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A Study of RO5503781 as a Single Agent or in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia

Primary Purpose

Myelogenous Leukemia, Acute

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

RO5503781 MBP

RO5503781 SDP

Idarubicin

Daunorubicin

Cytarabine

About this trial

This is an interventional treatment trial for Myelogenous Leukemia, Acute

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Documented/confirmed acute myelogenous leukemia (AML), except for acute promyelocytic leukemia
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 in Part 1 and Part 2, participants enrolled in the extension/tail portion, Part 3 and Part 4 must have an ECOG performance status of 0 or 1
All non-hematological adverse events of any prior chemotherapy, surgery or radiotherapy must have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade less than or equal to (</=) 2 prior to starting therapy
Adequate hepatic and renal function
Willing to submit the blood sampling and bone marrow sampling required by protocol

Additional inclusion criteria for Parts 1-4 may apply.

Exclusion Criteria:

Participants receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 14 days of first receipt of study drug, with the exception of hydroxyurea as defined in protocol
History of allergic or toxic reactions attributed to cytarabine (Part 2) or history of allergic reactions to components of the formulated product
Current evidence of central nervous system (CNS) leukemia
Participants with severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
Participants with evidence of electrolyte imbalance greater than or equal to (>/=) Grade 2 which cannot be corrected prior to study initiation
Pregnant or breastfeeding women
Human immunodeficiency virus (HIV) - positive participants receiving anti-retroviral therapy
Participants who refuse to potentially receive blood products and/or have a hypersensitivity to blood products

Additional exclusion criteria for Parts 1-4 may apply.

Sites / Locations

USC Norris Cancer Center
New York Medical College
Thomas Jefferson University
Cancer Therapy & Research Ctr; Dept Institute for Drug Development
Peter Maccallum Cancer Centre
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
Institut J Paoli I Calmettes; Onco Hematologie 2
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh
Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology
Asan Medical Center
The Beatson West of Scotland Cancer Centre; Cancer Clinical Trials Unit

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Part 1: RO5503781

Part 2: RO5503781 + Cytarabine

Part3:RO5503781+Cytarabine+Anthracycline

Part 4: Optimized RO5503781 + Cytarabine

Arm Description

Participants will receive RO5503781 alone in escalating doses on Days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity.

Participants will receive RO5503781 in escalating doses on Days 1 to 5 and cytarabine on Days 1 to 6 of each 28-day cycle until disease progression or unacceptable toxicity.

Participants will receive RO5503781 on Days 1 to 5, cytarabine on Days 1 to 7, and anthracycline (daunorubicin or idarubicin) on Days 1 to 3 of each 28-day cycle until disease progression or unacceptable toxicity.

Participants will receive optimized RO5503781 formulation on Days 1 to 5 and cytarabine on Days 1 to 6 of each 28-day cycle until disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) and/ or Recommended Phase 2 Dose (RP2D) of RO5503781

Proportion of Participants with Dose-Limiting Toxicities (DLTs)

Safety: Proportion of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary Outcome Measures

Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) (in Micrograms per Milliliters [mcg/mL]) of RO5503781, Cytarabine,1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Timeframe for RO5503781: Predose (0 hour [Hr]), and 1, 2, 3, 4, 6, 10 Hr Postdose on Cy 1 Days 1, 5; Predose (0 Hr) on Cy 1 Day 2; Cy1 Day 6; Cy 1 Days 8, 9, 15 (Parts 1, 2, 4 only) (Cy length=28 days) Timeframe for cytarabine, 1-beta-D-arabinofuranosyluracil (cytarabine metabolite): Parts 2,4: Predose (0Hr), 1, 2, 3, 4, 6, 10 Hr Postdose on Cy1 Days 1, 5; Predose (0Hr) on Cy1 Day 2; Cy1 Day 6; Cy 1 Days 8, 9, 15; Part 3: Predose (0 Hr) on Cy1 Day 1; Predose (0 Hr), 1, 2, 3, 4, 6, 10 Hr Postdose on Cy1 Day 5; Cy1 Day 6 (Cy=28days) Timeframe for daunorubicin, daunorubicinol (daunorubicin metabolite), idarubicin, and idarubicinol (idarubicin metabolite): Part 3: Predose (0 Hr), and 1, 2, 3, 4, 6, 10 Hr Postdose on Cy 1 Days 1, 5; Predose (0 Hr) on Cy1 Day 2; Cy1 Day 6 (Cy length=28 days)

Pharmacokinetics: Time to Reach Maximum Plasma Concentrations (Tmax) in hours of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Terminal Half-Life (t1/2) (in hours) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Area Under Plasma Concentration-Time Curve Over One Dosing Internal (AUCtau) (in mcg*hour/mL) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Area Under Plasma Concentration-Time Curve From 0 to the Last Measurable Concentration (AUClast) (in mcg*hour/mL) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Area Under Plasma Concentration-Time Curve From 0 to Infinity (AUCinf) (in mcg*hour/mL) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Apparent Oral Clearance (CL/F) (in liters/hour) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Apparent Volume of Distribution (V/F) (in liters) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacokinetics: Apparent Elimination Rate Constant (kel) (in 1/hour) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Pharmacodynamics: Macrophage Inhibitory Cytokine-1 (MIC1) Serum Levels

Pharmacodynamics: Proportion of Participants With Tumor Suppressor Protein 53 (p53) Mutation, as Assessed by Gene Sequencing and/or Research-Use AmpliChip p53 Test

Pharmacodynamics: Murine Double Minute-2 (MDM2) Messenger Ribonucleic Acid (mRNA) Expression, as Assessed by Quantitative Real Time Polymerase Chain Reaction (RT-PCR)

Proportion of Participants With Complete Remission (CR) as best response during study and follow up period, as Assessed Using Bone Marrow and Hematological Examinations

Proportion of Participants With Complete Remission Without Platelet Recovery (CRp) as best response during study and follow up period as Assessed Using Bone Marrow and Hematological Examinations

Proportion of Participants With Complete Remission With Insufficient Recovery of Peripheral Counts (CRi) or Morphologic Leukemia Free State (MLFS) as Best Response During Study and Follow Up as Assessed Using Bone Marrow and Hematological Examinations

Proportion of Participants With Partial Response (PR) as Best Response During Study and Follow Up Period, as Assessed Using Bone Marrow and Hematological Examinations

Proportion of Participants With Hematologic Improvement (SD/HI) as Best Response During Study and Follow Up Period, as Assessed Using Bone Marrow and Hematological Examinations

Proportion of Participants With Disease Progression as Best Response During Study and Follow Up Period

Full Information

NCT ID

NCT01773408

First Posted

January 18, 2013

Last Updated

January 24, 2017

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT01773408

Brief Title

A Study of RO5503781 as a Single Agent or in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia

Official Title

A Multi-Center, Open-Label, Phase 1/1b Study of Escalating Doses of RO5503781 Administered Orally as 1) a Single Agent, 2) In Combination With Cytarabine, or 3) With Cytarabine and Anthracycline and 4) Assessing PK and Safety of New Optimized Formulation of RO5503781 With Cytarabine in Patients With Acute Myelogenous Leukemia (AML)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2017

Overall Recruitment Status

Completed

Study Start Date

February 2013 (undefined)

Primary Completion Date

June 2016 (Actual)

Study Completion Date

June 2016 (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 Phase 1/1b, open-label study will evaluate the safety and pharmacokinetics of escalating doses of RO5503781 as a single agent or in combination with cytarabine in participants with acute myelogenous leukemia. In Part 1, RO5503781 will be administered in escalating doses as a single agent, and in Part 2, RO5503781 will be administered in combination with cytarabine. An optional Part 3 in which RO5503781 will be administered with cytarabine and anthracycline may be considered . In Part 4, the safety and pharmacokinetic profile of an optimized formulation of RO5503781 in combination with cytarabine will be assessed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

122 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: RO5503781

Arm Type

Experimental

Arm Description

Participants will receive RO5503781 alone in escalating doses on Days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity.

Arm Title

Part 2: RO5503781 + Cytarabine

Arm Type

Experimental

Arm Description

Participants will receive RO5503781 in escalating doses on Days 1 to 5 and cytarabine on Days 1 to 6 of each 28-day cycle until disease progression or unacceptable toxicity.

Arm Title

Part3:RO5503781+Cytarabine+Anthracycline

Arm Type

Experimental

Arm Description

Arm Title

Part 4: Optimized RO5503781 + Cytarabine

Arm Type

Experimental

Arm Description

Participants will receive optimized RO5503781 formulation on Days 1 to 5 and cytarabine on Days 1 to 6 of each 28-day cycle until disease progression or unacceptable toxicity.

Intervention Type

Drug

Intervention Name(s)

RO5503781 MBP

Intervention Description

Participants will receive RO5503781 tablets daily (current formulation) containing microprecipitated bulk powder (MBP) at a starting dose of 400 milligrams (mg).

Intervention Type

Drug

Intervention Name(s)

RO5503781 SDP

Intervention Description

Participants will receive RO5503781 tablets daily (new optimized formulation) containing spray-dried powder (SDP) at recommended dose(s) for development from Phase 1b to Phase 3.

Intervention Type

Drug

Intervention Name(s)

Idarubicin

Intervention Description

Idarubicin will be administered as per standard clinical practice.

Intervention Type

Drug

Intervention Name(s)

Daunorubicin

Intervention Description

Daunorubicin will be administered as per standard clinical practice.

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Intervention Description

Parts 2 and 4: Participants will receive cytarabine 1000 milligrams per meter squared (mg/m^2) intravenous (IV) infusion daily. Part 3: Participants will receive cytarabine 100-200 mg/m^2 IV infusion daily.

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) and/ or Recommended Phase 2 Dose (RP2D) of RO5503781

Time Frame

Day 1 up to Day 42

Title

Proportion of Participants with Dose-Limiting Toxicities (DLTs)

Time Frame

Day 1 up to Day 42

Title

Safety: Proportion of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame

Baseline up to approximately 2 years

Secondary Outcome Measure Information:

Title

Description

Time Frame

Predose (0 Hr) on Cycle (Cy) 1 Day 1 up to Cy 1 Day 15 (Cy length=28 days) (detailed timeframe for individual drug is provided in outcome measure description)

Title

Pharmacokinetics: Time to Reach Maximum Plasma Concentrations (Tmax) in hours of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Description

Time Frame

Predose (0 Hr) on Cy1 Day 1 up to Cy 1 Day 15 (Cy length=28 days) (detailed timeframe for individual drug is provided in outcome measure description).

Title

Pharmacokinetics: Terminal Half-Life (t1/2) (in hours) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol

Description

Time Frame