A Study of the Safety and Pharmacokinetics of RO6839921, An MDM2 Antagonist, in Patients With Advanced Cancers, Including Acute Myeloid Leukemia.

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Neoplasms, Myelogenous Leukemia, Acute

Intervention / Treatment
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* Drug: RO6839921
* Drug: RO6839921
* Drug: RO6839921


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute myeloid leukemia patients<br> | Drug: RO6839921<br>* 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.<br>|
| Experimental: Cohort 0<br> | Drug: RO6839921<br>* Non-escalating IV doses given on Days 1-5 of Cycle 1.<br>|
| Experimental: Solid tumor patients<br> | Drug: RO6839921<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events |  | Approximately 1 year | 
| Incidence of dose-limiting toxicities |  | Approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma area under the concentration-time curve (AUC) of RO6839921. |  | Up to Day 22 | 
| Changes in serum macrophage inhibitory cytokine-1 (MIC-1) expression measured by enzyme-linked immunosorbent assay (ELISA) |  | Up to Day 22 |