Combination Liposomal Irinotecan and Pembrolizumab For Triple-Negative Breast Cancer (TNBC) With Brain Metastases (BM)

• ClinicalTrials.gov Identifier: NCT05255666
• Recruitment Status: Not yet recruiting
• First Posted: February 24, 2022
• Last Update Posted: May 17, 2023
• Sponsor: Washington University School of Medicine
• Collaborators: Merck Sharp & Dohme LLC; Ipsen
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

The study is a phase II with safety lead in, single arm, study using Nal-IRI in combination with pembrolizumab. Nal-IRI will be given IV every 2 weeks starting at 50mg/m2. Pembrolizumab will be given 400mg IV every 6 weeks. Treatment will continue until progression, intolerable side effects or patient/doctor decision to discontinue treatment.

Condition or disease	Intervention/treatment	Phase
Triple Negative Breast Cancer; Brain Metastases	Drug: Pembrolizumab; Drug: Liposomal Irinotecan	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of the Combination of Liposomal Irinotecan (Nal-IRI) and Pembrolizumab for Triple-Negative Breast Cancer (TNBC) With Brain Metastases (BM)
• Estimated Study Start Date: July 31, 2023
• Estimated Primary Completion Date: January 31, 2027
• Estimated Study Completion Date: January 31, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab + Liposomal Irinotecan; 400 mg of pembrolizumab intravenously on Day 1 of each Cycle (Cycle is 42 days); 50 mg/m^2 of liposomal irinotecan (Nal-IRI) intravenously every 2 weeks of each Cycle (Cycle is 42 days)	Drug: Pembrolizumab; 400 mg intravenously; Other Name: Keytruda; Drug: Liposomal Irinotecan; Starting at 50 mg/m^2. The dose may be increased to 70 mg/m^2 if tolerated or dose reduced to 35 mg/m^ if treatment-emergent severe adverse event (TESAE) occurs.; Other Name: NaI-IRI

Outcome Measures

Primary Outcome Measures :

1. Central Nervous System Disease Control Rate (DCR) [ Time Frame: 6 months ]
   -DCR is defined as the rate of complete response (CR) + rate of partial response (PR), and rate of stable disease (SD) at 6 months and will be determined as per modified Neuro-Oncology-Brain Metastases (RANO-BM) criteria

Secondary Outcome Measures :

1. Safety and tolerability as measured by the number of grade 3 and 4 adverse events [ Time Frame: Through 90 days after completion of treatment (estimated to be 9 months) ]
   -Defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5
2. Central Nervous System Objective Response Rate (ORR) [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
   -ORR will include CNS complete response (CR) + partial response (PR) and will be determined as per modified RANO-BM criteria.
3. Non-Central Nervous System Objective Response Rate (ORR) [ Time Frame: Through completion of treatment (estimated to be 6 months) ]
   -ORR will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST 1.1
4. Progression Free Survival (PFS) [ Time Frame: Through completion of follow-up (estimated to be 3 years and 6 months) ]
   -PFS is defined as the time from Day 1 of treatment until the criteria for disease progression is met as defined by RECIST 1.1 and/or RANO-BM or death as a result of any cause.
5. Overall Survival (OS) [ Time Frame: Through completion of follow-up (estimated to be 3 years and 6 months) ]
   -OS is defined as the time from Day 1 of treatment until death as a result of any cause.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0-1 within 28 days prior to registration.
• Histological or cytological confirmation of triple-negative breast cancer (TNBC) NOTE: TNBC will be defined as expression of ER<10%, PR< 10% and HER2 negative either by IHC (0, 1+ are negative, 2+ equivocal) or in situ hybridization method (ratio <2.0 is negative). AJCC, 8th edition.
• Subjects must have brain metastasis; new or progressive with at least one lesion ≥ 5 mm in at least one dimension. NOTE: the number of brain lesions is not limited.
• Measurable disease according to RECIST 1.1 and/or RANO-BM within 28 days prior to registration.
• Prior treatment with immunotherapy is allowed. Patients CANNOT have received prior liposomal irinotecan or irinotecan. Patients who received prior sacituzumab govitecan are eligible if without disease progression for at least 16 weeks on therapy and a washout of at least 24 weeks prior to C1D1. NOTE: No more than 4 prior lines of therapy in the metastatic setting is allowed.
• Prior cancer treatment including investigational agents must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline.

• Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration.

  • Hematological

    • Absolute Neutrophil Count (ANC): ≥ 1.5 K/mm3
    • Hemoglobin (Hgb): ≥ 9 g/dL; without erythropoietin dependency and without packed red blood cell (PRBC) transfusion within 2 weeks of registration
    • Platelet Count (PLT): ≥100 000/µL

  • Renal

    • Creatinine OR: ≤1.5 × ULN OR
    • Calculated creatinine clearance: ≥30 mL/min

  • Hepatic

    • Total Bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
    • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT): ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
    • Albumin: > 30 g/L
  • Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Life expectancy of ≥ 12 weeks as assessed by the investigator.
• Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use an effective method(s) of contraception as outlined in the protocol.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study (or that legally authorized representative will do so on their behalf).

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Has a known history of Human Immunodeficiency Virus (HIV) infection. NOTE: No HIV testing is required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. NOTE: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• Has a known history of active TB (Bacillus Tuberculosis).
• Has an active infection requiring systemic therapy.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has received colony-stimulating factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor [GM-CSF]) within 2 weeks prior to the first dose of study drug.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to C1D1.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Has had an allogenic tissue/solid organ transplant.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Is pregnant or breastfeeding.

Contacts and Locations

Contacts

Contact: Ashley Frith, M.D.; 636-916-9307; afrith@wustl.edu

Locations

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

Contact: Ashley Frith, M.D. 636-916-9307 afrith@wustl.edu

Principal Investigator: Ashley Frith, M.D.

Sub-Investigator: Cynthia X Ma, M.D., Ph.D.

Sub-Investigator: Jing Xi, M.D., MPH

Sub-Investigator: Omar Butt, M.D., Ph.D.

Sub-Investigator: Jingqin (Rosy) Luo, Ph.D.

Sponsors and Collaborators

Washington University School of Medicine

Merck Sharp & Dohme LLC

Ipsen

Investigators

• Principal Investigator: Ashley Frith, M.D.; Washington University School of Medicine

More Information

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT05255666
• Other Study ID Numbers: 202111198
• First Posted: February 24, 2022
• Last Update Posted: May 17, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Neoplastic Processes; Pathologic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pembrolizumab; Irinotecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors