Myelogenous Leukemia, AcutePhase 1NCT01773408
A Study of RO5503781 as a Single Agent or in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia
A Phase 1 study testing RO5503781 MBP, RO5503781 SDP and Idarubicin in people with Myelogenous Leukemia, Acute, run by Hoffmann-La Roche at 12 sites in 7 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelogenous Leukemia, Acute
- What is being tested?
- RO5503781 MBP, RO5503781 SDP and Idarubicin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 122 participants
- Where
- 12 sitesin 7 countries
- Study dates
- Feb 2013to Jun 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
12 sites in 7 countries.
12 sites in 7 countries
United States4 sites
USC Norris Cancer Center
Los Angeles, California, 90033
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
Cancer Therapy & Research Ctr; Dept Institute for Drug Development
San Antonio, Texas, 78229
New York Medical College
Valhalla, New York, 10595
Canada2 sites
McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
Montreal, Quebec, H3T 1E2
University Health Network; Princess Margaret Hospital; Medical Oncology Dept
Toronto, Ontario, M5G 2M9
South Korea2 sites
Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology
Seoul, 03080
Asan Medical Center
Seoul, 05505
Italy1 site
Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpigh
Bologna, Emilia-Romagna, 40138
United Kingdom1 site
The Beatson West of Scotland Cancer Centre; Cancer Clinical Trials Unit
Glasgow, G12 0YN
About this study
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)
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.
- Conditions
- Myelogenous Leukemia, Acute
- Being tested
- RO5503781 MBP, RO5503781 SDP, Idarubicin, Daunorubicin, Cytarabine
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RO5503781 MBPDrug
Participants will receive RO5503781 tablets daily (current formulation) containing microprecipitated bulk powder (MBP) at a starting dose of 400 milligrams (mg).
RO5503781 SDPDrug
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.
IdarubicinDrug
Idarubicin will be administered as per standard clinical practice.
DaunorubicinDrug
Daunorubicin will be administered as per standard clinical practice.
CytarabineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Part 1: RO5503781 | Experimental | Participants will receive RO5503781 alone in escalating doses on Days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity. Receives: Drug: RO5503781 MBP |
| Part 2: RO5503781 + Cytarabine | Experimental | 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. Receives: Drug: RO5503781 MBP; Drug: Cytarabine |
| Part3:RO5503781+Cytarabine+Anthracycline | Experimental | 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. Receives: Drug: RO5503781 MBP; Drug: Idarubicin; Drug: Daunorubicin; Drug: Cytarabine |
| Part 4: Optimized RO5503781 + Cytarabine | Experimental | 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. Receives: Drug: RO5503781 SDP; Drug: Cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) and/ or Recommended Phase 2 Dose (RP2D) of RO5503781
Measured: Day 1 up to Day 42
Proportion of Participants with Dose-Limiting Toxicities (DLTs)
Measured: Day 1 up to Day 42
Safety: Proportion of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Measured: Baseline up to approximately 2 years
Secondary outcomes (18)
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)
Measured: 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)
Pharmacokinetics: Time to Reach Maximum Plasma Concentrations (Tmax) in hours 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)
Measured: 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).
