This is a Phase 1, first-in-human, open-label, non-randomized, dose escalation, trial to explore the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity signals of MSC2363318A.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
101
Part 1: MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression. Additional dose escalations will continue until Maximum Tolerated Dose (MTD) is reached, the food effect will be investigated in a separate group. Part 2 (Cohort 1): MSC2363318A will be administered orally once daily for repeated 21-day cycles until intolerable toxicity or disease progression in subjects with PAM pathway alterations. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle).
Part 2 Cohort 2: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Trastuzumab. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Trastuzumab is a recombinant IgGI kappa humanized monoclonal antibody administered weekly by intravenous infusion.
University of Alabama at Birmingham
Birmingham, Alabama, United States
Cedars Sinai Medical Center
Los Angeles, California, United States
Number of dose limiting toxicities (DLTs) in Dose Escalation and Trastuzumab or Tamoxifen combination arms
Time frame: Up to Day 21 of Cycle 1
Number of subjects with Treatment-emergent adverse events (TEAEs), Serious Adverse Events (SAEs), and deaths in cohort for subjects with PAM pathway alterations
Time frame: Baseline up to Day 30 after the last dose of study treatment
Observed Maximum Plasma Concentration (Cmax)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Time To Reach Maximum Plasma Concentration (Tmax)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Area Under Plasma Concentration Versus Time Curve From Time Zero to Last Sampling Time (AUC0-t)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Area Under Plasma Concentration Versus Time Curve Within One Dosing Interval (AUCtau)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Apparent Terminal Half-life ( t1/2)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Apparent Oral Clearance (CL/F)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Part 2 Cohort 3: MSC2363318A will be administered orally once daily for repeated 21-day cycles in combination with Tamoxifen. Dose reductions or treatment interruptions will be made at the discretion of the Investigator. If treatment interruption is required due to an acute or less severe but intolerable MSC2363318A-related event, at least a 1-week break is recommended. If, at retreatment, the dose reduction is not required, then the "continuous daily dosing regimen" may be replaced with an "intermittent dose regimen" of 2 weeks on, 1 week off (i.e. daily dosing from Day 1 to Day 15 followed by no dosing on Day 16 to Day 21 of the cycle). Tamoxifen is a nonsteroidal antiestrogen administered daily by oral administration.
University of California at San Diego, Moores Cancer Center
San Diego, California, United States
Sylvester Comprehensive Cancer Center
Miami, Florida, United States
Metairie Oncology
Metairie, Louisiana, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Henry Ford Hospital
Detroit, Michigan, United States
Washington University School of Medicine
St Louis, Missouri, United States
Mount Sinai
New York, New York, United States
...and 5 more locations
Apparent Oral Clearance Steady State (CLss/F)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Apparent Volume of Distribution (Vz/F)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Apparent Volume of Distribution at Steady State (Vss/F)
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Factor to Assess the Increase of Drug Concentration in Plasma Until Steady State is Reached [Racc(AUC)]
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Factor to Assess the Maximal Increase of Drug Concentration in Plasma [Racc (Cmax)]
Time frame: Days 1, 2, 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2, Cycle 3
Number of subjects with best overall response according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1) or Cheson 2007
Time frame: Evaluation were performed on Day 1 of every alternate cycle until tumor progression
Percentage of subjects with clinical benefit
Percentage of subjects with clinical benefit is defined as subjects with complete response (CR) or partial response (PR) at week 12, based on tumor assessment as determined by RECIST version 1.1 or Cheson 2007.
Time frame: Week 12
Disease control rate (DCR) for Cohort 2 only
Time frame: Week 6
Progression-free survival (PFS) rate for Cohorts 2 and 3 only
Time frame: up to 6 months