A Study to Investigate the Bioequivalence or Relative Bioavailability of Three New Idasanutlin Tablet Variants Following Oral Administration in Participants With Solid Tumors

A Multi-Center, Open-Label, Clinical Pharmacology Study for Idasanutlin, an MDM2 Antagonist With a Hybrid Randomized/Sequential, Single-Dose, 4-Period, Crossover Design to Investigate the Bioequivalence or Relative Bioavailability of Three New Idasanutlin Tablet Variants Following Oral Administration in Patients With Solid Tumors

This multi-center, open-label, pharmacokinetic study will evaluate the bioequivalence (BE) or relative bioavailability (rBA) of three new idasanutlin-tablet variants compared to the reference tablet formulation following oral administration of a 300 milligrams (mg) dose in participants with solid tumors for whom no further treatment options are available. Following the four administrations of idasanutlin in the BE/rBA cycle of the study (Cycle 1), participants who have no clinically defined progressive disease and who recover from any prior treatment toxicity to Grade less than or equal to (</=) 1 may enter the optional treatment extension phase. This extension phase will continue for additional 28-day cycles or until disease progression or unacceptable toxicity is observed.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Idasanutlin

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital / McGill University
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045-2517
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center; Medical Oncology
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University; Wash Uni. Sch. Of Med
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada (CCCN) - Central Valley
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center; Stephenson Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • New Orleans Center for Clinical Research
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Charles A. Sammons Cancer Center
    • Dallas, Texas, United States, 75230
      • Mary Crowley Medical Research Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have histologically or cytologically confirmed advanced malignancies, except all forms of leukemia and lymphoma, for which standard curative or palliative measures do not exist, are no longer effective, or are not acceptable to the participant
• Measureable or evaluable disease by RECIST v1.1 for solid tumors prior to the administration of study drug
• Ability to understand and willingness to sign a written informed consent form and comply with all study requirements
• Life expectancy of greater than or equal to (>/=)12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• New York Heart Association (NYHA) status of less than or equal to (</=)1
• Women of childbearing potential and men should remain abstinent or agree to use an effective form of contraception and to continue its use for the duration of study treatment and for a period of time after the last dose of study treatment
• Adequate bone marrow function, hepatic function, and renal function

Exclusion Criteria:

• Participants with prostate cancer who are unable to interrupt treatment with ketoconazole; ketoconazole treatment must be discontinued 2 weeks prior to first dose of study medication and is not allowed during Cycle 1, but may be used in the optional extension phase.
• Administration of investigational agents or investigational drugs </=4 weeks or less than (<)5 times the terminal half-life prior to study treatment start, whichever is longer
• Active gastrointestinal (GI) conditions and uncontrolled irritable bowel disease or pre-existing GI disorders that may interfere with proper absorption of the study drug
• History of allergic reactions attributed to components of the formulated product
• History of seizure disorders or unstable central nervous system metastases
• Presence of any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
• Evidence of electrolyte imbalance
• Pregnant or breast feeding
• Known coagulopathy, platelet disorder or history of non-drug-induced thrombocytopenia
• Current treatment with oral or parenteral anti-coagulants/antiplatelet agents
• Acute toxicities from any prior anti-tumor therapy, surgery, or radiotherapy that has not resolved to Grade </=2, except alopecia
• Last dose of prior anti-tumor therapy <21 days prior to the first administration of idasanutlin or <5 times terminal half-life of that therapy, whichever is shorter
• Refusal to potentially receive blood products and/or have a hypersensitivity to blood products
• Known bone marrow disorders which may interfere with bone marrow recovery or participants with delayed recovery from prior chemoradiotherapy
• Planned procedure or surgery during the study
• History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
• Blood transfusion within 4 weeks prior to screening
• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias
• Current treatment with medications that are well known to prolong the QT interval

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Sequence 1: ABCD; Treatment A: A single dose of the current idasanutlin tablet A formulation (reference variant) on Cycle 1, Day 1 (one cycle is 28 days). Treatment B: A single dose of new idasanutlin tablet B (to investigate BE compared to tablet A) on Cycle 1, Day 8. Treatment C: A single dose of new idasanutlin tablet C (to investigate rBA compared to tablet A; rBA 1) on Cycle 1, Day 15. Treatment D: A single dose of new idasanutlin tablet D (to investigate rBA compared to tablet A; rBA 2) on Cycle 1, Day 22. Following completion of the BE/rBA cycle (Cycle 1), participants may continue to receive optional treatment cycles of the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.	Drug: Idasanutlin; Participants will receive one 300-mg dose of each of the four different oral tablet formulations of idasanutlin (tablet A [reference], B, C, D) during Cycle 1, in the order specified for their assigned treatment arm (Treatment Sequence 1-4). Participants who enter the optional treatment extension phase will receive the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.; Other Names: RO5503781
Experimental: Treatment Sequence 2: ABDC; Treatment A: A single dose of the current idasanutlin tablet A formulation (reference variant) on Cycle 1, Day 1 (one cycle is 28 days). Treatment B: A single dose of new idasanutlin tablet B (to investigate BE compared to tablet A) on Cycle 1, Day 8. Treatment D: A single dose of new idasanutlin tablet D (to investigate rBA compared to tablet A; rBA 2) on Cycle 1, Day 15. Treatment C: A single dose of new idasanutlin tablet C (to investigate rBA compared to tablet A; rBA 1) on Cycle 1, Day 22. Following completion of the BE/rBA cycle (Cycle 1), participants may continue to receive optional treatment cycles of the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.	Drug: Idasanutlin; Participants will receive one 300-mg dose of each of the four different oral tablet formulations of idasanutlin (tablet A [reference], B, C, D) during Cycle 1, in the order specified for their assigned treatment arm (Treatment Sequence 1-4). Participants who enter the optional treatment extension phase will receive the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.; Other Names: RO5503781
Experimental: Treatment Sequence 3: BACD; Treatment B: A single dose of new idasanutlin tablet B (to investigate BE compared to tablet A) on Cycle 1, Day 1 (one cycle is 28 days). Treatment A: A single dose of the current idasanutlin tablet A formulation (reference variant) on Cycle 1, Day 8. Treatment C: A single dose of new idasanutlin tablet C (to investigate rBA compared to tablet A; rBA 1) on Cycle 1, Day 15. Treatment D: A single dose of new idasanutlin tablet D (to investigate rBA compared to tablet A; rBA 2) on Cycle 1, Day 22. Following completion of the BE/rBA cycle (Cycle 1), participants may continue to receive optional treatment cycles of the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.	Drug: Idasanutlin; Participants will receive one 300-mg dose of each of the four different oral tablet formulations of idasanutlin (tablet A [reference], B, C, D) during Cycle 1, in the order specified for their assigned treatment arm (Treatment Sequence 1-4). Participants who enter the optional treatment extension phase will receive the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.; Other Names: RO5503781
Experimental: Treatment Sequence 4: BADC; Treatment B: A single dose of new idasanutlin tablet B (to investigate BE compared to tablet A) on Cycle 1, Day 1 (one cycle is 28 days). Treatment A: A single dose of the current idasanutlin tablet A formulation (reference variant) on Cycle 1, Day 8. Treatment D: A single dose of new idasanutlin tablet D (to investigate rBA compared to tablet A; rBA 2) on Cycle 1, Day 15. Treatment C: A single dose of new tablet C (to investigate rBA compared to tablet A; rBA 1) on Cycle 1, Day 22. Following completion of the BE/rBA cycle (Cycle 1), participants may continue to receive optional treatment cycles of the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.	Drug: Idasanutlin; Participants will receive one 300-mg dose of each of the four different oral tablet formulations of idasanutlin (tablet A [reference], B, C, D) during Cycle 1, in the order specified for their assigned treatment arm (Treatment Sequence 1-4). Participants who enter the optional treatment extension phase will receive the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.; Other Names: RO5503781
Experimental: Optional Treatment Extension Arm; Following completion of the BE/rBA cycle (Cycle 1), participants who have no clinically defined progressive disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and who recover from any prior treatment toxicity to Grade </=1 may enter the optional treatment extension phase. Participants will receive 200 mg idasanutlin orally (200-mg tablet reference formulation) daily for 5 days, followed by 23 days of rest. This extension phase will continue for additional 28-day cycles or until disease progression or unacceptable toxicity is observed.	Drug: Idasanutlin; Participants will receive one 300-mg dose of each of the four different oral tablet formulations of idasanutlin (tablet A [reference], B, C, D) during Cycle 1, in the order specified for their assigned treatment arm (Treatment Sequence 1-4). Participants who enter the optional treatment extension phase will receive the reference tablet formulation of idasanutlin, as specified in the Optional Treatment Extension Arm description.; Other Names: RO5503781

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Curve (AUC) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)
Maximum Observed Plasma Concentration (Cmax) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to Maximum Observed Plasma Concentration (tmax) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)
Apparent Clearance (CL/F) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)
Apparent Volume of Distribution (Vd/F) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)
Half-life (t1/2) of Idasanutlin	Predose (within 2 hours), 1, 2, 4, 6, and 10 hours on Days 1, 8, 15, and 22; on Days 2, 3, 5, 9, 10, 12, 16, 17, 19, 23, 24, and 26; Day 29 (end of Cycle 1) or Cycle 2 Day 1 (for participants in the optional treatment extension phase) (cycle=28 days)
Percentage of Participants With Adverse Events	Baseline up to end of study (up to approximately 1.5 years)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Actual): June 11, 2019
• Study Completion (Actual): June 11, 2019

Study Registration Dates

• First Submitted: November 30, 2017
• First Submitted That Met QC Criteria: November 30, 2017
• First Posted (Actual): December 5, 2017

Study Record Updates

• Last Update Posted (Actual): June 19, 2019
• Last Update Submitted That Met QC Criteria: June 18, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: NP39051

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No