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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04580121
• Other study ID #: WP42004
• Secondary ID: 2020-000216-30
• Status: Completed
• Phase: Phase 1
• Start date: November 4, 2020
• Est. completion date: August 9, 2023

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: August 9, 2023
• Est. primary completion date: August 9, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre; Medical Oncology	Melbourne	Victoria
Australia	The Alfred	Melbourne	Victoria
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø
France	Institut Paoli Calmettes; Departement D' Onco-Hematologie	Marseille
France	Hopital De Haut Leveque; Hematologie Clinique	Pessac
Germany	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
Italy	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia
Italy	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Spain	Institut Catala d?Oncologia Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
Spain	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid
Spain	Hospital Universitario la Fe; Servicio de Hematologia	Valencia
Taiwan	China Medical University Hospital; Oncology and Hematology	Taichung
Taiwan	National Cheng Kung University Hospital; Oncology	Tainan
Taiwan	National Taiwan Universtiy Hospital; Division of Hematology	Taipei
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	UC Davis Comprehensive Cancer Center	Sacramento	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants with Adverse Events (AEs)		From baseline up to 9 months
Primary	Percentage of Participants with Dose-Limiting Toxicities (DLTs)		From baseline up to 28 days
Primary	Recommended Phase II Dose (RP2D)		From baseline up to 7 months
Secondary	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
Secondary	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).	From baseline up to approximately 4 years
Secondary	Transfusion Independence		From baseline up to 7 months
Secondary	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)
Secondary	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)
Secondary	Time to Hematological Relapse (Group II Only)		From baseline until the time of documented hematological relapse
Secondary	Early Mortality Rate		From baseline to Day 30, and to Day 60
Secondary	Progression-free Survival (PFS)		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)
Secondary	Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment		From baseline up to 7 months
Secondary	Area Under the Curve (AUC) of RO7283420		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.
Secondary	Maximum Concentration (Cmax) of RO7283420		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.
Secondary	Minimum Concentration (Cmin) of RO7283420		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.
Secondary	Clearance (Cl) of RO7283420		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.
Secondary	Volume (V) of RO7283420		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.
Secondary	Half-life (T1/2) of RO7283420		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.
Secondary	Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420		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