Triple Negative Breast Cancer
Conditions
Keywords
Triple Negative Breast Cancer, Nivolumab, Capecitabine
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.
Interventions
DRUGNivolumab
Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.
DRUGCapecitabine
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
Sponsors
Bristol-Myers Squibb
Georgetown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in the Peripheral Immunoscore (PIS) at Week 6 | 6 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change of Peripheral Immuno Score (PIS) at Week 12 | 12 weeks | 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. |
| Grade 3 and 4 Adverse Events | From date of consent until 100 days after the last dose of study treatment, approximately up to 11 months | 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. |
| Invasive Disease Free Survival (DRFS) | 2 years | 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. |
| Circulating Tumor DNA | 6 weeks and 12 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A- Nivolumab Nivolumab 360 mg iv q3weeks for x 6 cycles
Nivolumab: Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases. | 15 |
| Arm B- Capecitabine Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles
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 | 15 |
| Arm C Nivolumab + Capecitabine Nivolumab 360mg iv q3weeks + Capecitabine 1250mg/m2 bid D1-D14 q3 weeks x 6 cycles
Nivolumab: Nivolumab is a human programmed death receptor-1 (PD-1) antibody currently approved in different diseases.
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 | 15 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Disease progression | 4 | 2 | 0 |
Baseline characteristics
| Characteristic | Arm A- Nivolumab | Arm B- Capecitabine | Arm C Nivolumab + Capecitabine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 13 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 13 Participants | 13 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 6 Participants | 8 Participants | 25 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 15 Participants | 45 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 15 | 2 / 15 | 2 / 15 |
| other Total, other adverse events | 14 / 15 | 15 / 15 | 15 / 15 |
| serious Total, serious adverse events | 3 / 15 | 0 / 15 | 3 / 15 |
Outcome results
Primary
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.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A- Nivolumab | Percent Change in the Peripheral Immunoscore (PIS) at Week 6 | 30.63 % Change in PIS |
| Arm B- Capecitabine | Percent Change in the Peripheral Immunoscore (PIS) at Week 6 | -21.9 % Change in PIS |
| Arm C Nivolumab + Capecitabine | Percent Change in the Peripheral Immunoscore (PIS) at Week 6 | 32.285 % Change in PIS |
Secondary
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.
Time frame: 6 weeks and 12 weeks
Population: The number analyzed reflects those patients that had samples that were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A- Nivolumab | Circulating Tumor DNA | Week 6 | 6 Participants |
| Arm A- Nivolumab | Circulating Tumor DNA | Baseline | 6 Participants |
| Arm A- Nivolumab | Circulating Tumor DNA | Week 12 | 6 Participants |
| Arm B- Capecitabine | Circulating Tumor DNA | Week 6 | 2 Participants |
| Arm B- Capecitabine | Circulating Tumor DNA | Baseline | 4 Participants |
| Arm B- Capecitabine | Circulating Tumor DNA | Week 12 | 3 Participants |
| Arm C Nivolumab + Capecitabine | Circulating Tumor DNA | Baseline | 4 Participants |
| Arm C Nivolumab + Capecitabine | Circulating Tumor DNA | Week 12 | 1 Participants |
| Arm C Nivolumab + Capecitabine | Circulating Tumor DNA | Week 6 | 1 Participants |
Secondary
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.
Time frame: From date of consent until 100 days after the last dose of study treatment, approximately up to 11 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A- Nivolumab | Grade 3 and 4 Adverse Events | Grade 4 Adverse Events | 0 number of adverse events |
| Arm A- Nivolumab | Grade 3 and 4 Adverse Events | Grade 3 Adverse Events | 2 number of adverse events |
| Arm B- Capecitabine | Grade 3 and 4 Adverse Events | Grade 4 Adverse Events | 0 number of adverse events |
| Arm B- Capecitabine | Grade 3 and 4 Adverse Events | Grade 3 Adverse Events | 8 number of adverse events |
| Arm C Nivolumab + Capecitabine | Grade 3 and 4 Adverse Events | Grade 4 Adverse Events | 0 number of adverse events |
| Arm C Nivolumab + Capecitabine | Grade 3 and 4 Adverse Events | Grade 3 Adverse Events | 3 number of adverse events |
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A- Nivolumab | Invasive Disease Free Survival (DRFS) | 16.75 Months |
| Arm B- Capecitabine | Invasive Disease Free Survival (DRFS) | 16.04 Months |
| Arm C Nivolumab + Capecitabine | Invasive Disease Free Survival (DRFS) | 21.37 Months |
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A- Nivolumab | Percent Change of Peripheral Immuno Score (PIS) at Week 12 | 33.3 % Change in PIS |
| Arm B- Capecitabine | Percent Change of Peripheral Immuno Score (PIS) at Week 12 | -16.2 % Change in PIS |
| Arm C Nivolumab + Capecitabine | Percent Change of Peripheral Immuno Score (PIS) at Week 12 | 18.83 % Change in PIS |