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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04580121
Recruitment Status : Recruiting
First Posted : October 8, 2020
Last Update Posted : October 8, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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: Tocilizumab Drug: Dasatinib 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) 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, at the discretion of the Investigator (based on the assessment of clinical benefit), the participant could receive up to 3 additional treatment cycles.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : November 18, 2020
Estimated Primary Completion Date : October 1, 2024
Estimated Study Completion Date : October 1, 2024


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 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 Name: 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.

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).
Drug: RO7283420
RO7283420 will be administered to participants by intravenous (IV) infusion 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 Name: 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.

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 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 Name: 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.




Primary Outcome Measures :
  1. Percentage of Participants with Adverse Events (AEs) [ Time Frame: From baseline up to 9 months ]
  2. Percentage of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: From baseline up to 28 days ]

Secondary Outcome Measures :
  1. Maximum Reduction (%) from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow [ Time Frame: From baseline up to 7 months ]
  2. Percentage of Participants with >= 50% Reduction from Baseline in Blast Count in Peripheral Blood and/or Bone Marrow [ Time Frame: From baseline up to 7 months ]
  3. Number of MRD (Measurable Residual Disease) Negative Participants over time According to Local MRD Assessment [ Time Frame: From baseline up to 7 months ]
  4. Area Under the Curve (AUC) of RO7283420 [ Time Frame: 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) ]
  5. Maximum Concentration (Cmax) of RO7283420 [ Time Frame: 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) ]
  6. Minimum Concentration (Cmin) of RO7283420 [ Time Frame: 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) ]
  7. Clearance (Cl) of RO7283420 [ Time Frame: 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) ]
  8. Volume (V) of RO7283420 [ Time Frame: 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) ]
  9. Half-life (T1/2) of RO7283420 [ Time Frame: 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) ]
  10. Incidence and Titer of Anti-drug Antibodies (ADA) against RO7283420 [ Time Frame: 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 and Group II) will be included.
  • Participants who have received hematopoietic stem cell transplant (HSCT) must have the HSCT performed ≥ 28 days prior to screening, having demonstrated hematological engraftment and do not have an active Graft versus Host disease
  • 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 and 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)
  • Glomerular proteinuria (Grade >= 2) with presence of transferrin and/or IgG in the urine
  • Another primary malignancy (other than AML) that requires active therapy. Adjuvant hormonal therapy is allowed
  • History of autoimmune disease
  • Clinical evidence or history of central nervous system (CNS) leukemia
  • Presence of isolated 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04580121


Contacts
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Contact: Reference Study ID Number: WP42004 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
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Australia, Victoria
Peter MacCallum Cancer Centre; Medical Oncology Not yet recruiting
Melbourne, Victoria, Australia, 3000
The Alfred Not yet recruiting
Melbourne, Victoria, Australia, 3124
Denmark
Rigshospitalet; Hæmatologisk Klinik Not yet recruiting
København Ø, Denmark, 2100
Italy
ASST PAPA GIOVANNI XXIII; Ematologia Not yet recruiting
Bergamo, Lombardia, Italy, 24127
Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia Not yet recruiting
Rozzano, Lombardia, Italy, 20089
Ospedale Santa Chiara; Unita Operativa Di Ematologia Not yet recruiting
Pisa, Toscana, Italy, 56100
Spain
Institut Catala d´Oncologia Hospital Germans Trias i Pujol Not yet recruiting
Badalona, Barcelona, Spain, 08916
Hospital Universitari Vall d'Hebron; Servicio de Hematologia Not yet recruiting
Barcelona, Spain, 08035
Hospital Clínic i Provincial; Servicio de Hematología y Oncología Recruiting
Barcelona, Spain, 08036
Hospital Univ. 12 de Octubre; Servicio de Hematologia Not yet recruiting
Madrid, Spain, 28041
Hospital Universitario la Fe; Servicio de Hematologia Not yet recruiting
Valencia, Spain, 46026
Taiwan
China Medical University Hospital; Oncology and Hematology Not yet recruiting
Taichung, Taiwan, 404
National Cheng Kung University Hospital; Oncology Not yet recruiting
Tainan, Taiwan, 00704
National Taiwan Universtiy Hospital; Division of Hematology Not yet recruiting
Taipei, Taiwan, 100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04580121    
Other Study ID Numbers: WP42004
2020-000216-30 ( EudraCT Number )
First Posted: October 8, 2020    Key Record Dates
Last Update Posted: October 8, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Dasatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action