G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer
- Conditions
- Carcinoma, Ductal, BreastMetastatic Breast CancerStage IV Breast CancerBreast Cancer FemaleBreast NeoplasmBreast CancerAdvanced Breast Cancer
- Interventions
- Registration Number
- NCT03455270
- Lead Sponsor
- G1 Therapeutics, Inc.
- Brief Summary
This is a study to investigate the potential clinical benefit of G1T48 as an oral selective estrogen receptor degrader (SERD) alone and in combination with palbociclib, a cyclin dependent kinase 4/6 (CDK 4/6) inhibitor, in patients with estrogen receptor-positive, HER2-negative metastatic breast cancer.
The study is an open-label design, consisting of 3 parts: dose-finding portion including food effect (Part 1), G1T48 monotherapy expansion portion (Part 2), and G1T48 in combination with palbociclib expansion portion (Part 3). All parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 184 patients may be enrolled in the study.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 107
-
For Part 1, postmenopausal women only
-
For Parts 2 and 3, any menopausal status
-
Confirmed diagnosis of ER-positive, HER2-negative advanced breast cancer, not amenable to curative therapy
-
For Part 1, prior treatment with less than 4 prior lines of chemotherapy
-
For Part 2, prior treatment with less than 2 prior line of chemotherapy
-
For Part 3, prior treatment with no more than 1 prior line of chemotherapy
-
For Parts 1 and 2, prior treatment with less than 4 prior endocrine therapies for metastatic breast cancer
-
For Part 3, prior treatment with no more than 1 prior line of endocrine therapies for metastatic breast cancer
-
For Parts 1 and 2, patients must satisfy 1 of the following criteria for prior therapy:
- Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor
- Progressed after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer
-
For Part 3, patients must satisfy 1 of the following criteria for prior therapy:
- Received ≥ 24 months of endocrine therapy in the adjuvant setting prior to recurrence or progression
- Received ≥ 6 months of endocrine therapy in the advanced/metastatic setting prior to progression
-
For Part 1, evaluable or measurable disease
-
For Parts 2 and 3, evaluable (approximately 25%) or measurable disease (approximately 75%) as defined by RECIST, Version 1.1 including bone-only disease
-
ECOG performance status 0 to 1
-
Adequate organ function
- For Part 3, prior treatment with CDK4/6 inhibitor, investigational oral SERDs or SERCAs in any setting
- Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease
- Anticancer therapy within 14 days of first G1T48 dose or within 28 days for antibody-based therapy
- Concurrent radiotherapy, radiotherapy within 14 days of first G1T48 dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow
- Prior hematopoietic stem cell or bone marrow transplantation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 2: Monotherapy Dose Expansion (G1T48) G1T48 Patients in Part 2 will receive G1T48 once-daily at the dose determined in Part 1. Part 1: Dose Escalation (G1T48) G1T48 Patients in Part 1 will receive a single oral dose of G1T48 on Cycle 1 Day -3 and will begin once-daily dosing on Cycle 1 Day 1. The initial dose cohort shall receive an identified starting dose and subsequent cohorts shall receive higher doses based on the safety and PK data obtained from the previous dose levels. Part 1: Food Effect Cohort (G1T48) G1T48 In Part 1, additional G1T48 cohort(s) of 8 patients may be enrolled to assess the effect of different fat content meals (eg, high fat, moderate fat, or low-fat) on the rate and extent of the absorption of G1T48. Patients will receive a single oral dose of G1T48 on Cycle 1 Day -10 and on Cycle 1 Day -3. Patients will begin G1T48 once-daily dosing on Cycle 1 Day 1. Part 3: Combination Dose Expansion (G1T48+palbociclib) G1T48 Patients in Part 3 will receive G1T48 once-daily at the dose determined in Part 2 in combination with palbociclib once-daily on Days 1 to 21 of each 28-day cycle. Part 3: Combination Dose Expansion (G1T48+palbociclib) Palbociclib Patients in Part 3 will receive G1T48 once-daily at the dose determined in Part 2 in combination with palbociclib once-daily on Days 1 to 21 of each 28-day cycle.
- Primary Outcome Measures
Name Time Method Dose Limiting Toxicity Cycle 1 Day -3 to Cycle 1 Day 28 Number of Treatment Related Adverse Event, including Abnormal Laboratory Events 21 months All AEs, including clinical laboratory, vitals signs, physical examinations and ECGs will be analyzed in all patients receiving study drug(s) from the signing of the informed consent until 30 days after the last dose of study medication(s).
Recommended Phase 2 dose 12 months G1T48 alone and in combination with palbociclib; progression-free survival (PFS)
- Secondary Outcome Measures
Name Time Method Pharmacokinetics of G1T48 and metabolites: Maximum Plasma Concentration (Cmax) Part 1, Cycle 1 Day -3 to Cycle 2 Day 1. Part 2, Cycle 2 Day 1 to Cycle 3 Day 1. Part 3, Cycle 2 Day 1 to Cycle 3 Day 1. Tumor response based on RECIST, Version 1.1 21 months G1T48 alone and in combination with palbociclib;
Effect of food on bioavailability of G1T48 Part 1, Cycle 1 Day -10 to Cycle 1 Day 1. Pharmacokinetics of G1T48 and metabolites: Area under Curve - plasma concentration (AUC) Part 1, Cycle 1 Day -3 to Cycle 2 Day 1. Part 2, Cycle 2 Day 1 to Cycle 3 Day 1. Part 3, Cycle 2 Day 1 to Cycle 3 Day 1. Pharmacokinetics of palbociclib: Plasma - Trough concentration Part 3, Cycle 2 Day 1 to Cycle 3 Day 1. Pharmacokinetics of G1T48 and metabolites: Plasma: terminal half life (T1/2) Part 1, Cycle 1 Day -3 to Cycle 2 Day 1. Part 2, Cycle 2 Day 1 to Cycle 3 Day 1. Part 3, Cycle 2 Day 1 to Cycle 3 Day 1. Pharmacokinetics of G1T48 and metabolites: Plasma - Volume of distribution Part 1, Cycle 1 Day -3 to Cycle 2 Day 1. Part 2, Cycle 2 Day 1 to Cycle 3 Day 1. Part 3, Cycle 2 Day 1 to Cycle 3 Day 1.
Trial Locations
- Locations (15)
Spizhenko Clinic
🇺🇦Kiev, Ukraine
Institut Jules Bordet
🇧🇪Brussels, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
Stanford Women Cancer Center
🇺🇸Stanford, California, United States
Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Sarah Cannon Research Institute at Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
MHAT for Womens Health - Nadezhda OOD
🇧🇬Sofia, Bulgaria
ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology
🇲🇩Chisinau, Moldova, Republic of
University Medical Center Groningen
🇳🇱Groningen, Netherlands
VU University Medical Center
🇳🇱Amsterdam, Netherlands
Erasmus Medical Center
🇳🇱Rotterdam, Netherlands
Northwestern University - Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Beverly Hills Cancer Center
🇺🇸Beverly Hills, California, United States
ARENSIA Exploratory Medicine LLC
🇬🇪Tbilisi, Georgia