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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04580121

Collaborator

(none)

160

Enrollment

Locations

Arms

47.4

Anticipated Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: RO7283420 Drug: RO7283420 Drug: Tocilizumab Drug: Dasatinib Drug: Dexamethasone Drug: Paracetamol/acetaminophen Drug: Diphenhydramine	Phase 1

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 (participants not in CR or CRi i.e. with >=5% blast cells in the bone marrow (BM) or presence of circulating blast)
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.

Each participant will receive up to 6 cycles of treatment with RO7283420. At the end of cycle 6, only participants achieving at least partial remission may receive three additional treatment cycles.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

160 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 4, 2020

Anticipated Primary Completion Date :

Oct 18, 2024

Anticipated Study Completion Date :

Oct 18, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RO7283420 Part A 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 RO7283420 will be administered to participants by intravenous (IV) infusion or subcutaneous (SC) injection Q3W at a starting dose of 0.15mg. 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. Other Names: Actemra, RoActemra 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. 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. 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. 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.
Experimental: RO7283420 Part B 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 of RO7283420 once Q3W starting on C1D1 up to Cycle 6 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). If needed, a step-up dosing regimen with more frequent administrations of RO7283420 during cycle 1 will be evaluated.	Drug: RO7283420 RO7283420 will be administered to participants by intravenous (IV) infusion or subcutaneous (SC) injection Q3W at a starting dose of 0.15mg. 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. Other Names: Actemra, RoActemra 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. 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. 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. 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.
Experimental: RO7283420 Part C Participants will receive the respective RP2D for Group I and Group II.	Drug: RO7283420 RO7283420 at RP2D will be administered by IV infusion or SC injection as per dosing schedule determined in Part B. 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. Other Names: Actemra, RoActemra 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. 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. 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. 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.

Arm

Intervention/Treatment

Experimental: RO7283420 Part A

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

RO7283420 will be administered to participants by intravenous (IV) infusion or subcutaneous (SC) injection Q3W at a starting dose of 0.15mg.

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.

Other Names:

Actemra, RoActemra

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.

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.

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.

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.

Experimental: RO7283420 Part B

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 of RO7283420 once Q3W starting on C1D1 up to Cycle 6 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). If needed, a step-up dosing regimen with more frequent administrations of RO7283420 during cycle 1 will be evaluated.

Drug: RO7283420

RO7283420 will be administered to participants by intravenous (IV) infusion or subcutaneous (SC) injection Q3W at a starting dose of 0.15mg.

Drug: Tocilizumab

Other Names:

Actemra, RoActemra

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.

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.

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.

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.

Experimental: RO7283420 Part C

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

Drug: RO7283420

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

Drug: Tocilizumab

Other Names:

Actemra, RoActemra

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.

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.

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.

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.

Outcome Measures

Primary Outcome Measures

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]

Secondary Outcome Measures

Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow [From baseline up to 7 months]
Percentage of Participants with >= 50% Reduction from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow [From baseline up to 7 months]
Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment [From baseline up to 7 months]
Area Under the Curve (AUC) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
Maximum Concentration (Cmax) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
Minimum Concentration (Cmin) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
Clearance (Cl) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
Volume (V) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
Half-life (T1/2) of RO7283420 [Day 1, 2, 3, 8, 15 of Cycle 1 (each cycle is 21 days); Day 1 of Cycle 2-9, at end of treatment visit (28 days after the last dose of RO7283420)]
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, at end of treatment visit (28 days after the last dose of RO7283420)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
3	Washington University; Wash Uni. Sch. Of Med	Saint Louis	Missouri	United States	63110
4	Peter MacCallum Cancer Centre; Medical Oncology	Melbourne	Victoria	Australia	3000
5	The Alfred	Melbourne	Victoria	Australia	3124
6	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 1Z5
7	Rigshospitalet; Hæmatologisk Klinik, Klinisk Afprøvnings Team KAT	København Ø		Denmark	2100
8	Institut Paoli Calmettes; Departement D' Onco-Hematologie	Marseille		France	13273
9	Hopital De Haut Leveque; Hematologie Clinique	Pessac		France	33604
10	Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I	Dresden		Germany	01307
11	Klinikum der Universität München, Campus Großhadern; Medizinische Klinik und Poliklinik III	München		Germany	81377
12	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia	Italy	24127
13	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia	Italy	20089
14	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana	Italy	56100
15	Institut Catala d´Oncologia Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
16	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
17	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona		Spain	08036
18	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid		Spain	28041
19	Hospital Universitario la Fe; Servicio de Hematologia	Valencia		Spain	46026
20	China Medical University Hospital; Oncology and Hematology	Taichung		Taiwan	404
21	National Cheng Kung University Hospital; Oncology	Tainan		Taiwan	00704
22	National Taiwan Universtiy Hospital; Division of Hematology	Taipei		Taiwan	100
23	Churchill Hospital	Oxford		United Kingdom	OX3 7LJ
24	Royal Marsden NHS Foundation Trust	Sutton		United Kingdom	SM2 5PT