Clinical trial NCT01462175: A First-In-Human Study of RO5503781 in Participants With Advanced Malignancies Except Leukemia
Official title: A Multi-center, Open Label, First in Human Phase I Dose Escalation Study of Single Agent RO5503781, a Small Molecule MDM2 Antagonist, Administered Orally in Patients With Advanced Malignancies, Except Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-10-31
Enrollment: 99
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 multicenter, open label, dose-escalating study will evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RO5503781, administered once daily (QD) or once weekly (QW) in participants with advanced malignancies except leukemia. Participants will receive multiple escalating oral doses in two different dosing schedules (Sch) until disease progression or unacceptable toxicity occurs.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed advanced malignancies, except all forms of leukemia, for which standard curative or palliative measures do not exist, are no longer effective, or are not acceptable to the participants
* Measurable disease (according to RECIST or Cheson criteria) or evaluable disease prior to administration of study drug
* Minimum weight of 35 kg and life expectancy of greater than or equal to (\>=) 12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Acute toxicities from any prior anti-tumor therapy, surgery, or radiotherapy must have resolved to NCT-CTCAE Grade less than or equal to (\<=) 1
* Adequate renal, hepatic and bone marrow function
* Participants with stable Central Nervous System (CNS) metastasis and with chronic, stable and rate controlled atrial fibrillation
* Participants in consideration for the biomarker cohorts or apoptosis imaging cohort must consent and be able to undergo paired biopsies for tumor biomarker analyses
* Able to participate and willing to give written informed consent and to comply with the study restrictions

Exclusion Criteria:

* History of any form of leukemia except for Stage 0 and 1 chronic lymphocytic leukemia (CLL) not requiring treatment in addition to the underlying solid tumor
* Use of hormonal therapy within 2 weeks and use of other investigational agents or having received investigational drugs \<= 4 weeks prior to study treatment start
* History of seizure disorders or unstable CNS metastases
* Severe and/or uncontrolled cardiovascular disease or disorder
* Active (acute or chronic) or uncontrolled infection
* Pregnant or breastfeeding women
* HIV-positive participants who are currently receiving anti-retroviral treatment
* Known coagulopathy, platelet disorder or history of non-drug induced thrombocytopenia
* Participants receiving oral or parenteral anticoagulants/antiplatelet agents; anticoagulant flushes for maintenance of indwelling catheters are allowed
* Participants with known bone marrow disorder which may interfere with bone marrow recovery
* Participants with hypersensitivity reaction to 18Fluorothymidine (FLT or 18F) compounds

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: up to 28 days
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: up to 28 days
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: approximately 1.5 years
Secondary outcomes:
measure: Plasma Concentration of RO5503781
timeFrame: Sch A: pre-dose (PrD; 0 hour), 1, 2, 3, 4, 6, 8, 12 hours post-dose (PoD) on Day 1, 15; PrD (0 hour) on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Urine Concentration of RO5503781
timeFrame: Schedule A and B: Pre-dose, 0-4, 4-8, 8-12, 12-24 hours post-dose on Day 1, Day 2
measure: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Standardized Uptake Value (SUV) obtained from the Positron Emission Tomography With 18-Fluorothymidine [(18F)-FLT-PET) Images
timeFrame: Baseline, Cycle1 Day 5, Cycle 3 Day 1
measure: Pharmacodynamics: p21 Levels in Tumor as Measured by Immunohistochemistry
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Tumor suppressor gene (p53) Levels in Tumor as Measured by Immunohistochemistry
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Murine Double Minute 2 (MDM2) Levels in Tumor as Mesured by Reverse transcription polymerase chain reaction (RT-PCR)
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Ki-67 Levels in Tumor as Measured by Immunohistochemistry
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Levels in Tumor as Measured by Immunohistochemistry
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Progression Free Survival (PFS) According to Cheson Criteria
timeFrame: andomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: p53 Mutation Status in Tumor as Measured by AmpliChip p53 Test
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Mouse Double Minute 2 Homolog (MDM2) Gene Copy Number in Tumor as Measured by in situ Hybridization
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
timeFrame: PrD (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours PoD on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Area Under the Curve from Time Zero to end of dosing interval (AUCtau)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Area Under the Curve From Time Zero to Extrapolated 168 hours [AUC(0-168)]
timeFrame: Prd (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Maximum Observed Plasma Concentration (Cmax)
timeFrame: PrD (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: PrD (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Plasma Decay Half-Life (t1/2)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Plasma Decay Half-Life (t1/2)
timeFrame: PrD (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Terminal Elimination Rate Constant (Kel)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Food-Effect: Terminal Elimination Rate Constant (Kel)
timeFrame: PrD (0 hour), 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1, 8, 15; on Day 2, 3, 4/5, 6/7, 9, 10, 11/12, 13/14, 16, 17, 18/19, 20/21, 22
measure: Apparent Oral Clearance (CL/F)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Apparent Volume of Distribution (Vz/F)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
measure: Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Cheson Criteria
timeFrame: Randomization until progressive disease or death (assessed at baseline and every 8 weeks thereafter until progressive disease, death or end of study [up to approximately 1.5 years])
measure: Pharmacodynamics: Macrophage Inhibitory Cytokine 1 (MIC-1) Levels in Blood as Measured by Enzyme-linked Immunosorbent Assay (ELISA)
timeFrame: Sch A: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 15; PrD on Day 8; on Day 2, 3, 4/5, 6/7, 16, 17, 18/19, 20/21, 22; Sch B: PrD (0 hour), 1, 2, 3, 4, 6, 8, 12 hours PoD on Day 1, 5; Day 6, 7, 8/9, 10/11, 12
Other outcomes:
Locations:
city: Melbourne
country: Australia
state: Victoria
city: Hamilton
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Bordeaux
country: France
city: Lyon
country: France
city: Seoul
country: Korea, Republic of
city: Groningen
country: Netherlands
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Italiano A, Miller WH Jr, Blay JY, Gietema JA, Bang YJ, Mileshkin LR, Hirte HW, Higgins B, Blotner S, Nichols GL, Chen LC, Petry C, Yang QJ, Schmitt C, Jamois C, Siu LL. Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors. Invest New Drugs. 2021 Dec;39(6):1587-1597. doi: 10.1007/s10637-021-01141-2. Epub 2021 Jun 28.