Pharmacokinetics: Terminal Half-Life (t1/2) (in hours) 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)
Measured: 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)
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
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)
Measured: 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)
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
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)
Measured: 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)
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
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)
Measured: 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)
Pharmacokinetics: Apparent Oral Clearance (CL/F) (in liters/hour) 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)
Measured: 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)
Pharmacokinetics: Apparent Volume of Distribution (V/F) (in liters) 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)
Measured: Predose (0 Hr) on 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)
Pharmacokinetics: Apparent Elimination Rate Constant (kel) (in 1/hour) 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)
Measured: Predose (0 Hr) on 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)
Pharmacodynamics: Macrophage Inhibitory Cytokine-1 (MIC1) Serum Levels
Measured: 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 1 Days 8, 9, 15 (Parts 1, 2, 4 only) (Cy length=28 days)
Pharmacodynamics: Proportion of Participants With Tumor Suppressor Protein 53 (p53) Mutation, as Assessed by Gene Sequencing and/or Research-Use AmpliChip p53 Test
Measured: Predose (0 Hr), and 6 Hr postdose on Cy 1 Days 1, 5; predose (0 Hr) on Cy 1 Day 2; Cy 1 Day 6; at disease progression/relapse (up to approximately 3.25 years)
Pharmacodynamics: Murine Double Minute-2 (MDM2) Messenger Ribonucleic Acid (mRNA) Expression, as Assessed by Quantitative Real Time Polymerase Chain Reaction (RT-PCR)
Measured: Predose (0 Hr), and 6 Hr postdose on Cy 1 Days 1, 5; predose (0 Hr) on Cy 1 Day 2; Cy 1 Day 6; at disease progression/relapse (up to approximately 3.25 years)
Proportion of Participants With Complete Remission (CR) as best response during study and follow up period, as Assessed Using Bone Marrow and Hematological Examinations
Measured: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CR from occurrence of CR to 1 year (overall up to approximately 3.25 years)
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
Measured: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CRp from occurrence of CRp to 1 year (overall up to approximately 3.25 years)
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
Measured: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CRi from occurrence of CRi to 1 year (overall up to approximately 3.25 years)
Proportion of Participants With Partial Response (PR) as Best Response During Study and Follow Up Period, as Assessed Using Bone Marrow and Hematological Examinations
Measured: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with PR from occurrence of PR to 1 year (overall up to approximately 3.25 years)
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
Measured: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2months for participants with SD/HI from occurrence of SD/HI to 1 year (overall up to approximately 3.25years)
Proportion of Participants With Disease Progression as Best Response During Study and Follow Up Period
Measured: Baseline up to approximately 3.25 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2013 (estimated)
- Study startFeb 2013
- Primary completionJun 2016
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Myelogenous Leukemia, AcuteStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 122 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01773408
- Sponsor's protocol ID
- NP28679
- Other IDs
- 2012-004882-41
- Status last verified
- Jan 2017
- First submitted
- 18 Jan 2013
- Last updated
- 25 Jan 2017
- Results posted
- No
Publications
Yee K, Papayannidis C, Vey N, Dickinson MJ, Kelly KR, Assouline S, Kasner M, Seiter K, Drummond MW, Yoon SS, Lee JH, Blotner S, Jukofsky L, Pierceall WE, Zhi J, Simon S, Higgins B, Nichols G, Monnet A, Muehlbauer S, Ott M, Chen LC, Martinelli G. Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study small star, filled. Leuk Res. 2021 Jan;100:106489. doi: 10.1016/j.leukres.2020.106489. Epub 2020 Dec 1.
PubMed 33302031
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT01773408
- Acronym / sponsor ID
- NP28679
- Conditions
- Myelogenous Leukemia, Acute
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 122 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Study start
- Feb 2013
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 23 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Part 1: RO5503781 | Experimental | Drug: RO5503781 MBPParticipants will receive RO5503781 alone in escalating doses on Days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity. |
| Part 2: RO5503781 + Cytarabine | Experimental | Drug: RO5503781 MBP, Drug: CytarabineParticipants 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. |
| Part3:RO5503781+Cytarabine+Anthracycline | Experimental | Drug: RO5503781 MBP, Drug: Idarubicin, Drug: Daunorubicin, Drug: CytarabineParticipants 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. |
| Part 4: Optimized RO5503781 + Cytarabine | Experimental | Drug: RO5503781 SDP, Drug: CytarabineParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RO5503781 MBPParticipants will receive RO5503781 tablets daily (current formulation) containing microprecipitated bulk powder (MBP) at a starting dose of 400 milligrams (mg). | Drug | Part 1: RO5503781, Part 2: RO5503781 + Cytarabine, Part3:RO5503781+Cytarabine+Anthracycline |
| RO5503781 SDPParticipants 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. | Drug | Part 4: Optimized RO5503781 + Cytarabine |
| IdarubicinIdarubicin will be administered as per standard clinical practice. | Drug | Part3:RO5503781+Cytarabine+Anthracycline |
| DaunorubicinDaunorubicin will be administered as per standard clinical practice. | Drug | Part3:RO5503781+Cytarabine+Anthracycline |
| CytarabineParts 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. | Drug | Part 2: RO5503781 + Cytarabine, Part 4: Optimized RO5503781 + Cytarabine, Part3:RO5503781+Cytarabine+Anthracycline |
Primary outcome
Maximum Tolerated Dose (MTD) and/ or Recommended Phase 2 Dose (RP2D) of RO5503781
Time frame: Day 1 up to Day 42
Proportion of Participants with Dose-Limiting Toxicities (DLTs)
Time frame: Day 1 up to Day 42
Safety: Proportion of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to approximately 2 years
18 secondary outcomes
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) (in Micrograms per Milliliters [mcg/mL]) of RO5503781, Cytarabine,1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
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)
Pharmacokinetics: Time to Reach Maximum Plasma Concentrations (Tmax) in hours of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
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).
