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

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

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.

Study Overview

• Status: Completed
• Conditions: Triple Negative Breast Cancer
• Intervention / Treatment: Drug: Nivolumab; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. 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
2. Residual disease of 1.0 cm at least of the primary tumor and/or node positive disease (at least ypN1)
3. 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.
4. Recovery of all toxicities from previous therapies to at least grade 1, except alopecia and ≤ grade 2 neuropathy which are allowed.

5. 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
6. ECOG PS 0-2
7. 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.

8. At the time of registration (randomization), patients must have the following laboratory results (obtained within 28 days prior to registration):

   1. A serum TSH prior to registration to obtain a baseline value.

   2. 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.

   3. 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.

   4. 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.
   5. 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.
9. Signed ICF
10. Age ≥18

Exclusion criteria:

1. Stage IV disease
2. Receipt of adjuvant chemotherapy
3. 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
4. Previous exposure to capecitabine, fluorouracil or immunotherapy with anti-PD1, anti-PDL1, anti-CTLA4 or similar drugs.
5. Active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic therapy
6. 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.
7. History of (non-infectious) pneumonitis that required steroids or evidence of active pneumonia
8. Uncontrolled disease
9. Chronic use of systemic steroids
10. Live vaccine within 30 days prior to registration.
11. Incapacity to provide consent or to follow clinical trial procedures
12. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Nivolumab 360 mg iv q3weeks for x 6 cycles	Drug: Nivolumab; Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.; Other Names: Opdivo
Active Comparator: Arm B; Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles	Drug: Capecitabine; 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; Other Names: Xeloda
Experimental: Arm C; Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles	Drug: Nivolumab; Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.; Other Names: Opdivo; Drug: Capecitabine; 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; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in the Peripheral Immunoscore (PIS) at Week 6	PIS were developed using methods previously described (Farsaci, B. et al. Cancer Immunol. Res. 2016), based on tertile distribution of frequencies and ratios of peripheral immune cell subsets in patients prior to therapy. Immune subsets were calculated as a % of PBMC and sorted by frequency. Points were assigned to each subset in a given patient based on tertile distribution. For subsets with an expected positive effect on anti-tumor immunity zero (0) points were assigned to the low bin, one (1) point for the middle bin, and two (2) points if in the high bin. For subsets with an expected negative effect on anti-tumor immunity zero (0) points were assigned to the high bin, one (1) point for the middle bin, and two (2) points if in the low bin. The peripheral immunoscore for a given patient was the sum of points assigned to the individual PBMC subsets that were included within the immunoscore. Positive change means enhanced and negative change means reduced immune function.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change of Peripheral Immuno Score (PIS) at Week 12	PISs were developed using methods previously described (Farsaci, B. et al. Cancer Immunol. Res. 2016), based on tertile distribution of frequencies and ratios of peripheral immune cell subsets in patients prior to therapy. Immune subsets were calculated as a % of PBMC and sorted by frequency. Points were assigned to each subset in a given patient based on tertile distribution. For subsets with an expected positive effect on anti-tumor immunity zero (0) points were assigned to the low bin, one (1) point for the middle bin, and two (2) points if in the high bin. For subsets with an expected negative effect on anti-tumor immunity zero (0) points were assigned to the high bin, one (1) point for the middle bin, and two (2) points if in the low bin. The peripheral immunoscore for a given patient was the sum of points assigned to the individual PBMC subsets that were included within the immunoscore. Positivie change mean enhanced and negative change means reduced immune function.	12 weeks
Grade 3 and 4 Adverse Events	The number of grade 3 and 4 adverse events as assessed clinically by an investigator, according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.03]. Grade 4 adverse events were associated with worse outcomes.	From date of consent until 100 days after the last dose of study treatment, approximately up to 11 months
Invasive Disease Free Survival (DRFS)	iDFS was defined as the time from date of randomization to the date of first invasive disease recurrence, second invasive primary cancer (breast or not), or death from any cause.	2 years
Circulating Tumor DNA	Out of the patients with available ct-DNA samples at baseline, week 6 and week 12, the proportion of patients with detectable ct-DNA at the same timepoints.	6 weeks and 12 weeks

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Chair: Candace Mainor, MD, MedStar Georgetown University Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2018
• Primary Completion (Actual): November 3, 2021
• Study Completion (Actual): May 2, 2024

Study Registration Dates

• First Submitted: March 20, 2018
• First Submitted That Met QC Criteria: April 2, 2018
• First Posted (Actual): April 4, 2018

Study Record Updates

• Last Update Posted (Actual): December 3, 2024
• Last Update Submitted That Met QC Criteria: November 7, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Capecitabine; Nivolumab; Triple Negative Breast Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Capecitabine; Nivolumab
• Other Study ID Numbers: 2017-1535

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No