Efficacy of Interleukin-2 in Triple Negative Breast Cancer
Study Details
Study Description
Brief Summary
This study is a single arm, non-randomized experimental study design. It will provide us opportunity to conduct a pilot study to evaluate the efficacy of an intralesional immunotherapy (e.g. IL-2) in early stage TNBC as a well-tolerated, low-risk intervention with the potential to improve outcomes without the toxicity of systemic treatment. Following are the objectives of this study:
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Utilize new and existing infrastructure within the Breast Health and Women Program at the IWK to conduct the institutions first surgery-driven breast cancer trial
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Evaluate the feasibility of patient accrual in a window of opportunity trial design
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Evaluate the efficacy of intralesional IL-2 to produce a pathologic response in TNBC.
The participants with TNBC will be receiving 3-4 injections of Interleukin-2. Total dose per injection is 25 million international units per mm width of tumor to max dose of 10 million IU. Half of total dose will be injected in the center of lesion/tumor and remaining half of total dose at periphery / peri-tumoral.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1/Phase 2 |
Detailed Description
Breast cancer is a leading cause of cancer related death in women. Triple negative breast cancer (TNBC) is a subtype of breast cancer based on immunohistochemistry lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor-2 (HER2) expression. It is known to disproportionately affects younger women and women of African ancestry. TNBCs account for approximately 15-20% of all newly diagnosed breast cancer. Compared to other subtypes of breast cancer, including hormone sensitive disease, TNBC is associated with a high risk of distant metastases and is associated with a lower disease-free and overall survival. As TNBCs lack expression for ER, PR and HER-2, targeted therapies are ineffective. Immunotherapy has emerged as an important treatment strategy in TNBC. Traditionally, breast cancer has been considered a 'cold' cancer but the disease is highly heterogenous and TNBC appears to be more immunogenic (i.e. 'hot'). Compared to other forms of the disease, TNBC is associated with a higher mutational burden, tumor infiltrating lymphocytes (TILs) and PD-L1 expression. The later is associated with response to immunotherapy. Indeed, systemic immunotherapy is now approved as first line therapy for metastatic and unresectable PD-L1 positive TNBC. Systemic immunotherapy may also increase the incidence of pathologic complete response after neoadjuvant therapy in early stage TNBC, although the impact on disease-free and overall survival is less clear. Improvement in pathologic complete response is weighed against rare but life-threatening immune related side-effects of immunotherapy, including adrenal insufficiency, pneumonitis causing respiratory arrest and multi-organ dysfunction syndrome.
Interleukin-2 is one of the first immunomodulating agents to be approved for cancer treatment, including renal cell carcinoma and melanoma. The cytokine plays an important role in the maintenance CD4+ regulatory T-cells and the differentiation of CD4+ T-cells into a variety of subsets. It also promotes CD8+ T-cell and NK cell cytotoxicity activity and modulates T-cell differentiation in response to antigen presentation. Systemically, IL-2 is limited by a short half-life and significant toxicities. The intralesional injection of IL-2 eliminates the undesirable grade II/III toxicities and often severe side effects of the therapy, while achieving high doses of IL-2 at the tumor site. The most common side effect of intralesional IL-2 is inflammation at the site of injection and mild flu like symptoms, including fatigue and nausea. Rarely patients may experience low-grade fever or headache, which are easily controlled by over-the-counter medications. A number of studies have reported on the use of intralesional IL-2 in management of in-transit melanoma. In this patient population, intralesional IL-2 produces a durable complete response. Much less has been published on its use in other cancers, such as breast cancer. However, there is case report level evidence to suggest that intralesional IL-2 can produce a pathologic complete response in metastatic / unresectable TNBC.
The present study considers the significant scope that remains to improve the outcomes for women with TNBC. This study seeks to build upon the growing body of evidence in support of immunomodulation in the treatment of TNBC, while also exploring a different and less toxic route of administration (i.e. intralesional as opposed to systemic). In the window of opportunity between the time of initial surgical consultation and planned OR for patients proceeding with upfront surgery, this study proposes to provide intralesional IL-2 with immediate pathologic assessment.
This 'window of opportunity' design will provide us opportunity to conduct a pilot study to evaluate the efficacy of an intralesional immunotherapy (e.g. IL-2) in early stage TNBC as a well-tolerated, low-risk intervention with the potential to improve outcomes without the toxicity of systemic treatment. As systemic immunotherapy moves from the metastatic setting to the adjuvant setting and is increasingly being used in earlier and earlier stage disease, the rationale for systemic therapy with systemic side effects to treat a local disease becomes harder to justify. This study seeks to challenge the notion that the only effective immunotherapy in the treatment of TNBC is systemic and perhaps a local administration can produce the immune response needed to affect significant pathologic response.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Intervention Arm Intralesional IL-2 therapy x 4 weeks between initial consultation and planned surgery |
Drug: Proleukin 1.3 MG Injection
All the recruited participants will receive 4 intra-lesional injections of Interleukin-2 with a dose of 250,000 international units (IU) per mm width of tumor to max dose of 10 million IU.
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Outcome Measures
Primary Outcome Measures
- Pathologic complete response (pCR) as defined by the residual cancer burden (RCB) index (RCB 0-IV) [measured immediately after surgery during routine pathological assessment]
Presence of in-situ disease alone will be considered a pCR
Secondary Outcome Measures
- Programmed death ligand-1 (PD-L1) and tumor infiltrative lymphocyte (TIL) expression [measured immediately after surgery during routine pathological assessment]
Expression of PD-L1 and TIL in each specimen
- Disease free survival [from time of surgery to 5 years of follow-up]
- Overall survival [from time of surgery to 5 years of follow-up]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Women with biopsy proven TNBC who are not scheduled to receive neoadjuvant chemotherapy.
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Tumors ≤ 2 cm (clinical T1N0)
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Planned upfront surgery (patient preference)
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Medically unable to receive neoadjuvant chemotherapy
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18 - 80 years of age.
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Able to provide consent for the study.
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Able to come to the hospital for the intralesional injections.
Exclusion Criteria:
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No diagnosis of TNBC.
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Not able to provide consent for the study.
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Not able to come to the hospital for study visits.
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Presence of any contraindication for IL-2 therapy (abnormal thallium stress test, abnormal pulmonary function test, organ allograft and toxicities with a previous dosage).
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Participant has experienced IL-2 related toxicities during an earlier course of therapy (sustained ventricular tachycardia; cardiac arrythmias unresponsive to management; chest pain with ECG changes consistent with angina or myocardial infarction; cardiac tamponade; intubation required > 72 hours; renal failure requiring dialysis > 72 hours; coma, or toxic psychosis > 48 hours; repetitive or difficult to control seizures; bowel ischemia; gastrointestinal bleeding requiring surgery)
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If participant is on cancer treatment drugs and steroids to avoid drug interactions.
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Known pregnancy and breast feeding. There are no known studies to support the use of interleukin in pregnancy and breast-feeding mothers.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Gregory Knapp
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IL-2.001