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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04580121




Registration number
NCT04580121
Ethics application status
Date submitted
1/10/2020
Date registered
8/10/2020
Date last updated
3/06/2024

Titles & IDs
Public title
A Dose Escalation and Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7283420.
Scientific 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
Secondary ID [1] 0 0
2020-000216-30
Secondary ID [2] 0 0
WP42004
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO7283420
Treatment: Drugs - RO7283420
Treatment: Drugs - Tocilizumab
Treatment: Drugs - Dasatinib
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Paracetamol/acetaminophen
Treatment: Drugs - Diphenhydramine

Experimental: 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.

Experimental: 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.

Experimental: Part C: Dose Expansion - Participants will receive the respective RP2D for Group I and Group II.


Treatment: Drugs: 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.

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

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants with Adverse Events (AEs)
Timepoint [1] 0 0
From baseline up to 9 months
Primary outcome [2] 0 0
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
Timepoint [2] 0 0
From baseline up to 28 days
Primary outcome [3] 0 0
Recommended Phase II Dose (RP2D)
Timepoint [3] 0 0
From baseline up to 7 months
Secondary outcome [1] 0 0
Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow (Group I Dose Escalation Cohorts only)
Timepoint [1] 0 0
From baseline up to 7 months
Secondary outcome [2] 0 0
Percentage of Participants who Achieve a Response
Timepoint [2] 0 0
From baseline up to approximately 4 years
Secondary outcome [3] 0 0
Transfusion Independence
Timepoint [3] 0 0
From baseline up to 7 months
Secondary outcome [4] 0 0
Event-free Survival (EFS)
Timepoint [4] 0 0
From baseline to the time to progression, relapse, death from any cause, or start of a new treatment (up to approximately 4 years)
Secondary outcome [5] 0 0
Duration of Response (DoR)
Timepoint [5] 0 0
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 outcome [6] 0 0
Time to Hematological Relapse (Group II Only)
Timepoint [6] 0 0
From baseline until the time of documented hematological relapse
Secondary outcome [7] 0 0
Early Mortality Rate
Timepoint [7] 0 0
From baseline to Day 30, and to Day 60
Secondary outcome [8] 0 0
Progression-free Survival (PFS)
Timepoint [8] 0 0
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 outcome [9] 0 0
Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment
Timepoint [9] 0 0
From baseline up to 7 months
Secondary outcome [10] 0 0
Area Under the Curve (AUC) of RO7283420
Timepoint [10] 0 0
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 outcome [11] 0 0
Maximum Concentration (Cmax) of RO7283420
Timepoint [11] 0 0
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 outcome [12] 0 0
Minimum Concentration (Cmin) of RO7283420
Timepoint [12] 0 0
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 outcome [13] 0 0
Clearance (Cl) of RO7283420
Timepoint [13] 0 0
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 outcome [14] 0 0
Volume (V) of RO7283420
Timepoint [14] 0 0
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 outcome [15] 0 0
Half-life (T1/2) of RO7283420
Timepoint [15] 0 0
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 outcome [16] 0 0
Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420
Timepoint [16] 0 0
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

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
4/11/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
9/08/2023
Sample size
Target
Accrual to date
Final
59
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre; Medical Oncology - Melbourne
Recruitment hospital [2] 0 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
3124 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas
Country [3] 0 0
Canada
State/province [3] 0 0
Ontario
Country [4] 0 0
Denmark
State/province [4] 0 0
København Ø
Country [5] 0 0
France
State/province [5] 0 0
Marseille
Country [6] 0 0
France
State/province [6] 0 0
Pessac
Country [7] 0 0
Germany
State/province [7] 0 0
Dresden
Country [8] 0 0
Germany
State/province [8] 0 0
München
Country [9] 0 0
Italy
State/province [9] 0 0
Lombardia
Country [10] 0 0
Italy
State/province [10] 0 0
Toscana
Country [11] 0 0
Spain
State/province [11] 0 0
Barcelona
Country [12] 0 0
Spain
State/province [12] 0 0
Madrid
Country [13] 0 0
Spain
State/province [13] 0 0
Valencia
Country [14] 0 0
Taiwan
State/province [14] 0 0
Taichung
Country [15] 0 0
Taiwan
State/province [15] 0 0
Tainan
Country [16] 0 0
Taiwan
State/province [16] 0 0
Taipei
Country [17] 0 0
United Kingdom
State/province [17] 0 0
Oxford
Country [18] 0 0
United Kingdom
State/province [18] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/ct2/show/NCT04580121
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04580121