Metastatic triple-negative breast cancer Breast cancer, prostate cancer, ovarian cancer, head and neck cancer, NSCLC, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, renal cell carcinoma or melanoma MedDRA version: 20.1 Level: PT Classification code 10055113 Term: Breast cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10075566 Term: Triple negative brea
Conditions
Interventions
Trade Name: Daraprim
Product Code: GLG-801
Pharmaceutical Form: Tablet
INN or Proposed INN: PYRIMETHAMINE
CAS Number: 58-14-0
Concentration unit: mg milligram(s)
Concentration type: up to
Concentratio
Sponsors
GLG Pharma S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Phase I Patients must meet the following criteria to enter the study: 1) Men or women at least 18 years of age; 2) Eastern Cooperative Oncology Group performance status = 2; 3) Females must be surgically sterile or at least 1 year post-menopausal. Women of childbearing potential must agree to use effective methods of birth control during the treatment period from the first dose of study drug until 3 months following the last dose of study drug. Acceptable methods of contraception include non-hormonal intrauterine device and barrier methods (male condom, female condom, diaphragm or cervical cap) with spermicide. Female patients who normally abstain from sexual activity may be recruited providing they remain abstinent during the study or if they become sexually active, they must agree to use effective methods of birth control as described above. 4) Males, if sexually active, must be either surgically sterile, or agree to be abstinent or use an effective method of birth control (condom with spermicide) through 3 months after the last dose of GLG-801; 5) Life expectancy of at least 3 months; 6) Have one of the following cancers with prior histologic confirmation breast, prostate, ovarian, head and neck, NSCLC, colorectal, gastric, esophageal, bladder, renal cell or melanoma, that has been refractory to two or more standard systemic treatment regimens for their disease with ability to collect tumor biopsy (primary or metastases) during screening period and in further observation according to protocol; 7) Be at least 30 days since the last dose of any prior chemotherapy regimen or other anticancer agent(s), and has had all toxicities caused by prior therapy resolve or no greater than grade 1 by the NCI Common Terminology for AE criteria before Day 1; 8) Subject is able to swallow and retain oral medication and does not have uncontrolled emesis; 9) Written informed consent obtained from the patient prior to performing any study-related procedures, including screening visits. Phase II Patients must meet the following criteria to enter the study: 1) Women at least 18 years of age 2) Eastern Cooperative Oncology Group performance status = 2 3) Must be surgically sterile or at least 1 year post-menopausal. Women of childbearing potential must agree to use effective methods of birth control during the treatment period from the first dose of study drug until 3 months following the last dose of study drug. Acceptable methods of contraception include non-hormonal intrauterine device and barrier methods (male condom, female condom, diaphragm or cervical cap) with spermicide. Patients who normally abstain from sexual activity may be recruited providing they remain abstinent during the study or if they become sexually active, they must agree to use effective methods of birth control as described above 4) Life expectancy of at least 3 months 5) Have metastatic triple-negative breast cancer following failure of at least two lines of chemotherapy for disseminated disease 6) Be at least 30 days since the last dose of any prior chemotherapy regimen or other anticancer agent(s), and has had all toxicities caused by prior therapy resolve or no greater than grade 1 by the NCI Common Terminology for AE criteria before Day 1 7) Subject is able to swallow and retain oral medication and does not have uncontrolled emesis 8) Written informed consent obtained from the patient prior to performing any study-related procedures, including screening visits 9) Must be
Exclusion criteria
Exclusion criteria: 1) Receipt of GLG-801 in any previous clinical study; 2) History of allergy or reaction to any component of the GLG-801 formulation; 3) Received palliative local or bone lesion radiation within 30 days prior to visit Day1; 4) History of malignancy other than those listed under inclusion criteria; 5) Hemoglobin = 10.0 g/dL, platelets 5 × ULN range; ALT > 5 × ULN range. Subjects with Gilbert's syndrome may have a bilirubin = 1.5 × ULN, if no evidence of biliary obstruction exists; 7) Folic acid level below normal reference ranges before Day 1; 8) Abnormal values of any of the screening coagulation tests (PT, AT, INR) by the local laboratory normal criteria, or receiving anticoagulant therapy for thromboembolic disease; 9) Clinical history of significant central nervous system (CNS) pathology, e.g., primary or secondary brain cancer, uncontrolled headaches, multiple occurrences of confusion, dementia, multiple previous infarcts, or major brain surgery; 10) Any known psychiatric conditions; 11) History of seizures; 12) Active infection or known bacteremia requiring antimicrobial therapy within 2 weeks prior to initiation of GLG-801; 13) Vaccination (either preventive or therapeutic for infectious disease or cancer) within 2 weeks prior to initiation of GLG-801; 14) Infection with human immunodeficiency virus (HIV-1 or HIV-2), acute or chronic infection with hepatitis B or C, or acute infection with hepatitis A; 15) History of serious, chronic autoimmune disease, eg, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis; or autoimmune hemolytic anemia or thrombocytopenia; 16) Elective surgery planned during the study period through 30 days after discontinuation of GLG-801; 17) Autologous or allogenic stem cell or bone marrow transplant; or any solid organ transplant; 18) Chronic or regular dosing with a systemic prednisone exceeding 10 mg/day or equivalent, or any other systemic immunosuppressive therapy, during 4 weeks prior to initiation of GLG-801 or anticipated need during the trial; 19) Any finding upon physical examination or history of any disease or behavior that, in the opinion of the investigator or medical monitor, that may compromise the safety of the patient in the study, interfere with compliance to the protocol, or confound the analysis of the study including known active abuse of drugs or alcohol; 20) Subjects with active brain metastases or leptomeningeal disease at screening must have clinically controlled neurologic symptoms and have received previous adequate treatment, defined as surgical excision and/or radiation therapy with stable neurologic function and no evidence of CNS disease progression as determined by comparing a computed tomography (CT) scan or magnetic resonance imaging (MRI) scan performed during screening to a prior scan performed at least 4 weeks earlier and provided that the subject is asymptomatic, has no evidence of cavitation or hemorrhage, and does not require corticosteroids; 21) Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption; 22) Symptomatic pleural effusion or ascites requiring periodic paracentesis; 23) Respiratory insufficiency requiring oxygen therapy; 24) History of acute myocardial infarction, stroke, transien
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I •To evaluate safety and tolerability of escalating dose levels of GLG-801 in adult patients with advanced, refractory, solid tumors. •To determine RP2D based on MTD. Phase II •To determine the response (radiologic ORR), in patients with metastatic TNBC (based on Recist 1.1. Criteria) •To confirm the safety and tolerability of GLG-801 in patients with advanced TNBC at RP2D as determined in Phase I portion of this study. ;Secondary Objective: Phase I To assess steady state serum concentration of GLG-801 - doses 50, 75 and 100 mg administrated once daily Phase II Proteomic analysis cancer samples - detection of proteins in tissue samples (20 subsets of biopsies of 60 patients; pre- and post-treatment), including 1. Basic analysis: HER2, ER (estrogen receptor), PR (progesterone receptor), STAT3 (cytoplasmic/nuclear/total) p-STAT3. 2. Proliferation markers:Ki-67; Cyclin D1. 3. Downstream markers of STAT3 activation Survivin, PDL-1. 4. TNBC markers:CK17, EGFR To evaluate whether GLG-801 modifies STAT3 (cytoplasmic/nuclear/total) and p-STAT3 levels in tumor biopsy specimens and/or in CTCs To evaluate CTCs level To evaluate effect of concentration at steady state on STAT3 inhibition and overall response as well as to assess GLG-801 levels overtime To evaluate whether GLG-801 clinical activity is dependent on TNBC subtype To evaluate whether baseline STAT3 activity in cancer tissue/CTCs predicts response to GLG-801 ;Primary end point(s): Phase I 1.Evaluation of safety and tolerability (% dropout) of escalating dose levels of GLG-801 2.Determination of RP2D based on MTD Phase II 1.Determination of the response (radiologic ORR), in patients with metastatic TNBC (based on Recist 1.1. Criteria) 2.Confirmation of the safety and tolerability of GLG-801 in patients with advanced TNBC, at RP2D as determined in Phase I portion of this study ;Timepoint(s) of evaluation of this end point: Day 29, Day 85 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I 1. Assessment of steady state serum concentration of GLG-801 with the three different doses 50, 75 and 100 mg administrated once daily Phase II 1. Proteomic analysis cancer samples - detection of proteins in tissue samples (biopsies in a subset of 20 of the planned 60 patients, pre- and post-treatment), including a. Basal detection: HER2, ER (estrogen receptor), PR (progesterone receptor), STAT3 (cytoplasmic/nuclear/total), p-STAT3 b. Proliferation markers: Ki-67; Cyclin D1 c. Downstream markers of STAT3 activation Survivin, PDL-1 d. TNBC markers: CK17, EGFR 2. Evaluation of GLG-801 effect on STAT3 (cytoplasmic, nuclear or total), p-STAT3 in tumor samples and/or in circulating tumor cells (CTCs), percentage of pSTAT3 positive cells STAT3 and pSTAT3 levels in all detected CTCs, 3. CTCs level 4. Assessment of GLG-801 levels during treatment.;Timepoint(s) of evaluation of this end point: Day 29, Day 85 | — |
Countries
Poland
Contacts
Public ContactClinical Trial Information
GLG Pharma S.A
Outcome results
None listed