Study of Eryaspase in Combination With Chemotherapy Versus Chemotherapy Alone for the Treatment of TNBC (TRYbeCA-2)

Study Overview
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Brief Summary
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This is an open-label, multicenter, randomized, Phase 2/3 study in patients with locally recurrent or metastatic triple-negative breast cancer (TNBC) with no more than one prior systemic therapy for locally recurrent or metastatic disease.

Detailed Description
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The study will consist of 2 parts: Part 1 is an open-label, multicenter, randomized Phase 2 exploratory study that will investigate the clinical activity of the combination of eryaspase and gemcitabine/carboplatin in patients with locally recurrent or metastatic TNBC. Data analysis of Part 1 will inform choices for the final design and patient population in Part 2 (Phase 3 study). Patients recruited into Part 1 will not be included in the Intent-to-Treat patient (ITT) population of Part 2 of the study. Part 2 will be a randomized Phase 3 study designed to evaluate the efficacy of the combination of eryaspase and gemcitabine/carboplatin in TNBC patients. The current protocol will focus on Part 1. Part 1 is the focus of the current protocol, with a primary endpoint of DCR. DCR data as determined by an IRR will determine whether or not proceeding to Part 2 is warranted. If so, Part 2 will be implemented via a major amendment to the protocol. Meanwhile, sites will remain open with the expectation that Part 2 will be activated After providing informed consent and completing the screening assessments, patients who meet all inclusion and no exclusion criteria will be randomized in a 1:1 ratio to one of the following treatment arms: Arm A (experimental arm): eryaspase 100 U/kg on Days 1 and 8 of combination chemotherapy with gemcitabine/carboplatin, or Arm B (control arm): gemcitabine/carboplatin combination. Treatment will continue until objective disease progression, unacceptable toxicity, or the patient's withdrawal of consent. A survival follow-up period will include the collection of survival, progression of disease if applicable, subsequent anti-cancer therapy every 12 weeks (± 1 week)

Official Title
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A Randomized Phase 2/3 Study of Eryaspase in Combination With Gemcitabine and Carboplatin Chemotherapy Versus Chemotherapy Alone for the Treatment of Patients With Metastatic or Locally Recurrent Triple-Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: eryaspase (L-asparaginase encapsulated in red blood cells)
* Drug: Gemcitabine
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male, 18 years of age or older. Histologically or cytologically confirmed diagnosis of invasive breast cancer. Metastatic or locally recurrent inoperable breast cancer with no more than one prior systemic therapy. 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 Estrogen receptor (ER), defined as <1% staining by IHC (2). AND progesterone receptors (PgR), defined as <1% staining by IHC. Measurable lesion(s) per RECIST 1.1. Available archival or fresh tumor tissue. Adequate performance status (PS) score. Life expectancy of >12 weeks according to the Investigator's clinical judgment. Females of childbearing potential must have a negative pregnancy test at screening and an additional pregnancy test prior to first dose. 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. Adequate laboratory parameters at baseline (obtained <14 days prior to randomization) 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. Exclusion Criteria: Pregnant or lactating females. Known BRCA1 or BRCA2 mutation carrier. Bone as the only site of disease. Presence of untreated symptomatic central nervous system (CNS) metastases as determined by MRI or CT scan performed during screening. Prior radiotherapy to the only area of measurable disease. 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. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 3 months of randomization. Neurosensory neuropathy >Grade 2 at baseline. Known history of infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C. Known hypersensitivity to gemcitabine, platinum compounds or asparaginase. Patients who have received live or live attenuated vaccines within 3 weeks of randomization. Pre-existing coagulopathy (e.g. hemophilia). 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. Any other severe acute or chronic condition/treatments that may increase the risk of study participation 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eryaspase plus Chemotherapy<br>eryaspase 100 U/kg dosed at Day 1 and Day 8 of each 3-week cycle in combination with Gemcitabine IV infusion 1000 mg/m2, Day 1 and Day 8. Carboplatin IV infusion at a calculated area under the curve (AUC) of 2.0 (AUC2), Day 1 and Day 8. | Drug: eryaspase (L-asparaginase encapsulated in red blood cells)<br>* IV infusion 100 U/kg<br>* Other names: ERY001, GRASPA;Drug: Gemcitabine<br>* IV infusion 1000 mg/m2<br>* Other names: Gemzar;Drug: Carboplatin<br>* IV infusion AUC2<br>* Other names: Paraplatin;|
| Active Comparator: Chemotherapy alone<br>Gemcitabine plus carboplatin dosed at Day 1 and Day 8 of each 3-week cycle | Drug: Gemcitabine<br>* IV infusion 1000 mg/m2<br>* Other names: Gemzar;Drug: Carboplatin<br>* IV infusion AUC2<br>* Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | 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. | 1 year after last patient randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | To compare the DCR between the two treatment arms as determined by the Investigator's assessment. | 1 year after last patient randomized | 
| Objective response rate (ORR) | To compare the objective response rate (ORR) between the two treatment arms as determined by the independent radiological review (IRR). | 1 year after last patient randomized. | 
| Progression-Free Survival (PFS) | To compare progression-free survival (PFS) between the two treatment arms. | 1 year after last patient randomized. | 
| Duration of Response (DoR) | To compare the duration of response (DoR) between the two treatment arms. | 1 year after last patient randomized. | 
| Overall Survival (OS) | To compare overall survival (OS) between the two treatment arms. | 1 year after last patient randomized. | 
| Incidence of treatment emergent adverse events as assessed by CTCAE v5.0 | To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone by assessing the number of patients with treatment emergent adverse events per CTCAE v5.0. | Collected from time of informed consent until 30 days after last study treatment. | 
| Clinical response assessed by F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging | 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. | Collected at baseline and within 3 days of the end of Cycle 1 in all patients. | 
| Eryaspase induced immunogenecity | To determine the anti-asparaginase antibodies titer. | Samples will be collected pre-dose at Cycle 1 Day 1 and pre-dose at Cycle 3 Day 1 (each Cycle is 21 days) | 
| Biomarkers potentials in predicting eryaspase activity. | To determine DNA, RNA and protein levels present in tumor tissues and blood samples. | Tissue samples will be collected at baseline. Blood samples for biomarker analysis will be collected during screening, at Cycle 1 Day 1 and Day 8, and at Day 1 of every second cycle ( each is 21 days) until End of Treatment (EOT) visit. | 
| Pharmacokinetics of eryaspase | To determine total and plasma asparaginase activity (U/L) | Samples will be collected the first day (D1) and the eight day (D8) of Cycle 1 and Cycle 3 treatment (each Cycle is 21 days) and at End of treatment (EOT) | 
| Pharmacodynamics of eryaspase | To determine plasma concentrations of asparagine and glutamine (µmol/L) | Samples will be collected the first day (D1) and the eight day (D8) of Cycle 1 and Cycle 3 treatment (each Cycle is 21 days) and at End of treatment (EOT) |