A study to investigate the safety, and effect of G1T38 on breast cancer when used in combination with Fulvestrant and to investigate level of G1T38 in the blood during treatment.

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2016-001485-29-GB
• Date of registration: 03/11/2016
• Prospective Registration: Yes
• Primary sponsor: G1 Therapeutics, Inc
• Public title: A study to investigate the safety, and effect of G1T38 on breast cancer when used in combination with Fulvestrant and to investigate level of G1T38 in the blood during treatment.
• Scientific title: Phase 1/2 Safety, Pharmacokinetic, and Antitumor Activity Study of G1T38 in Combination with Fulvestrant in Patients with Hormone Receptor-Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer after Endocrine Failure
• Date of first enrolment: 21/03/2017
• Target sample size: 109
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001485-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Georgia, Moldova, Republic of, United Kingdom

Contacts

• Name: Clinical Information Point
• Affiliation: G1 Therapeutics

• Name: Clinical Information Point
• Affiliation: G1 Therapeutics

Key inclusion & exclusion criteria

Inclusion criteria:
1. Women or men, 18 years or older
2. Histologically or cytologically confirmed diagnosis of breast cancer, with evidence of metastatic or locally advanced disease, not amenable to curative therapy (ie, surgical resection +/- radiation therapy)
3. Documented diagnosis of HR-positive tumor, ER-positive, and/or progesterone receptor-positive, defined as = 1% positive stained cells, utilizing an assay consistent with local standards
4. Documented HER2-negative tumor (immunohistochemistry [IHC] score of 0 or 1+ or negative by in situ hybridization (fluorescence, dual, chromogenic, or silver in situ hybridization) defined as HER2/CEP17 ratio < 2 or for single probe assessment, HER2 copy number < 4
5. Any menopausal status:
a. Postmenopausal women are defined as at least 60 years of age, have undergone bilateral oophorectomy, medically confirmed ovarian failure or are younger than 60 years of age and have had cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have serum levels of estradiol and follicle stimulating hormone within the laboratory’s reference range for postmenopausal females
b. Pre- or perimenopausal women can be enrolled if amenable to be treated with the LHRH agonist goserelin. Patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 28 days prior to first dose of G1T38. If patients have received an alternative LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.
6. Patients must satisfy one of the following criteria for prior therapy:
a. Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor or tamoxifen
b. Progressed during treatment or within 2 months after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer, or prior endocrine therapy for advanced/metastatic breast cancer if pre- or perimenopausal
For advanced/metastatic disease
• Part 1: a maximum of 2 prior chemotherapy regimens is allowed in addition to prior endocrine therapy
• Part 2: a maximum of 1 prior chemotherapy regimen is allowed in addition to prior endocrine therapy
7. For Part 1 of the study, evaluable or measurable disease as defined by RECIST, Version 1.1
8. For Part 2 of the study, approximately 75% of patients enrolled on protocol Version 7.0 or later must have measurable disease as defined by RECIST Version 1.1, including bone-only disease. Patients with measurable bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately measured by CT or MRI per RECIST Version 1.1. Up to approximately 25% of patients with bone-only disease that is non-measurable by RECIST Version 1.1 may be enrolled. Tumor lesions previously irradiated or subjected to other loco-regional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented
9. ECOG performance status 0 to 1
10. Must meet all of the following laboratory parameters criteria:
a. Hemoglobin = 90 g/L in absence of red cell transfusion within 14 days of first dose of G1T38

Exclusion criteria:
A patient will not be eligible for participation in this study if any of the following criteria apply.
1. For Part 1 of the study, prior treatment with fulvestrant
2. For Part 2 of the study, prior treatment with any CDK inhibitor or fulvestrant
3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 28 days prior to first dose of G1T38.
4. Major surgery within 14 days of first screening visit
5. Receipt of chemotherapy within 21 days of first dose of G1T38
6. Receipt of any investigational medication within 28 days of first dose of G1T38
7. Concurrent radiotherapy to any site or radiotherapy within 14 days of first dose of G1T38 or previous radiotherapy to the target lesion sites (the sites that are to be followed for determination of a response) or prior radiotherapy to > 25% of bone marrow
8. Use of any of the following prohibited, orally administered cytochrome P450 CYP(3A) substrates with a narrow therapeutic index within 14 days of first dose of G1T38:
a. Astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, everolimus, pimozide, quinidine, sirolimus and tacrolimus
9. Patients taking bisphosphonates or denosumab for the treatment of osteoporosis or management of existing bone metastases must have been on a stable dose for at least 14 days prior to first dose of G1T38
10. Chronic use of systemic corticosteroids. Steroids given for physiological replacement (up to 10 mg prednisone or equivalent), as anti-emetics, by inhalation, and short course (up to 10 days) of oral/topical steroids given for allergic reactions or asthma flares are allowed.
11. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association [NYHA] functional classification system)
12. Known history of stroke, cerebrovascular accident, or myocardial infarction within 6 months prior to enrollment
13. Known serious active infection (eg, HIV, hepatitis B or C, tuberculosis, etc.). A negative screening test is not required for participation.
14. Psychiatric illness/social situations that would limit study compliance
15. Other uncontrolled serious chronic disease or conditions that in the investigator’s opinion could affect patient safety, compliance or follow-up in the protocol
16. Legal incapacity or limited legal capacity
17. Prior hematopoietic stem cell or bone marrow transplantation
18. QTc interval > 450 msec for males or > 470 msec for females using Fridericia method on screening ECG or known history of QTc prolongation
19. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of G1T38, such as history of GI surgery which may result in intestinal blind loops and patients with cli

