ICON

ICON CA209-9FN: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with luminal B breast cancer. PI: Jon Amund Kyte.

Inclusion criteria

Patients must meet all of the following criteria to be eligible for study entry:

1. Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as ER+ >1% in metastatic biopsy (archival material or study biopsy) or cytology and HER2 negative in the last biopsy or cytology evaluable for HER2. HER2-analysis is to be perfomed according to national criteria.
2. Luminal B breast cancer, defined by the PAM50 panel performed on primary tumor or metastasis biopsy or cytology.
3. Adequate core or excisional study biopsy of a metastatic tumor lesion not previously irradiated. No anti-tumor treatment is allowed between the time point for biopsy and study entry.
4. Measurable metastatic disease according to RECIST
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Signed Informed Consent Form
7. Women or men aged ≥ 18 years
8. A minimum of 24 months since adjuvant/neoadjuvant chemotherapy with antracyclins
9. A maximum of one previous line with chemotherapy in the metastatic setting
10. Chemotherapy is considered as preferred treatment
11. Previous endocrine and targeted therapy is allowed
12. No use of systemic corticosteroids at study entry
13. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
14. Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 5 months after the last dose of study therapy.
15. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy
16. Able to swallow and retain orally administered medication
17. Adequate organ function as defined in Table 1

Table 1  Adequate Organ Function Laboratory Values

System	Laboratory Value
Hematological
Absolute neutrophil count (ANC)	≥1.50 x109/L
Lymphocyte count	≥0.80 x109/L
Platelets	≥100,000 / mcL
Hemoglobin	≥8 g/dL without transfusion or EPO dependency (within  10 days of assessment)
Renal
Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl)	≤1.5 X upper limit of normal (ULN) OR   ≥40 mL/min for subject with creatinine levels > 1.5 X institutional ULN
Hepatic
Serum total bilirubin	≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)	≤ 2.5 X ULN  OR ≤ 5 X ULN for subjects with liver metastases
Albumin	>25 g/L
Coagulation
International Normalized Ratio (INR) or Prothrombin Time (PT)	≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.

Exclusion criteria

The subject must be excluded from participating in the trial if the subject has/is:

1. Malignancies other than breast cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
2. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 8 weeks prior to randomization
3. Known CNS disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met:
   1. Measurable disease outside the CNS
   2. Asymptomatic for CNS disease > 4 months.
   3. Only supratentorial metastases allowed
   4. No evidence of progression after completion of CNS-directed therapy
   5. No ongoing requirement for dexamethasone as therapy for CNS disease
   6. No radiation of brain lesions within 4 months prior to randomization
   7. No leptomeningeal disease
4. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed
5. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
6. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
7. Pregnant or breastfeeding
8. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome)
9. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
10. Severe infection within 21 days prior to randomization, requiring hospitalization
11. Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible
12. Major surgical procedure within 21 days prior to randomization or anticipation of the
need for a major surgical procedure during the course of the study other than for diagnosis. Placement of central venous access catheter(s) is not considered a major surgical procedure and is therefore permitted
13. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
14. Known hypersensitivity to any of the components of the investigational products
15. A history of autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet all of the following conditions:
    1. Rash must cover less than 10% of body surface area.
    2. Disease is well controlled at baseline and only requiring low potency topical steroids
    3. No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
16. Undergone allogeneic stem cell or solid organ transplantation
17. A history of idiopathic pulmonary fibrosis or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
18. A positive test for HIV
19. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HbsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
20. Active tuberculosis
21. Currently receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
22. Received treatment with immune checkpoint modulators, including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies
23. Received treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
24. Received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
    1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study
    2. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI
    3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed
25. Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to study Cycle 1, Day 1.
26. A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
27. Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
28. Received a live vaccine within 30 days of planned start of study therapy, or is expected to receive such a vaccine while on therapy
    1. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
29. Any reason why, in the opinion of the investigator, the patient should not participate

ICON criteria (word doc).

Contact information: Jon Amund Kyte, Jon.Amund.Kyte(a)rr-research.no