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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01462175
First received: October 27, 2011
Last updated: August 1, 2016
Last verified: August 2016
  Purpose
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.

Condition Intervention Phase
Neoplasms
Drug: RO5503781
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: up to 28 days ] [ Designated as safety issue: Yes ]
  • Percentage of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: up to 28 days ] [ Designated as safety issue: Yes ]
  • Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: approximately 1.5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Area Under the Curve from Time Zero to end of dosing interval (AUCtau) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Maximum Observed Plasma Concentration (Cmax) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Plasma Decay Half-Life (t1/2) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Terminal Elimination Rate Constant (Kel) [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Apparent Oral Clearance (CL/F) [ 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 ] [ Designated as safety issue: No ]
  • Apparent Volume of Distribution (Vz/F) [ 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 ] [ Designated as safety issue: No ]
  • 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]) ] [ Designated as safety issue: No ]
  • Pharmacodynamics: Macrophage Inhibitory Cytokine 1 (MIC-1) Levels in Blood as Measured by Enzyme-linked Immunosorbent Assay (ELISA) [ 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 ] [ Designated as safety issue: No ]

Enrollment: 99
Study Start Date: November 2011
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: RO5503781
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.
Drug: RO5503781

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01462175

Locations
Australia, Victoria
Melbourne, Victoria, Australia, 3000
Canada, Ontario
Hamilton, Ontario, Canada, L8V 5C2
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Montreal, Quebec, Canada, H3T 1E2
France
Bordeaux, France, 33076
Lyon, France, 69373
Korea, Republic of
Seoul, Korea, Republic of, 110-744
Netherlands
Groningen, Netherlands, 9713 GZ
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01462175     History of Changes
Other Study ID Numbers: NP27872  2011-002767-15 
Study First Received: October 27, 2011
Last Updated: August 1, 2016
Health Authority: France: Agence Francaise de Securite Sanitaire des Produits de Sante

ClinicalTrials.gov processed this record on August 23, 2016