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
- 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
- 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.
- 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.
- 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
- 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