Clinical Trials /

Sacituzumab Govitecan +/- Pembrolizumab in Metastatic TNBC

NCT04468061

Description:

This research study involves testing the safety and efficacy of an investigational intervention for patients with triple-negative breast cancer (TNBC) that has spread, or metastasized, to other parts the body and is PD-L1-negative. The names of the study interventions involved in this study are: - Sacituzumab govitecan (IMMU-132) - Pembrolizumab (Keytruda®; MK-3475)

Related Conditions:
  • Invasive Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sacituzumab Govitecan +/- Pembrolizumab in Metastatic TNBC
  • Official Title: Saci-IO TNBC: Randomized Phase II Study of Sacituzumab Govitecan With or Without Pembrolizumab in PD-L1-negative Metastatic Triple Negative Breast Cancer (TNBC)

Clinical Trial IDs

  • ORG STUDY ID: 20-166
  • NCT ID: NCT04468061

Conditions

  • Breast Cancer
  • Triple Negative Breast Cancer
  • PD-L1 Negative

Interventions

DrugSynonymsArms
Sacituzumab GovitecanIMMU-132, TrodelvyRetreatment
PembrolizumabKeytrudaRetreatment

Purpose

This research study involves testing the safety and efficacy of an investigational intervention for patients with triple-negative breast cancer (TNBC) that has spread, or metastasized, to other parts the body and is PD-L1-negative. The names of the study interventions involved in this study are: - Sacituzumab govitecan (IMMU-132) - Pembrolizumab (Keytruda®; MK-3475)

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug or a combination of investigational drugs to
      learn whether the drug or drug combination works in treating a specific disease.
      "Investigational" means that the drug or drug combination is being studied.

      The U.S. Food and Drug Administration (FDA) has approved Sacituzumab Govitecan for metastatic
      triple-negative breast cancer, but it is currently approved only for patients who have had 2
      or more prior regimens for metastatic disease. The U.S. Food and Drug Administration (FDA)
      has not approved Pembrolizumab for metastatic triple-negative breast cancer but it has been
      approved for other uses.

      In this research study, we are:

        -  Studying Sacituzumab Govitecan alone or in combination with Pembrolizumab as a possible
           treatment for patients with metastatic triple-negative breast cancers that are
           PD-L1-negative.

        -  Sacituzumab Govitecan is composed of a chemotherapy drug, called Irinotecan, which is
           attached to an antibody. Antibodies are proteins normally made by the immune system that
           bind to substances that don't belong in the body to prevent harm. The antibody in this
           study binds to certain types of cancer tumors, including triple-negative breast tumors.

        -  Pembrolizumab is an immunotherapy, called an anti-PD-1 or a checkpoint inhibitor, and is
           an antibody (a type of human protein) designed to allow the body's own immune system to
           seek out and destroy tumors. It has been used in previous research studies to treat
           breast cancer, where it has been shown to be effective.

        -  The overall goal of this study is to evaluate the effectiveness of either Sacituzumab
           Govitecan alone or in combination with Pembrolizumab, in delaying the worsening of
           triple-negative breast cancers that are PD-L1-negative.

      The research study procedures include: screening for eligibility, research blood collections,
      at least two research biopsies, paired research stool collections, questionnaires, data
      collection, and study treatment including evaluations and follow up visits.

      Participants will be randomized into one of two groups.

        -  Group A: Sacituzumab Govitecan on days 1 and 8 and Pembrolizumab on day 1 of a 21-day
           cycle

        -  Group B: Sacituzumab Govitecan alone on days 1 and 8 of a 21-day cycle

      Participants will receive study treatment for as long as they are benefitting from this
      therapy. Participants will be followed for the rest of their life.

      It is expected that about 110 people will take part in this research study.
    

Trial Arms

NameTypeDescriptionInterventions
Sacituzumab Govitecan + PembrolizumabExperimentalParticipants will receive Sacituzumab Govitecan + Pembrolizumab at a pre-determined dose during a 21 day cycle. Sacituzumab Govitecan will be given on days 1 and 8 of the 21 day cycle Pembrolizumab will be given on day 1 of the 21 day cycle.
  • Sacituzumab Govitecan
  • Pembrolizumab
Sacituzumab GovitecanExperimentalParticipants will receive Sacituzumab Govitecan at a pre-determined dose during a 21 day cycle. Sacituzumab Govitecan will be given on days 1 and 8 of a 21-day cycle
  • Sacituzumab Govitecan
RetreatmentExperimentalParticipants randomized to the combination arm (Sacituzumab Govitecan + Pembrolizumab) who stop with CR after at least 24 weeks of treatment may be eligible for additional pembrolizumab and/or sacituzumab govitecan therapy if they progress after stopping study treatment. This is termed the Second Course Phase and is only available if the study remains open and the subject meets conditions: .
  • Sacituzumab Govitecan
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed invasive breast
             cancer with unresectable locally advanced or metastatic disease. Participants without
             pathologic or cytologic confirmation of metastatic disease should have unequivocal
             evidence of metastasis from physical examination or radiologic evaluation.

