Ivermectin and Pembrolizumab for the Treatment of Metastatic Triple Negative Breast Cancer
Study Details
Study Description
Brief Summary
This phase II trial studies the side effects and best dose of ivermectin in combination with pembrolizumab and to see how well they they work in shrinking tumors in patients with triple negative breast cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ivermectin may help block the formation of growths that may become cancer. Giving ivermectin with pembrolizumab may increase the effect of pembrolizumab in shrinking tumors in patients with triple negative breast cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
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To determine the efficacy of ivermectin in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC) using objective response rate (ORR).
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To assess the safety and tolerability of ivermectin in combination with pembrolizumab using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)5.0 in three doses.
SECONDARY OBJECTIVES:
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To determine the optimal biological dose (OBD) of ivermectin when administered with pembrolizumab.
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To evaluate the following efficacy outcomes: progression free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR).
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To evaluate patients' quality of life (QOL) by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
EXPLORATORY OBJECTIVES:
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To study the change in peripheral blood immune profiles associated with the combination therapy.
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To study the tumor immune profile and tumor microenvironment changes associated with the combination therapy using Nanostring Digital Spatial Profiler (DSP).
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To study tumor immunogenic cell death (ICD) using on-treatment biopsy. IV. To study the association of gut microbiota and response to the combination therapy.
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Evaluate the pharmacokinetics of ivermectin in combination with pembrolizumab.
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To evaluate any dose related changes in the immunological correlatives along with association with area under the curve (AUC) (or other pharmacokinetic metrics).
OUTLINE: This is a dose-escalation study of ivermectin.
Patients receive ivermectin orally (PO) once daily (QD) on days 1-3, 8-10, and 15-17. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days and then periodically thereafter.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (ivermectin, pembrolizumab) Patients receive ivermectin PO QD on days 1-3, 8-10, and 15-17. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. |
Drug: Ivermectin
Given PO
Other Names:
Biological: Pembrolizumab
Given IV
Other Names:
Other: Quality-of-Life Assessment
Ancillary studies
Other Names:
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Outcome Measures
Primary Outcome Measures
- Objective response rate [Up to 2 years]
Measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Incidence of adverse events [Up to 30 days after treatment completion]
Evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The toxicities observed will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by CTCAE and nadir or maximum values for the laboratory measures), time of onset (i.e., course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by course.
Secondary Outcome Measures
- Objective response rate [Up to 2 years]
Measured using Immune-related (i)RECIST 1.1.
- Optimal biological dose of ivermectin [Up to 2 years]
Based on a combination of clinical activity, safety, and correlatives.
- Progression free survival [From start of therapy to progression, death or last contact, assessed up to 2 years]
- Overall survival [From start of therapy to death or last contact, assessed up to 2 years]
- Duration of response [From the date of first objective response recorded (complete response [CR] or partial response [PR]) until progression, death or last contact, assessed up to 2 years]
- Clinical benefit rate [Up to 2 years]
Defined as progression-free for at least 6 months or CR or PR.
- Patients' quality of life [Up to 2 years]
Evaluated by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 per standardized EORTC scoring guidelines.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Documented informed consent of the participant and/or legally authorized representative
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Assent, when appropriate, will be obtained per institutional guidelines
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Agreement to research biopsies on study and once during study, exceptions may be granted with study principal investigator (PI) approval. End of study biopsy is optional
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Age: >= 18 years
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Eastern Cooperative Oncology Group (ECOG) =< 1
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Life expectancy >= 3 months
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Ability to read and understand English, Mandarin, Armenian or Spanish for questionnaires
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Histologically confirmed metastatic triple negative breast cancer. Triple negative status will be defined as estrogen receptor (ER) and progesterone receptor (PR) =< 10% and HER2 negative (by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH]), per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
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Patients must have progressed on (or intolerant of or ineligible for) 1, no more than 2 prior lines of chemotherapy and/or immune checkpoint inhibitor for advanced/metastatic disease
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Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
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Fully recovered from the acute toxic effects (except alopecia) to =< grade 2 from prior anti-cancer therapy
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Absolute neutrophil count (ANC) >= 1,500/mm^3
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Platelets >= 100,000/mm^3
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Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
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Total serum bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
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Aspartate aminotransferase (AST) =< 1.5 x ULN or =< 3 x ULN with liver metastases
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Alanine aminotransferase (ALT) =< 1.5 x ULN or =< 3 x ULN with liver metastases
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Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 30 mL/min for participant with creatinine levels >1.5 x institutional ULN
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International normalized ratio (INR) or prothrombin time (PT), activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
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Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram
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Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
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If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
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A male participant must agree to use a contraception during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period
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A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
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Not a woman of childbearing potential (WOCBP) OR
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Females of child-bearing potential must be willing to use effective contraception during study and for 30 days after the last dose
Exclusion Criteria:
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Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
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Chemotherapy, radiation therapy, biological therapy, immunotherapy within 28 days prior to day 1 of protocol therapy
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Participants must not have received radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
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Other investigational products. Participants may not be currently participating in or participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
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Participants on any dose of warfarin. Use of low molecular weight heparin, antithrombin agents, anti-platelet agents or factor Xa inhibitors is allowed
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Herbal medications (cannabidiol [CBD] allowed)
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Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
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Issues with tolerating oral medication (e.g., inability to swallow pills, malabsorption issues, ongoing nausea or vomiting during screening)
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Women who are or are planning to become pregnant or breastfeed
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Known allergy to any of the components within the study agents and/or their excipients
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No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for at least three years
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Participants must not have known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
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Intercurrent or historic medical condition that increases subject risk in the opinion of the Investigator. Eligibility may be revisited for intercurrent medical conditions once resolution/recovery is deemed adequate by the investigator (e.g., recovery from major surgery, completion of treatment for severe infection).
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Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
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Has an active infection requiring systemic therapy
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Has a known history of human immunodeficiency virus (HIV) infection
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Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
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Has a known history of active TB (Mycobacterium tuberculosis)
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Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
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Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
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Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
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Has had an allogenic tissue/solid organ transplant
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Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at screening
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Subjects having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is < 1 g/24 hours
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Has active 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., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
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Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
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Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Medical Center | Duarte | California | United States | 91010 |
Sponsors and Collaborators
- City of Hope Medical Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Yuan Yuan, City of Hope Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 21682
- NCI-2022-02421
- 21682
- P30CA033572