| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone Receptor-Positive, HER2 Negative Metastatic Breast Cancer after Endocrine Failure |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
b. Absolute neutrophil count ≥ 1.5 × 109/L
c. Platelet count ≥ 100 × 109/L
d. Estimated GFR of ≥ 50 mL/min (by Cockcroft-Gault formula or 51Cr EDTA)
e. Total bilirubin ≤ 1.5 × upper limit of normal (ULN); <3 x ULN if documented Gilbert’s disease
f. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases
11. Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE Grade ≤1 (except alopecia and peripheral neuropathy) prior to first dose of G1T38: peripheral neuropathy must have recovered to <Grade 2.
12. If female and sexually active, effective nonhormonal contraception must be used during the study and for 4 months after the last dose of study drug unless they have medically confirmed postmenopausal status (see 5(a) above), irreversible premature ovarian failure, bilateral oophorectomy, bilateral salpingectomy, or complete or partial hysterectomy. Acceptable methods include an intrauterine device, a vasectomized partner, and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository). If male and sexually active, a condom, with spermicide, must be used during the study and for 4 months after the last dose of study drug, or must be vasectomized.
13. Patient must agree to provide archival tumor tissue, if available, prior to first dose of G1T38. Patients for whom no archival tissue is available are eligible.
14. Able to swallow whole capsules
15. Evidence of a personally signed and dated informed consent document indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study |
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| E.4 | Principal 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 clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE Grade > 1
20. History of other malignancies, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for ≥ 3 years
21. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant
22. Known history of hypersensitivity to any of the inactive ingredients in fulvestrant (benzyl alcohol, benzyl benzoate, castor oil)
23. Known hypersensitivity to LHRH agonists, LHRH agonist analogues, or any of the components of goserelin injection (pre- and perimenopausal patients only)
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| E.5 End points |
| E.5.1 | 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study as per the protocol |
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| E.5.2 | 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-∞, 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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study as per the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Georgia |
| Moldova, Republic of |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study includes a survival follow-up phase. This survival follow-up phase will continue until at least 50% of the patients in Part 2 have died. This study will be completed when the Survival Follow-up Phase has been completed, or upon sponsor termination of the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 35 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 35 |
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