Guided Treatment Based on Mini-PDX in Metastatic Triple Negative Breast Cancer

Study Overview
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Brief Summary
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Triple-negative breast cancer constitutes 15-20% of cases of breast cancer and is defined by the absence of estrogen receptors, progesterone receptors, and overexpression or gene amplification of HER2. Although the addition of immune checkpoint inhibitors could improve the outcome of patients with metastatic triple-negative breast cancer (mTNBC), chemotherapy has been the standard of care for systemic treatment for patients with mTNBC. Prognoses remain poor, with reported median overall survival estimates of approximately 18 months or less with available treatments. A meta-analysis of seven clinical trials showed that the median objective response rate (ORR) of second or later line of chemotherapy in mTNBC was only 11%. Patient-derived xenograft (PDX) tumor model, which preserves the histologic and genetic characteristics of patients' tumors, has shown its predictive value of clinical outcomes and are used for preclinical drug evaluation, biomarker identification, biological studies, and personalized medicine strategies. However, long time period and low success rate has limited its application in clinical practice. Mini patient derived xenograft (miniPDX) offers an effective alternative as it only takes about 7 days for drug sensitivity test and could thus provide guidance for prompt personalized treatment for each patient. Thus, the investigators conduct this single-center, prospective, randomized controlled clinical study to investigate the efficacy of guided treatment based on Mini-PDX in patients with metastatic refractory triple negative breast cancer.

Official Title
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GUided Treatment Based on Mini-PDX in metastaTIc refractOry Triple Negative Breast Cancer(GUMPTION)：a Prospective Randomized Controlled Single Center Clinical Trial

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Personalized treatment guided by mini-PDX and RNA sequencing
* Drug: Nab paclitaxel
* Drug: Eribulin
* Drug: Vinorelbine
* Drug: Gemcitabine
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) Women aged 18-70 years; 2) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 3) Estimated lifetime is ≥ 3 months; 4) Histopathologically confirmed recurrent (unresectable) or metastatic triple-negative breast cancer; ER and PR negative is defined as ER <1% positive, PR <1% positive. HER-2 negative is defined as HER-2 (-) or (1+) by immunohistochemistry, HER-2 (2+) must be tested by FISH with negative result, HER-2 (1+) (1+), FISH is optional and negative; 5) Have at least one measurable target lesion according to RECIST 1.1 criteria; 6) Biopsy of the tumor lesion and the specimen passes laboratory quality control; 7) A minimum of 2 prior cytotoxic chemotherapy regimens (including at least one line of platinum-containing regimen) in metastatic settings are required prior to enrollment in this trial; 8) Adequate organ function, i.e. meeting the following criteria. Hb ≥ 90 g/L (no transfusion within 14 days); ANC ≥ 1.5 × 109 /L; PLT ≥ 75 × 109 /L. Liver function: total bilirubin TBIL ≤ 1.5×ULN (upper limit of normal); ALT and AST ≤ 3×ULN. serum Cr ≤ 1.5×ULN. 9) Subjects voluntarily joined the study, signed the informed consent form, were compliant and cooperated with the follow-up. Exclusion Criteria: 1）Pregnancy or lactation； 2）History of autoimmune disease； 3）Anticancer- and radiation therapy-related toxicities have not resolved or downgraded to Grade 1 or less; 4) Symptomatic central nervous system (CNS) disease; 5) Previous treatment of Immune checkpoint inhibitors; 6) History of other malignancies within the past five years, with the exception of cured non-malignant melanoma of the skin and carcinoma in situ of the cervix.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

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: Personalized treatment guided by Mini-PDX<br>The tumor tissue is used for drug sensitivity test by Mini-PDX, and acquiring the genetic information by RNA-sequence. Patients with mTNBC will receive personalized treatment guided by the experimental results of mini-PDX and RNA sequencing. | Drug: Personalized treatment guided by mini-PDX and RNA sequencing<br>* Personalized treatment guided by mini-PDX and RNA sequencing<br>|
| Active Comparator: Treatment of Physician's Choice (TPC)<br>TPC will be administered per standard of care. Patients randomized to TPC will receive chemotherapy, including but not limited to the following agents: nab-paclitaxel, eribulin, vinorelbine, gemcitabine, capecitabine. | Drug: Nab paclitaxel<br>* Nab-paclitaxel 125 mg/m2，ivgtt，d1, 8, 15, q4w<br>Drug: Eribulin<br>* Eribulin 1.4 mg/m2, d1,8 q3w<br>Drug: Vinorelbine<br>* Vinorelbine 25mg/m2 d1,8, q3w<br>Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m2, d1,8, q3w<br>Drug: Capecitabine<br>* Capecitabine 1250 mg/m2 bid po<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | To compare the Objective Response Rate (ORR) of patients who recieve persionalized treatment based on mini-PDX model with ORR of patients who receive Treatment of Physician's Choice (TPC). ORR is defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) according to RECIST 1.1. ORR will be calculated based on the Investigator assessment of response. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | Through study completion, an expected average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from the date of randomization to the date of death from any cause. Patients will be followed until their date of death or until final database closure. Patients who are lost-to-follow-up or are alive at the time of analysis will be censored at the time they were last known to be alive or at the date of event cut-off for OS analysis. | Through study completion, an expected average of 1 year | 
| Progression-Free Survival | Progression-free survival is defined as the time from the date of randomization to the first evidence of documented disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. | Through study completion, an expected average of 1 year | 
| Adverse events | Number of participants with adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 | Through study completion, an expected average of 1 year |