OXEL: Immune Checkpoint or Capecitabine or Combination Therapy as Adjuvant Therapy for TNBC With Residual Disease

Study Overview
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Brief Summary
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This pilot study will provide preliminary data regarding the role of PIS in predicting the benefit of immune checkpoint inhibition with or without chemotherapy for high risk patients with TNBC and residual disease after effective neoadjuvant chemotherapy.

Official Title
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OXEL: A Pilot Study of Immune Checkpoint or Capecitabine or Combination Therapy as Adjuvant Therapy for Triple Negative Breast Cancer With Residual Disease Following Neoadjuvant Chemotherapy

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Biopsy proven TNBC: ER- and PR- defined as ≤5% cells stain positive HER2 negativity defined as: IHC 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells Residual disease of 1.0 cm at least of the primary tumor and/or node positive disease (at least ypN1) Patients must have completed neoadjuvant chemotherapy; patients must NOT have received capecitabine as part of their neoadjuvant therapy regimen. Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after s urgery prior to randomization. . Carboplatin-containing neoadjuvant chemotherapy is also allowed). Patients who cannot complete all planned neoadjuvant treatment cycles for any reason are considered high risk and therefore are eligible for the study if they have residual disease. Recovery of all toxicities from previous therapies to at least grade 1, except alopecia and ≤ grade 2 neuropathy which are allowed. Must have completed definitive resection of primary tumor and have no evidence of unresected or metastatic disease at the time of study entry Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) is allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory ECOG PS 0-2 Patients must not be planning to receive concomitantly other biologic therapy, hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except radiation therapy while receiving treatment on this protocol. At the time of registration (randomization), patients must have the following laboratory results (obtained within 28 days prior to registration): A serum TSH prior to registration to obtain a baseline value. Patients must have adequate bone marrow function as evidenced by all of the following: ANC ≥ 1,500 microliter (mcL); Platelets ≥ 100,000/mcL; Hemoglobin ≥ 9 g/dL. Patients must have adequate hepatic function as evidenced by the following: Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL), and SGOT (AST) or SGPT (ALT) and alkaline phosphatase ≤ 2.5 x IULN. Patients must have adequate renal function as evidenced by ONE of the following: Serum creatinine ≤ IULN OR Measured or calculated creatinine clearance ≥ 60 mL/min. Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration and within 24h prior to the start of nivolumab. In addition, women of childbearing potential must agree to have a pregnancy test every 4 weeks while on nivolumab. Signed ICF Age ≥18 Exclusion criteria: Stage IV disease Receipt of adjuvant chemotherapy Diagnosis of other invasive cancer except for adequately treated cervix cancer or skin cancer, or more than 5 years since other diagnosis of invasive cancer without current evidence of disease Previous exposure to capecitabine, fluorouracil or immunotherapy with anti-PD1, anti-PDL1, anti-CTLA4 or similar drugs. Active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic therapy TB, active hepatitis B, active hepatitis C or other active infection. Patients who have completed curative therapy for HCV are eligible. Patients with known HIV infection are eligible if they meet each of the following 3 criteria: CD4 counts ≥ 350 mm3; serum HIV viral load of < 25,000 IU/ml and treated on a stable antiretroviral regimen. History of (non-infectious) pneumonitis that required steroids or evidence of active pneumonia Uncontrolled disease Chronic use of systemic steroids Live vaccine within 30 days prior to registration. Incapacity to provide consent or to follow clinical trial procedures Pregnancy, lactation, or planning to be pregnant Patients with microsatellite unstable tumors will not be excluded as immunotherapy as adjuvant therapy is not standard for these patients but we will prospective collect this data.

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: Arm A<br>Nivolumab 360 mg iv q3weeks for x 6 cycles | Drug: Nivolumab<br>* Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.<br>* Other names: Opdivo;|
| Active Comparator: Arm B<br>Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles | Drug: Capecitabine<br>* Capecitabine was selected for Arm B given the recent results from CREATE-X trial and the increasing use by the community (feasibility). Importantly, available data from other scenarios indicates that capecitabine does not have immunosuppressive effects<br>* Other names: Xeloda;|
| Experimental: Arm C<br>Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles | Drug: Nivolumab<br>* Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.<br>* Other names: Opdivo;Drug: Capecitabine<br>* Capecitabine was selected for Arm B given the recent results from CREATE-X trial and the increasing use by the community (feasibility). Importantly, available data from other scenarios indicates that capecitabine does not have immunosuppressive effects<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune activation measured by changes in the peripheral immunoscore (PIS) at week 6 | Quantification of immune activation measured by changes of PIS from baseline to week 6 in each arm. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune activation measured by changes of PIS at week 12 | Quantification of immune activation measured by changes of PIS from baseline to week 12 in each arm. | 12 weeks | 
| Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.03] | Quantification of grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.03] | 18 weeks + 30 days after last dose received | 
| Distant recurrence free survival (DRFS) and Overall Survival | To determine association between changes in PIS from baseline to week 6 and week 12 and clinical outcome variables (DRFS and OS at 3 years). After end of study visit, clinical follow up or telephone communication every 3 months (DRFS and OS at 3 years). Distant recurrence free survival (DRFS) is defined by time from study enrollment to date of first invasive distant disease recurrence, second invasive primary cancer (breast or not), or death due to any cause. | 3 years | 
| Immune activation in the tumor by IHC | Quantification of immune activation by IHC | 18 weeks | 
| Immune activation in the tumor by flow cytometry | Quantification of immune activation by flow cytometry | 18 weeks | 
| Immune activation in the tumor by ELISA | Quantification of immune activation by ELISA | 18 weeks | 
| Intracellular cytokine staining and CD8+ T-cell clonal expansion | Quantification of antigen-specific responses by intracellular cytokine staining and CD8+ T-cell clonal expansion | 18 weeks | 
| Circulating tumor DNA | Quantification of ct-DNA at different time points | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple Negative Breast Cancer, Nivolumab, Capecitabine