Back to resultsA Study of the Safety and Pharmacokinetics of RO6839921, An MDM2 Antagonist, in Patients With Advanced Cancers, Including Acute Myeloid Leukemia.
Primary Purpose
Neoplasms, Myelogenous Leukemia, Acute
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
RO6839921
RO6839921
RO6839921
Sponsored by
About this trial
This is an interventional treatment trial for Neoplasms, Myelogenous Leukemia, Acute
Eligibility Criteria
Inclusion Criteria:
Cohort 0 and Arm A
- Patient must have histologically or cytologically confirmed advanced cancer for which standard cures or relieving measures either do not exist, are ineffective or are not acceptable to the patient.
- Measureable disease according to RECIST criteria version 1.1.
- ECOG performance status of 0 to 1.
- Adequate bone marrow function.
Arm B
- Patients with documented acute myeloid leukemia (AML), except for acute promyelocytic leukemia.
- Patients with relapsed/refractory AML or patients who have not received prior therapy who are high risk according to European LeukemiaNet (ELN) criteria.
- ECOG performance status of 0 to 2.
For Cohort 0, Arms A and B
- Life expectancy of >/= 12 weeks.
- Age >/= 18 years or older.
- All patients must be willing to use effective methods of contraception until 10 days after the last dose; women must not be pregnant or breast-feeding.
- Adequate renal and hepatic function.
- Patients with stable central nervous system (CNS) tumors are eligible.
- There are no requirements or limitations on the amount or type of prior anti-tumor/anti-leukemia therapy.
Exclusion Criteria:
Cohort 0 and Arm A
- Patients with a history of any form of leukemia except for Stage 0 and 1 chronic lymphocytic leukemia (CLL) not requiring treatment.
- Patients receiving any cancer treatment within 21 days of start of study medication. Patients must also have recovered from severe side effects due to prior treatment before study start.
- Patients with known bone marrow disorders that may interfere with bone marrow recovery, or patients with delayed recovery from prior chemoradiotherapy.
- Patients with known bleeding or clotting disorders or non-drug-induced low platelet count.
Arm B
- Patients receiving any cancer treatment within 14 days of start of study medication. Hydroxyurea may be taken until first administration of the study drug. Patients must also have recovered from severe side effects due to prior treatment before study start.
For Cohort 0, Arms A and B
- Patients receiving any other test drugs within 30 days of start of study medication
- Patients receiving the cytochrome P450 inhibitors, substrates or inducers specified in the protocol.
- Anticoagulation or antiplatelet treatment must be discontinued 7 days prior to start of study medication.
- Patients who have received hormonal therapy (except for prostate cancer treatment and hormone replacement therapy) within the 2 weeks prior to start of study medication.
- Patients with evidence of electrolyte imbalance, which may be treated to meet eligibility.
- Serum albumin < 2.8 g/dL.
- HIV-positive patients who are currently receiving combination antiretroviral therapy.
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.
Sites / Locations
- University of Colorado
- Washington University
- Medical University of South Carolina; Hollings Cancer Center
- University Health Network; Princess Margaret Hospital; Medical Oncology Dept
- Jewish General Hospital / McGill University
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Acute myeloid leukemia patients
Cohort 0
Solid tumor patients
Arm Description
Outcomes
Primary Outcome Measures
Incidence of adverse events
Incidence of dose-limiting toxicities
Secondary Outcome Measures
Plasma area under the concentration-time curve (AUC) of RO6839921.
Changes in serum macrophage inhibitory cytokine-1 (MIC-1) expression measured by enzyme-linked immunosorbent assay (ELISA)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02098967
Brief Title
A Study of the Safety and Pharmacokinetics of RO6839921, An MDM2 Antagonist, in Patients With Advanced Cancers, Including Acute Myeloid Leukemia.
Official Title
A Multi-Center, Open-Label, First-in-Human, Phase I Dose-Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO6839921, An MDM2 Antagonist, Following Intravenous Administration in Patients With Advanced Malignancies, Including Acute Myeloid Leukemia (AML)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
April 21, 2014 (Actual)
Primary Completion Date
May 7, 2018 (Actual)
Study Completion Date
May 7, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
This open label, Phase I study of RO6839921 is a dose-escalation study with two arms. Prior to investigations in either arm, patients in a single cohort, Cohort 0, will receive non-escalating, intravenous (IV) doses of RO6839921 daily on Days 1-5 of a 28-day cycle. Interim PK and safety data from this cohort will be evaluated before initiating dose-escalation.
In arm A, RO6839921 will be given to patients with advanced solid tumor malignancies. In Arm B, RO6839921 will be given to patients with relapsed/refractory acute myeloid leukemia (AML). The arms will escalate independently. Escalation will begin in solid tumor patients (Arm A) in single patient cohorts, using a new Continual Reassessment Method (n-CRM). Escalation for AML patients will be initiated at or below the dose level that causes >/= Grade 2 hematologic side effects in Arm A. Escalation in AML patients will follow a rolling 6 design.
In both arms, RO6839921 will be administered by IV infusion on Days 1-5 of 28-day cycles.
