E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Triple-Negative Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Triple-Negative Breast Cancer |
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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 | 10075566 |
E.1.2 | Term | Triple negative 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 |
To determine whether the addition of eryaspase to gemcitabine and carboplatin improves the disease control rate (DCR) by modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by an independent radiological review (IRR) in patients with locally recurrent or metastatic triple-negative breast cancer (TNBC) compared with chemotherapy alone. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are: To compare DCR between the two treatment arms as determined by the Investigator’s assessment; To compare ORR between the two treatment arms as determined by the IRR; To compare DoR between the two treatment arms; To compare PFS between the two treatment arms; To compare OS between the two treatment arms; To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone; To evaluate the change in F-18 fluorodeoxyglucose (FDG) tumor uptake as a predictor of clinical response following one cycle of treatment with eryaspase and chemotherapy; To determine the PK and pharmacodynamics of eryaspase; To assess the immunogenicity of eryaspase as determined by the induction of antiasparaginase antibodies and neutralizing antibodies; To evaluate the relationship of clinical outcome with relevant biomarkers and tumorspecific mutational changes present in tumor tissues and blood samples |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient will be eligible for the study if all the following criteria are met: 1. Female or male, 18 years of age or older. 2. Histologically or cytologically confirmed diagnosis of invasive breast cancer. 3. Metastatic or locally recurrent inoperable breast cancer with no more than one prior systemic therapy. 4. Diagnosis (original primary tumor or subsequent relapse) of triple negative breast cancer, defined as the absence of expression of the following receptors in the primary and/or metastatic tumor tissue: - HER2 protein over-expression and/or gene amplification, defined as: a) fluorescent in situ hybridization (FISH)-negative: FISH ratio <2.2), or b) immunohistochemistry (IHC) 0-1+, or c) IHC 2+/3+ AND FISH-negative (FISH ratio <2.2) (1). - Estrogen receptor (ER), defined as <1% staining by IHC (2). - AND progesterone receptors (PgR), defined as <1% staining by IHC. 5. Measurable lesion(s) per RECIST 1.1. 6. Available archival or fresh tumor tissue. Formalin-fixed paraffin-embedded (FFPE) block is preferred, or a minimum of 10 unstained, consecutive FFPE slides of one archived block is required. 7. Adequate performance status (PS) score (see Appendix 11.2): o Eastern Cooperative Oncology Group (ECOG) PS score of 0, or o ECOG PS score 1 and score ≥80 on Karnofsky Performance Status (KPS) scale. 8. Life expectancy of >12 weeks according to the Investigator’s clinical judgment. 9. Females of childbearing potential must have a negative pregnancy test at screening and an additional negative pregnancy test prior to first dose. Sexually active males and females of childbearing potential must agree to use a highly effective method of contraception during treatment and for at least 6 months after the last dose of study treatment. 10. Adequate laboratory parameters at baseline (obtained <14 days prior to randomization): Laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the medical monitor: - Absolute neutrophil count ≥1.5 x 109/L. - Hemoglobin ≥9 g/dL. Patients with a baseline hemoglobin ≥13 g/dL should be discussed with the medical monitor. - Platelet count ≥100,000/mm3 (100 x 109/L). - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases). - Total bilirubin ≤ 1.5 x institutional ULN. - Serum creatinine within normal limits or calculated clearance >60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the institutional normal range. - Acceptable coagulation parameters: plasma antithrombin III >70%, fibrinogen ≥1.5 g/L, international normalized ratio (INR) <1.5, and partial thromboplastin time (PTT) ≤ institutional ULN. - Serum albumin ≥3.0 g/dL. 11. Patients must be able to understand and comply with the conditions of the protocol and must have read and understood the consent form and provided written informed consent. |
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E.4 | Principal exclusion criteria |
A patient is not eligible to participate in the study if any of the following criteria are met: 1. Pregnant or lactating females. 2. Known BRCA1 or BRCA2 mutation carrier. 3. Bone as the only site of disease. 4. Presence of untreated symptomatic central nervous system (CNS) metastases as determined by MRI or CT scan performed during screening. 5. Prior radiotherapy to the only area of measurable disease. 6. Prophylactic use of supportive bone-modifying therapy for skeletal-related events (e.g., bisphosphonate, pamidronate, or denosumab), unless treatment is initiated prior to or within 7 days after randomization. 7. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 3 months of randomization. 8. Neurosensory neuropathy >Grade 2 at baseline. 9. Known history of infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C. 10. Known hypersensitivity to gemcitabine, platinum compounds, or asparaginase. 11. Patients who have received live or live attenuated vaccines within 3 weeks of randomization. 12. Pre-existing coagulopathy (e.g. hemophilia). 13. History of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >2 years. 14. Any other severe acute or chronic condition/treatments that may increase the risk of study participation, including: - Current or history within 6 months prior to randomization of medically significant cardiovascular disease including symptomatic congestive heart failure >New York Heart Association (NYHA) Class II, unstable angina pectoris, clinically significant cardiac arrhythmia. - Psychiatric illness/social situations or any other serious uncontrolled medical disorders that in the opinion of the Investigator would limit compliance with study requirements. 15. Receiving therapy in a concurrent clinical study. Patients must agree not to participate in any other interventional clinical studies during their participation in this trial while on study treatment. Patients taking part in surveys or observational studies are eligible to participate in this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is DCR in PP population, assessed by independent radiological review. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
In light of the small sample size for Part 1, the one-sided p-value will be obtained using the stratified version of Fisher’s Exact test with stratification defined by the factors used for randomization. |
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E.5.2 | Secondary end point(s) |
To evaluate: - Progression-free survival (PFS) - Objective Response Rate (ORR) - Best overall response (BOR) - Duration of Treatment (DOT) - Duration of Response (DOR) - Overall Survival (OS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS is measured as interval from randomization until objective tumor progression or death from any cause, whichever occurs first. ORR is defined as the proportion of patients who achieve complete and/or partial response (CR/PR). DOT is time from randomization to discontinuation of study treatment for any reason. DOR is measured from time measurement criterias are first met for CR/PR (whichever is first recorded) per modified RECIST 1.1 until first date that recurrent disease or PD is objectively documented. OS is interval from date of randomization to date of death from any cause. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity; Biomarker assessment;Radiological disease assessment |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
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 | 2 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
Belgium |
Hungary |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 end of the study is defined as completion of the last patient’s last visit. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |