Clinical trial NCT02098967: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms, Myelogenous Leukemia, Acute
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-03-28
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: Approximately 1 year
measure: Incidence of dose-limiting toxicities
timeFrame: Approximately 1 year
Secondary outcomes:
measure: Plasma area under the concentration-time curve (AUC) of RO6839921.
timeFrame: Up to Day 22
measure: Changes in serum macrophage inhibitory cytokine-1 (MIC-1) expression measured by enzyme-linked immunosorbent assay (ELISA)
timeFrame: Up to Day 22
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Charleston
country: United States
facility: Medical University of South Carolina; Hollings Cancer Center
state: South Carolina
city: Toronto
country: Canada
facility: University Health Network; Princess Margaret Hospital; Medical Oncology Dept
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital / McGill University
state: Quebec
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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.
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.