There will be no intrapatient dose escalation. All patients may be treated until disease progression/relapse or unacceptable toxicity.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplasms, Myelogenous Leukemia, Acute
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
68 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Acute myeloid leukemia patients
Arm Type
Experimental
Arm Title
Cohort 0
Arm Type
Experimental
Arm Title
Solid tumor patients
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
RO6839921
Intervention Description
Non-escalating IV doses given on Days 1-5 of Cycle 1.
Intervention Type
Drug
Intervention Name(s)
RO6839921
Intervention Description
Escalating IV doses of RO6839921 in solid tumor patients. Dose escalation will be calculated using the new Continual Reassessment Method (nCRM). RO6839921 will be given on Days 1-5 of 28-day cycles. Treatment will continue until disease progression, unacceptable toxicity or study discontinuation.
Intervention Type
Drug
Intervention Name(s)
RO6839921
Intervention Description
Escalating IV doses of RO6839921 in AML patients. Escalation will follow an adapted rolling 6 design. Starting dose </= dose inducing Grade 2 toxicity in patients with solid tumors. RO6839921 will be given on Days 1-5 of 28-day cycles. Treatment will continue until disease progression, unacceptable toxicity or study discontinuation.
Primary Outcome Measure Information:
Title
Incidence of adverse events
Time Frame
Approximately 1 year
Title
Incidence of dose-limiting toxicities
Time Frame
Approximately 1 year
Secondary Outcome Measure Information:
Title
Plasma area under the concentration-time curve (AUC) of RO6839921.
Time Frame
Up to Day 22
Title
Changes in serum macrophage inhibitory cytokine-1 (MIC-1) expression measured by enzyme-linked immunosorbent assay (ELISA)
Time Frame
Up to Day 22
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Cohort 0 and Arm A
Patient must have histologically or cytologically confirmed advanced cancer for which standard cures or relieving measures either do not exist, are ineffective or are not acceptable to the patient.
Measureable disease according to RECIST criteria version 1.1.
ECOG performance status of 0 to 1.
Adequate bone marrow function.
Arm B
Patients with documented acute myeloid leukemia (AML), except for acute promyelocytic leukemia.
Patients with relapsed/refractory AML or patients who have not received prior therapy who are high risk according to European LeukemiaNet (ELN) criteria.
ECOG performance status of 0 to 2.
For Cohort 0, Arms A and B
Life expectancy of >/= 12 weeks.
Age >/= 18 years or older.
All patients must be willing to use effective methods of contraception until 10 days after the last dose; women must not be pregnant or breast-feeding.
Adequate renal and hepatic function.
Patients with stable central nervous system (CNS) tumors are eligible.
There are no requirements or limitations on the amount or type of prior anti-tumor/anti-leukemia therapy.
Exclusion Criteria:
Cohort 0 and Arm A
Patients with a history of any form of leukemia except for Stage 0 and 1 chronic lymphocytic leukemia (CLL) not requiring treatment.
Patients receiving any cancer treatment within 21 days of start of study medication. Patients must also have recovered from severe side effects due to prior treatment before study start.
Patients with known bone marrow disorders that may interfere with bone marrow recovery, or patients with delayed recovery from prior chemoradiotherapy.
Patients with known bleeding or clotting disorders or non-drug-induced low platelet count.
Arm B
- Patients receiving any cancer treatment within 14 days of start of study medication. Hydroxyurea may be taken until first administration of the study drug. Patients must also have recovered from severe side effects due to prior treatment before study start.
For Cohort 0, Arms A and B
Patients receiving any other test drugs within 30 days of start of study medication
Patients receiving the cytochrome P450 inhibitors, substrates or inducers specified in the protocol.
Anticoagulation or antiplatelet treatment must be discontinued 7 days prior to start of study medication.
Patients who have received hormonal therapy (except for prostate cancer treatment and hormone replacement therapy) within the 2 weeks prior to start of study medication.
Patients with evidence of electrolyte imbalance, which may be treated to meet eligibility.
Serum albumin < 2.8 g/dL.
HIV-positive patients who are currently receiving combination antiretroviral therapy.
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
University of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Medical University of South Carolina; Hollings Cancer Center
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Jewish General Hospital / McGill University
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
32020437
Citation
Uy GL, Assouline S, Young AM, Blotner S, Higgins B, Chen LC, Yee K. Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia. Invest New Drugs. 2020 Oct;38(5):1430-1441. doi: 10.1007/s10637-020-00907-4. Epub 2020 Feb 4.
Results Reference
derived
PubMed Identifier
31734832
Citation
Abdul Razak AR, Miller WH Jr, Uy GL, Blotner S, Young AM, Higgins B, Chen LC, Gore L. A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors. Invest New Drugs. 2020 Aug;38(4):1156-1165. doi: 10.1007/s10637-019-00869-2. Epub 2019 Nov 16.
Results Reference
derived
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A Study of the Safety and Pharmacokinetics of RO6839921, An MDM2 Antagonist, in Patients With Advanced Cancers, Including Acute Myeloid Leukemia.
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