

Secondary Outcome Measures

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

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).

Transfusion Independence

Event-free Survival (EFS)

Duration of Response (DoR)

Time to Hematological Relapse (Group II Only)

Early Mortality Rate

Progression-free Survival (PFS)

Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment

Area Under the Curve (AUC) of RO7283420

Maximum Concentration (Cmax) of RO7283420

Minimum Concentration (Cmin) of RO7283420

Clearance (Cl) of RO7283420

Volume (V) of RO7283420

Half-life (T1/2) of RO7283420

Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420

Full Information

NCT ID

NCT04580121

First Posted

October 1, 2020

Last Updated

October 12, 2023

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT04580121

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 4, 2020 (Actual)

Primary Completion Date

February 28, 2026 (Anticipated)

Study Completion Date

February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Part A: Single Participant Dose Escalation

Arm Type

Experimental

Arm Description

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.

Arm Title

Part B: Multiple Participant Dose Escalation

Arm Type

Experimental

Arm Description

Arm Title

Part C: Dose Expansion

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

RO7283420

Intervention Description

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

Intervention Name(s)

RO7283420

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Tocilizumab

Other Intervention Name(s)

Actemra, RoActemra

Intervention Description

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

Intervention Name(s)

Dasatinib

Intervention Description

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

Intervention Name(s)

Dexamethasone

Intervention Description

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

Intervention Name(s)

Paracetamol/acetaminophen

Intervention Description

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

Intervention Name(s)

Diphenhydramine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Percentage of Participants with Adverse Events (AEs)

Time Frame

From baseline up to 9 months

Title

Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Time Frame

From baseline up to 28 days

Title

Recommended Phase II Dose (RP2D)

Time Frame

From baseline up to 7 months

Secondary Outcome Measure Information:

Title

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

Title

Percentage of Participants who Achieve a Response

Description

Time Frame

From baseline up to approximately 4 years

Title

Transfusion Independence

Time Frame

From baseline up to 7 months

Title

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)

Title

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)

Title

Time to Hematological Relapse (Group II Only)

Time Frame

From baseline until the time of documented hematological relapse

Title

Early Mortality Rate

Time Frame

From baseline to Day 30, and to Day 60

Title

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)

Title

Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment

Time Frame

From baseline up to 7 months

Title

Area Under the Curve (AUC) of RO7283420

Time Frame