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Hormone Receptor-Positive, HER2 Negative Metastatic Breast Cancer after Endocrine Failure
MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: G1T38 Di-HCl
Product Code: G1T38
Pharmaceutical Form: Capsule
INN or Proposed INN: G1T38 Di-HCl
Current Sponsor code: G1T38 Di-HCl
Other descriptive name: G1T38
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Product Name: G1T38 Di-HCl
Product Code: G1T38
Pharmaceutical Form: Capsule
INN or Proposed INN: G1T28 Di-HCl
Current Sponsor code: G1T38 Di-HCl
Other descriptive name: G1T38
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: G1T38 Di-HCI
Product Code: G1T38
Pharmaceutical Form: Capsule
INN or Proposed INN: G1T38 Di-HCl
Current Sponsor code: G1T38 Di-HCl
Other descriptive name: G1T38
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

Main Objective: Evaluate DLTs associated with G1T38 administered with fulvestrant.
Determine the Phase 2 dose and dose interval of G1T38 administered with fulvestrant.
Evaluate and optimize the recommended phase 2 dose (RP2D).
Evaluate the safety and tolerability of G1T38 administered with fulvestrant.

Primary end point(s): The primary analysis is based on the assessment of safety and tolerability endpoints for this study:
Adverse events (AEs), dose-limiting toxicities (DLTs), vital signs measurements, physical examinations, electrocardiograms (ECGs), and clinical laboratory studies.

Adverse event data will be coded to system organ class and preferred term using the Medical Dictionary for Regulatory activities (MedDRA; Version 17.1 or later). The number and percentage of patients experiencing any treatment-emergent AE, overall, and by system organ class and preferred term will be tabulated. Treatment-emergent AEs will also be presented in 28-day increments. Adverse events related to treatment will be further summarized by the treatment to which it is attributed (eg, G1T38 or fulvestrant). DLTs and withdrawals due to AEs will be summarized or listed.

Observed values and changes from baseline in vital signs, ECG readings, and hematology and clinical chemistry parameters will be tabulated at each visit.

Timepoint(s) of evaluation of this end point: Throughout the study as per the protocol

Secondary Objective: Determine the pharmacokinetic parameters of G1T38.
Assess fulvestrant and goserelin Day 15 plasma concentrations when administered with G1T38.
Assess response rate and clinical benefit rate (CBR) based on RECIST, Version 1.1.
Assess progression-free survival (PFS) and overall survival (OS).

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Throughout the study as per the protocol

Secondary end point(s): Secondary analyses will be based on PK and antitumor endpoints.

Tumor response using RECIST 1.1, PK parameters of G1T38, plasma concentrations of fulvestrant and goserelin on Day 1 and Day 15, progression free survival, overall survival.

Pharmacokinetic analyses will be based on the PK set, and all analysis and reporting of plasma concentration and PK parameter data will be performed separately for each analyte.
The following PK parameters will be calculated (when data permit their calculation): Cmax, Tmax, AUC0-t, AUC0-8, t1/2, CL, and Vz. Exploratory PK modeling and simulations may also be performed.

The Overall Response Rate (ORR) is defined as the percentage of patients achieving a Complete Response (CR) or Partial Response (PR) based on RECIST, Version 1.1

Progression Free Survival (PFS) and Overall Survival (OS) will be analyzed based on time-to-event summary methods.

Secondary ID(s)

G1T38-02

Source(s) of Monetary Support

G1 Therapeutics

Ethics review

Status: Approved
Approval date:
Contact: