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

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ClinicalTrials.gov Identifier: NCT03362723
Recruitment Status : Completed
First Posted : December 5, 2017
Last Update Posted : June 19, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: Idasanutlin Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 27, 2017
Actual Primary Completion Date : June 11, 2019
Actual Study Completion Date : June 11, 2019

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: RO5503781




Primary Outcome Measures :
  1. Area Under the Curve (AUC) of Idasanutlin [ Time Frame: 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) ]
  2. Maximum Observed Plasma Concentration (Cmax) of Idasanutlin [ Time Frame: 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 :
  1. Time to Maximum Observed Plasma Concentration (tmax) of Idasanutlin [ Time Frame: 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) ]
  2. Apparent Clearance (CL/F) of Idasanutlin [ Time Frame: 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) ]
  3. Apparent Volume of Distribution (Vd/F) of Idasanutlin [ Time Frame: 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) ]
  4. Half-life (t1/2) of Idasanutlin [ Time Frame: 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) ]
  5. Percentage of Participants With Adverse Events [ Time Frame: Baseline up to end of study (up to approximately 1.5 years) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03362723


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

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03362723     History of Changes
Other Study ID Numbers: NP39051
First Posted: December 5, 2017    Key Record Dates
Last Update Posted: June 19, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No