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Completed

NCT Number: NCT01462175

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

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.

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Key information

Conditions

Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Melbourne, Victoria, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

RO5503781

Drug

Primary outcomes

  1. Maximum Tolerated Dose (MTD)

    Time frame: up to 28 days

  2. Percentage of Participants With Dose Limiting Toxicities (DLTs)

    Time frame: up to 28 days

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

    Time frame: approximately 1.5 years

Secondary outcomes

  1. 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

  2. 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

  3. 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])

  4. 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])

  5. 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

  6. 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])

  7. 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])

  8. 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])

  9. 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])

  10. 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])

  11. 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])

  12. 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])

  13. 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])

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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])

  29. 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

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Registry information

Official study 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

Important dates

Study start
2011
Primary completion
2014
Study completion
2014
First posted
Oct 31, 2011
Registry last updated
Nov 2, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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