Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01462175




Registration number
NCT01462175
Ethics application status
Date submitted
27/10/2011
Date registered
31/10/2011
Date last updated
2/11/2016

Titles & IDs
Public title
A First-In-Human Study of RO5503781 in Participants With Advanced Malignancies Except Leukemia
Scientific 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
Secondary ID [1] 0 0
2011-002767-15
Secondary ID [2] 0 0
NP27872
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - RO5503781

Experimental: Schedule A: RO5503781 QW - Participants will receive multiple ascending doses of RO5503781 orally once weekly (QW) x 3 followed by 13 days of rest in a 28 days cycle.

Experimental: Schedule B: RO5503781 QD - Participants will receive multiple ascending doses of RO5503781 orally QD x 5 followed by 13 days of rest in a 28 days cycle.


Treatment: Drugs: RO5503781
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Tolerated Dose (MTD)
Timepoint [1] 0 0
up to 28 days
Primary outcome [2] 0 0
Percentage of Participants With Dose Limiting Toxicities (DLTs)
Timepoint [2] 0 0
up to 28 days
Primary outcome [3] 0 0
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timepoint [3] 0 0
approximately 1.5 years
Secondary outcome [1] 0 0
Plasma Concentration of RO5503781
Timepoint [1] 0 0
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
Secondary outcome [2] 0 0
Urine Concentration of RO5503781
Timepoint [2] 0 0
Schedule A and B: Pre-dose, 0-4, 4-8, 8-12, 12-24 hours post-dose on Day 1, Day 2
Secondary outcome [3] 0 0
Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST)
Timepoint [3] 0 0
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])
Secondary outcome [4] 0 0
Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Response Evaluation Criteria in Solid Tumors (RECIST)
Timepoint [4] 0 0
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])
Secondary outcome [5] 0 0
Standardized Uptake Value (SUV) obtained from the Positron Emission Tomography With 18-Fluorothymidine [(18F)-FLT-PET) Images
Timepoint [5] 0 0
Baseline, Cycle1 Day 5, Cycle 3 Day 1
Secondary outcome [6] 0 0
Pharmacodynamics: p21 Levels in Tumor as Measured by Immunohistochemistry
Timepoint [6] 0 0
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])
Secondary outcome [7] 0 0
Pharmacodynamics: Tumor suppressor gene (p53) Levels in Tumor as Measured by Immunohistochemistry
Timepoint [7] 0 0
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])
Secondary outcome [8] 0 0
Pharmacodynamics: Murine Double Minute 2 (MDM2) Levels in Tumor as Mesured by Reverse transcription polymerase chain reaction (RT-PCR)
Timepoint [8] 0 0
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])
Secondary outcome [9] 0 0
Pharmacodynamics: Ki-67 Levels in Tumor as Measured by Immunohistochemistry
Timepoint [9] 0 0
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])
Secondary outcome [10] 0 0
Pharmacodynamics: Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Levels in Tumor as Measured by Immunohistochemistry
Timepoint [10] 0 0
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])
Secondary outcome [11] 0 0
Progression Free Survival (PFS) According to Cheson Criteria
Timepoint [11] 0 0
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])
Secondary outcome [12] 0 0
Pharmacodynamics: p53 Mutation Status in Tumor as Measured by AmpliChip p53 Test
Timepoint [12] 0 0
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])
Secondary outcome [13] 0 0
Pharmacodynamics: Mouse Double Minute 2 Homolog (MDM2) Gene Copy Number in Tumor as Measured by in situ Hybridization
Timepoint [13] 0 0
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])
Secondary outcome [14] 0 0
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
Timepoint [14] 0 0
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
Secondary outcome [15] 0 0
Food-Effect: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
Timepoint [15] 0 0
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
Secondary outcome [16] 0 0
Area Under the Curve from Time Zero to end of dosing interval (AUCtau)
Timepoint [16] 0 0
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
Secondary outcome [17] 0 0
Food-Effect: Area Under the Curve From Time Zero to Extrapolated 168 hours [AUC(0-168)]
Timepoint [17] 0 0
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
Secondary outcome [18] 0 0
Maximum Observed Plasma Concentration (Cmax)
Timepoint [18] 0 0
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
Secondary outcome [19] 0 0
Food-Effect: Maximum Observed Plasma Concentration (Cmax)
Timepoint [19] 0 0
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
Secondary outcome [20] 0 0
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Timepoint [20] 0 0
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
Secondary outcome [21] 0 0
Food-Effect: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Timepoint [21] 0 0
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
Secondary outcome [22] 0 0
Plasma Decay Half-Life (t1/2)
Timepoint [22] 0 0
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
Secondary outcome [23] 0 0
Food-Effect: Plasma Decay Half-Life (t1/2)
Timepoint [23] 0 0
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
Secondary outcome [24] 0 0
Terminal Elimination Rate Constant (Kel)
Timepoint [24] 0 0
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
Secondary outcome [25] 0 0
Food-Effect: Terminal Elimination Rate Constant (Kel)
Timepoint [25] 0 0
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
Secondary outcome [26] 0 0
Apparent Oral Clearance (CL/F)
Timepoint [26] 0 0
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
Secondary outcome [27] 0 0
Apparent Volume of Distribution (Vz/F)
Timepoint [27] 0 0
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
Secondary outcome [28] 0 0
Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Cheson Criteria
Timepoint [28] 0 0
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])
Secondary outcome [29] 0 0
Pharmacodynamics: Macrophage Inhibitory Cytokine 1 (MIC-1) Levels in Blood as Measured by Enzyme-linked Immunosorbent Assay (ELISA)
Timepoint [29] 0 0
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

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/11/2011
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/07/2014
Sample size
Target
Accrual to date
Final
99
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
- Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Ontario
Country [2] 0 0
Canada
State/province [2] 0 0
Quebec
Country [3] 0 0
France
State/province [3] 0 0
Bordeaux
Country [4] 0 0
France
State/province [4] 0 0
Lyon
Country [5] 0 0
Korea, Republic of
State/province [5] 0 0
Seoul
Country [6] 0 0
Netherlands
State/province [6] 0 0
Groningen

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01462175
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01462175