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

• ClinicalTrials.gov Identifier: NCT03487666
• Recruitment Status: Active, not recruiting
• First Posted: April 4, 2018
• Last Update Posted: March 15, 2022
• Sponsor: Georgetown University
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Georgetown University

Tracking Information

• First Submitted Date: March 20, 2018
• First Posted Date: April 4, 2018
• Last Update Posted Date: March 15, 2022
• Actual Study Start Date: May 21, 2018
• Actual Primary Completion Date: November 3, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 2, 2018)

Immune activation measured by changes in the peripheral immunoscore (PIS) at week 6 [ Time Frame: 6 weeks ]

Quantification of immune activation measured by changes of PIS from baseline to week 6 in each arm.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 2, 2018)

• Immune activation measured by changes of PIS at week 12 [ Time Frame: 12 weeks ]
  Quantification of immune activation measured by changes of PIS from baseline to week 12 in each arm.
• Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 [NCI CTCAE v4.03] [ Time Frame: 18 weeks + 30 days after last dose received ]
  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]
• Distant recurrence free survival (DRFS) and Overall Survival [ Time Frame: 3 years ]
  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.
• Immune activation in the tumor by IHC [ Time Frame: 18 weeks ]
  Quantification of immune activation by IHC
• Immune activation in the tumor by flow cytometry [ Time Frame: 18 weeks ]
  Quantification of immune activation by flow cytometry
• Immune activation in the tumor by ELISA [ Time Frame: 18 weeks ]
  Quantification of immune activation by ELISA
• Intracellular cytokine staining and CD8+ T-cell clonal expansion [ Time Frame: 18 weeks ]
  Quantification of antigen-specific responses by intracellular cytokine staining and CD8+ T-cell clonal expansion
• Circulating tumor DNA [ Time Frame: 12 weeks ]
  Quantification of ct-DNA at different time points

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: OXEL: Immune Checkpoint or Capecitabine or Combination Therapy as Adjuvant Therapy for TNBC With Residual Disease
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Triple Negative Breast Cancer

Intervention

• Drug: Nivolumab
  Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.
  Other Name: 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 Name: Xeloda

Study Arms

• Experimental: Arm A
  Nivolumab 360 mg iv q3weeks for x 6 cycles
  Intervention: Drug: Nivolumab
• Active Comparator: Arm B
  Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles
  Intervention: Drug: Capecitabine
• Experimental: Arm C
  Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles
  Interventions:

  • Drug: Nivolumab
  • Drug: Capecitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 2, 2018): 45
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2022
• Actual Primary Completion Date: November 3, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03487666
• Other Study ID Numbers: 2017-1535
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Georgetown University
• Original Responsible Party: Same as current
• Current Study Sponsor: Georgetown University
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Chair: Candace Mainor, MD; MedStar Georgetown University Hospital

• PRS Account: Georgetown University
• Verification Date: March 2022