          -  Estrogen-receptor and progesterone-receptor expression both ≤ 5% by
             immunohistochemistry (IHC), and HER2-negative status as determined by the current
             ASCO/CAP guidelines. If a patient has more than one histological result, the most
             recent sample will be considered for inclusion.

          -  Participants must have PD-L1-negative metastatic breast cancer defined as less than 1%
             expression of PD-L1 on tumor-infiltrating immune cells (IC) by the PD-L1 IHC SP142
             assay measured with standard of care testing.

          -  Participants must be treatment-naïve in the metastatic setting.

          -  Participants must have evaluable or measurable disease per RECIST 1.1. See Section 11
             for the assessment of measurable disease. For instance, patients with bone only
             disease will be allowed to participate.

          -  Participants must agree to undergo a research biopsy, if tumor is safely accessible,
             at baseline. Previously collected archival tissue will also be obtained on all
             participants. Tissue needs to be located and availability confirmed at time of
             registration (see Section 9 for more details). Participants must agree to a mandatory
             repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible.

          -  Prior chemotherapy: Participants must have received no prior chemotherapy for
             metastatic breast cancer and must have discontinued all chemotherapy at least 28 days
             prior to study treatment initiation. No prior irinotecan or topoisomerase I-containing
             antibody drug conjugates in the metastatic or neo/adjuvant setting are allowed. All
             toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or
             lower, unless otherwise specified in 3.1.13, except alopecia can be any grade and
             neuropathy can be grade 2 or lower.

          -  Prior biologic therapy: Patients must have received no prior biologic therapy for
             metastatic breast cancer and discontinued all biologic therapy at least 28 days prior
             to study treatment initiation. All toxicities related to prior biologic therapy must
             have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified in 3.1.13.

          -  Prior radiation therapy: Patients may have received prior radiation therapy. Radiation
             therapy must be completed at least 14 days prior to study treatment initiation, and
             all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0
             grade 1 or lower, unless otherwise specified in 3.1.13. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

          -  Previously treated brain metastases are permitted, with the following provisions:

               -  Prior SRS should complete ≥ 7 days before study treatment initiation

               -  Prior WBRT should complete ≥ 14 days before study treatment initiation. Note:
                  Reimaging at baseline post-treatment is not required, but baseline scans should
                  be after radiation or surgery or within 21 days of randomization.

               -  Any corticosteroid use for brain metastases must have been discontinued for ≥ 7
                  days prior to study treatment initiation.

          -  The subject is ≥ 18 years old.

          -  ECOG performance status 0-1 (Karnofsky > 60%, see Appendix A).

          -  Participants must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥1,000/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥ 9.0 g/dl

               -  INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as
                  long as PT or aPTT is in therapeutic range of anticoagulant

               -  Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)(or ≤2.0 x ULN in
                  patients with documented Gilbert's Syndrome)

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤5 × institutional ULN for
                  participants with documented liver metastases

               -  Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/
                  1.73m2 for participants with creatinine levels above institutional ULN.

          -  Female subjects of childbearing potential must have a negative serum or urine
             pregnancy test within 2 weeks prior to study treatment initiation.

        Childbearing potential is defined as participants who have not reached a postmenopausal
        state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause)
        and have not undergone surgical sterilization (removal of ovaries and/or uterus).

          -  Women of childbearing potential (WOCBP) must agree to use an adequate method of
             contraception. Contraception is required starting with the first dose of study
             medication through 150 days (5 months) after the last dose of study medication.
             Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal ligation, male sterilization, established and proper use of hormonal
             contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
             copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation,
             symptothermal, or postovulation methods) and withdrawal are not acceptable methods of
             contraception (Appendix B).

          -  Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception for the duration of study treatment with pembrolizumab and
             7 months after the last dose of study treatment (i.e., 90 days (duration of sperm
             turnover) plus the time required for the investigational drug to undergo approximately
             five half- lives, Appendix B).

          -  Participants on bisphosphonates or RANK ligand inhibitors may continue receiving
             therapy during study treatment and also may initiate therapy with these agents on
             study if clinically indicated.

          -  The participant must be capable of understanding and complying with the protocol and
             willing to sign a written informed consent document.

        Exclusion Criteria:

          -  Has received prior systemic anti-cancer therapy, including investigational agents,
             within 4 weeks of study treatment initiation or during the course of this study
             (bisphosphonates and RANK ligand inhibitors are allowed).

