G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER-Positive, HER2-Negative Advanced Breast Cancer

Sponsor

G1 Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03455270

Collaborator

(none)

107

Enrollment

Locations

Arms

52.7

Anticipated Duration (Months)

7.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Ductal, Breast Breast Cancer Female Breast Neoplasm Breast Cancer Metastatic Breast Cancer Advanced Breast Cancer Stage IV Breast Cancer	Drug: G1T48 Drug: Palbociclib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of Ascending Doses of G1T48 Alone and in Combination With Palbociclib in Women With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer

Actual Study Start Date :

May 9, 2018

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Dose Escalation (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.	Drug: G1T48 oral SERD Other Names: Rintodestrant
Experimental: Part 1: Food Effect Cohort (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.	Drug: G1T48 oral SERD Other Names: Rintodestrant
Experimental: Part 2: Monotherapy Dose Expansion (G1T48) Patients in Part 2 will receive G1T48 once-daily at the dose determined in Part 1.	Drug: G1T48 oral SERD Other Names: Rintodestrant
Experimental: Part 3: Combination Dose Expansion (G1T48+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.	Drug: G1T48 oral SERD Other Names: Rintodestrant Drug: Palbociclib CDK 4/6 Inhibitor Other Names: Ibrance

Outcome Measures

Primary Outcome Measures

Dose Limiting Toxicity [Cycle 1 Day -3 to Cycle 1 Day 28]
Recommended Phase 2 dose [12 months]
G1T48 alone and in combination with palbociclib; progression-free survival (PFS)
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).

Secondary Outcome Measures

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: 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.]
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 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.]
Pharmacokinetics of palbociclib: Plasma - Trough concentration [Part 3, Cycle 2 Day 1 to Cycle 3 Day 1.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beverly Hills Cancer Center	Beverly Hills	California	United States	90211
2	Stanford Women Cancer Center	Stanford	California	United States	94305
3	Northwestern University - Feinberg School of Medicine	Chicago	Illinois	United States	60611
4	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599-7305
5	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
6	Sarah Cannon Research Institute at Tennessee Oncology	Nashville	Tennessee	United States	37203
7	Institut Jules Bordet	Brussels		Belgium	1000
8	UZ Leuven	Leuven		Belgium	3000
9	MHAT for Womens Health - Nadezhda OOD	Sofia		Bulgaria	1330
10	ARENSIA Exploratory Medicine LLC	Tbilisi		Georgia	0112
11	ARENSIA Exploratory Medicine Phase I Unit, The Institute of Oncology	Chisinau		Moldova, Republic of	2025
12	VU University Medical Center	Amsterdam		Netherlands	1081 HV
13	University Medical Center Groningen	Groningen		Netherlands	9713 GZ
14	Erasmus Medical Center	Rotterdam		Netherlands	3015 GD
15	Spizhenko Clinic	Kiev		Ukraine	08112