A First-In-Human Study of RO5503781 in Participants With Advanced Malignancies Except Leukemia

Hoffmann-La Roche99 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neoplasms

Interventions

RO5503781DRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (8)

Unnamed facility

Melbourne, Victoria, Australia

Unnamed facility

Hamilton, Ontario, Canada

Unnamed facility

Toronto, Ontario, Canada

Unnamed facility

Montreal, Quebec, Canada

Outcomes

Primary Outcomes

Maximum Tolerated Dose (MTD)

Time frame: up to 28 days

Percentage of Participants With Dose Limiting Toxicities (DLTs)

Time frame: up to 28 days

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time frame: approximately 1.5 years

Secondary Outcomes

Plasma Concentration of RO5503781

Time frame: 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

Urine Concentration of RO5503781

Time frame: Schedule A and B: Pre-dose, 0-4, 4-8, 8-12, 12-24 hours post-dose on Day 1, Day 2

Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST)

Time frame: 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])

Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Response Evaluation Criteria in Solid Tumors (RECIST)

Time frame: 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])

Standardized Uptake Value (SUV) obtained from the Positron Emission Tomography With 18-Fluorothymidine [(18F)-FLT-PET) Images

Time frame: Baseline, Cycle1 Day 5, Cycle 3 Day 1

Data from ClinicalTrials.gov

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Unnamed facility

Bordeaux, France

Unnamed facility

Lyon, France

Unnamed facility

Groningen, Netherlands

Unnamed facility

Seoul, South Korea

Pharmacodynamics: p21 Levels in Tumor as Measured by Immunohistochemistry

Time frame: 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])

Pharmacodynamics: Tumor suppressor gene (p53) Levels in Tumor as Measured by Immunohistochemistry

Time frame: 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])

Pharmacodynamics: Murine Double Minute 2 (MDM2) Levels in Tumor as Mesured by Reverse transcription polymerase chain reaction (RT-PCR)

Time frame: 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])

Pharmacodynamics: Ki-67 Levels in Tumor as Measured by Immunohistochemistry

Time frame: 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])

Pharmacodynamics: Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Levels in Tumor as Measured by Immunohistochemistry

Time frame: 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])

Progression Free Survival (PFS) According to Cheson Criteria

Time frame: 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])

Pharmacodynamics: p53 Mutation Status in Tumor as Measured by AmpliChip p53 Test

Time frame: 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])

Pharmacodynamics: Mouse Double Minute 2 Homolog (MDM2) Gene Copy Number in Tumor as Measured by in situ Hybridization

Time frame: 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])

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)

Time frame: 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

Food-Effect: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)

Time frame: 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

Area Under the Curve from Time Zero to end of dosing interval (AUCtau)

Food-Effect: Area Under the Curve From Time Zero to Extrapolated 168 hours [AUC(0-168)]

Time frame: 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

Maximum Observed Plasma Concentration (Cmax)

Food-Effect: Maximum Observed Plasma Concentration (Cmax)

Time frame: 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

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Food-Effect: Time to Reach Maximum Observed Plasma Concentration (Tmax)

Time frame: 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

Plasma Decay Half-Life (t1/2)

Food-Effect: Plasma Decay Half-Life (t1/2)

Time frame: 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

Terminal Elimination Rate Constant (Kel)

Food-Effect: Terminal Elimination Rate Constant (Kel)

Time frame: 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

Apparent Oral Clearance (CL/F)

Apparent Volume of Distribution (Vz/F)

Percentage of Participants With Objective Response [Complete Response (CR) plus Partial Response(PR)] According to Cheson Criteria

Time frame: 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])

Pharmacodynamics: Macrophage Inhibitory Cytokine 1 (MIC-1) Levels in Blood as Measured by Enzyme-linked Immunosorbent Assay (ELISA)