          -  Prior therapy with any anti-PD-1, PD-L1, or PD-L2 agent or sacituzumab govitecan
             (IMMU-132). Prior therapy with irinotecan or topoisomerase I-containing antibody drug
             conjugates at any time for early stage or metastatic disease.

          -  Prior hypersensitivity to pembrolizumab or the excipients of pembrolizumab or
             sacituzumab govitecan (IMMU-132 therapy).

          -  Known history of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28 allele homozygosity,
             which is associated with increased risk for neutropenia and diarrhea related to
             irinotecan. Note: Concurrent administration of strong UGT1A1 inhibitors or inducers is
             not allowed during the course of the study

          -  Known brain metastases that are untreated, symptomatic, or require therapy to control
             symptoms.

          -  Major surgery within 2 weeks prior to study treatment initiation. Patients must have
             recovered from any effects of any major surgery.

          -  Uncontrolled, significant intercurrent or recent illness including, but not limited
             to, ongoing or active infection, uncontrolled non-malignant systemic disease,
             uncontrolled seizures, or psychiatric illness/social situation that would limit
             compliance with study requirements in the opinion of the treating investigator.

          -  Participant has a medical condition that requires chronic systemic steroid therapy (>
             10 mg of prednisone daily or equivalent) or any other form of immunosuppressive
             medication (including disease modifying agents) and has required such therapy in the
             last 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
             not considered a form of systemic therapy.

          -  Participant has documented history of autoimmune disease or syndrome that currently
             requires systemic steroids or immunosuppressive agents.

          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

          -  Individuals with a history of a second malignancy are ineligible except for the
             following circumstances. Individuals with a history of other malignancies are eligible
             if they have been disease-free for at least 3 years or are deemed by the investigator
             to be at low risk for recurrence of that malignancy. Individuals with the following
             cancers that have been diagnosed and treated within the past 3 years are eligible:
             cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer
             of the skin. Patients with other cancers diagnosed within the past 3 years and felt to
             be at low risk of recurrence should be discussed with the study principal investigator
             to determine eligibility.

          -  Participant has a known history of human immunodeficiency virus (HIV), Hepatitis B
             (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C
             virus (defined as detected HCV RNA [qualitative]) infection. HIV-positive participants
             are ineligible due to the potential for pharmacokinetic interactions of combination
             antiretroviral therapy with study drugs and the increased risk of fatal infections
             when treated with marrow-suppressive therapy. Note: No testing for HIV, Hepatitis B,
             or Hepatitis C is required unless mandated by local health authority.

          -  The participant has received a live vaccine within 28 days prior to study treatment
             initiation. Examples of live vaccines include, but are not limited to, the following:
             measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid
             vaccine. The use of the inactivated seasonal influenza vaccine is allowed.

          -  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.

          -  It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are
             excreted in human milk, and because of the potential for serious adverse reactions in
             the nursing infant, participants who are breast-feeding are not eligible for
             enrollment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:3 years
Safety Issue:
Description:Compare PFS of patients randomized to receive sacituzumab govitecan in combination with pembrolizumab (Arm A) versus those randomized to receive sacituzumab govitecan monotherapy (Arm B). Defined as the time from study randomization to disease progression, per RESICT 1.1 or medical judgment, the latter based on established clinical parameters, such as rising tumor markers and physical exam evidence of progression, i.e. worsening chest wall disease, or death due to any cause, whichever occurred first.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing Overall Survival (OS), defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive, will be reported with Kaplan Meier estimates.
Measure:Objective Response Rate (ORR)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing Objective Response Rate by RECIST 1.1
Measure:Duration of response (DOR)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing the duration of response (the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented or death due to any cause. Participants without events reported are censored at the last disease evaluation).
Measure:Time to objective response (TTOR)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing the time to objective response defined as the time from randomization to the date of the first documented CR or PR (whichever is first recorded).
Measure:Time to progression (TTP)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing Time to progression (TTP) defined as the time from randomization (or registration) to progression, or censored at date of last disease evaluation for those without progression reported.
Measure:Clinical benefit rate (CBR)
Time Frame:3 years
Safety Issue:
Description:Compare the efficacy of sacituzumab govitecan with pembrolizumab to that of sacituzumab govitecan alone by assessing Clinical benefit rate (CBR) according to RECIST 1.1, defined as CR, PR or stable disease for ≥ 24 weeks
Measure:Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Time Frame:3 years
Safety Issue:
Description:Evaluate the safety and tolerability of sacituzumab govitecan and pembrolizumab compared to sacituzumab govitecan alone by monitoring adverse events, including immune-related adverse events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Breast Cancer
  • Triple Negative Breast Cancer
  • PD-L1 Negative

Last Updated

March 11, 2021