Pharmacokinetics: Terminal Half-Life (t1/2) (in hours) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
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)
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
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)
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
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)
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
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)
Pharmacokinetics: Apparent Oral Clearance (CL/F) (in liters/hour) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
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)
Pharmacokinetics: Apparent Volume of Distribution (V/F) (in liters) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
Time frame: Predose (0 Hr) on 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)
Pharmacokinetics: Apparent Elimination Rate Constant (kel) (in 1/hour) of RO5503781, Cytarabine, 1-beta-D-Arabinofuranosyluracil, Daunorubicin, Daunorubicinol, Idarubicin, and Idarubicinol
Time frame: Predose (0 Hr) on 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)
Pharmacodynamics: Macrophage Inhibitory Cytokine-1 (MIC1) Serum Levels
Time frame: 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 1 Days 8, 9, 15 (Parts 1, 2, 4 only) (Cy length=28 days)
Pharmacodynamics: Proportion of Participants With Tumor Suppressor Protein 53 (p53) Mutation, as Assessed by Gene Sequencing and/or Research-Use AmpliChip p53 Test
Time frame: Predose (0 Hr), and 6 Hr postdose on Cy 1 Days 1, 5; predose (0 Hr) on Cy 1 Day 2; Cy 1 Day 6; at disease progression/relapse (up to approximately 3.25 years)
Pharmacodynamics: Murine Double Minute-2 (MDM2) Messenger Ribonucleic Acid (mRNA) Expression, as Assessed by Quantitative Real Time Polymerase Chain Reaction (RT-PCR)
Time frame: Predose (0 Hr), and 6 Hr postdose on Cy 1 Days 1, 5; predose (0 Hr) on Cy 1 Day 2; Cy 1 Day 6; at disease progression/relapse (up to approximately 3.25 years)
Proportion of Participants With Complete Remission (CR) as best response during study and follow up period, as Assessed Using Bone Marrow and Hematological Examinations
Time frame: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CR from occurrence of CR to 1 year (overall up to approximately 3.25 years)
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
Time frame: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CRp from occurrence of CRp to 1 year (overall up to approximately 3.25 years)
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
Time frame: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with CRi from occurrence of CRi to 1 year (overall up to approximately 3.25 years)
Proportion of Participants With Partial Response (PR) as Best Response During Study and Follow Up Period, as Assessed Using Bone Marrow and Hematological Examinations
Time frame: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2 months for participants with PR from occurrence of PR to 1 year (overall up to approximately 3.25 years)
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
Time frame: Day 1 of each treatment cycle starting from Cy 2 up to 28 days after last dose of RO5503781 (approximately 3.25 years); additionally, every 2months for participants with SD/HI from occurrence of SD/HI to 1 year (overall up to approximately 3.25years)
Proportion of Participants With Disease Progression as Best Response During Study and Follow Up Period
Time frame: Baseline up to approximately 3.25 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2017.
- Derived from this study: PubMed 33302031Yee K, Papayannidis C, Vey N, Dickinson MJ, Kelly KR, Assouline S, Kasner M, Seiter K, Drummond MW, Yoon SS, Lee JH, Blotner S, Jukofsky L, Pierceall WE, Zhi J, Simon S, Higgins B, Nichols G, Monnet A, Muehlbauer S, Ott M, Chen LC, Martinelli G. Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study small star, filled. Leuk Res. 2021 Jan;100:106489. doi: 10.1016/j.leukres.2020.106489. Epub 2020 Dec 1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trials study director
Hoffmann-La Roche
12 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing RO5503781 MBP, RO5503781 SDP and Idarubicin in people with Myelogenous Leukemia, Acute, run by Hoffmann-La Roche at 12 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States, Canada, South Korea, Australia, France and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) and/ or Recommended Phase 2 Dose (RP2D) of RO5503781 (time frame: Day 1 up to Day 42). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01773408, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2017.