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

NCT03362723 | Completed Phase 1 FDA Drug

• 1 other identifier: NP39051
• Study Type: interventional
• Target: 48
• Locations: 2 countries
• Sites: 11

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.

Conditions

Solid Tumors

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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)

Study Arms (5)

Treatment Sequence 1: ABCD

EXPERIMENTAL

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

Treatment Sequence 2: ABDC

EXPERIMENTAL

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

Treatment Sequence 3: BACD

EXPERIMENTAL

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

Treatment Sequence 4: BADC

EXPERIMENTAL

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

Optional Treatment Extension Arm

EXPERIMENTAL

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

Interventions

Idasanutlin DRUG

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.

Also known as: RO5503781

Optional Treatment Extension Arm; Treatment Sequence 1: ABCD; Treatment Sequence 2: ABDC; Treatment Sequence 3: BACD; Treatment Sequence 4: BADC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (11)

University of Colorado

Aurora, Colorado, 80045-2517, United States

Location

Yale Cancer Center; Medical Oncology

New Haven, Connecticut, 06520, United States

Location

Washington University; Wash Uni. Sch. Of Med

St Louis, Missouri, 63110, United States

Location

Comprehensive Cancer Centers of Nevada (CCCN) - Central Valley

Las Vegas, Nevada, 89169, United States

Location

University of Oklahoma Health Sciences Center; Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

New Orleans Center for Clinical Research

Knoxville, Tennessee, 37920, United States

Location

Mary Crowley Medical Research Center

Dallas, Texas, 75230, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

Jewish General Hospital / McGill University

Montreal, Quebec, H3T 1E2, Canada

Location

MeSH Terms

Interventions

RG7388

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2017
• First Posted: December 5, 2017
• Study Start: November 27, 2017
• Primary Completion: June 11, 2019
• Study Completion: June 11, 2019
• Last Updated: June 19, 2019

Record last verified: 2019-06

Locations

CA (2); US (9)