This is an open-label, phase II study that will evaluate how safe and well the combination of
niraparib, dostarlimab, and Radiation Therapy (RT) works in metastatic triple negative breast
cancer.
Niraparib is a type of drug called a "PARP inhibitor", which blocks DNA (the genetic material
of cells) damage from being repaired or may prevent damage from occurring in the first place.
In cancer treatment, inhibiting PARP may help kill cancer cells by not allowing the cancer
cells to repair its DNA damage or prevent DNA damage associated with metastatic triple
negative breast cancer from occurring.
Dostarlimab is a type of immunotherapy. It is believed to work by inhibiting (stopping) a
protein called PD-1 from working. The PD-1 protein controls parts of the immune system (the
system in a person's body that fights against diseases) by shutting down certain immune
responses that are responsible for recognizing and destroying cancer cells.
The investigators believe that dostarlimab may inhibit the PD-1 protein on triple negative
breast cancer cells, thus allowing the immune cells to recognize and destroy cancer
cells.Radiation therapy is a standard-of-care treatment that is given to stop the growth of
tumors. Radiation therapy can also stimulate the immune system, which leads to the
destruction of tumor cells in the treated areas. Combining radiation therapy with anti-cancer
drugs like dostarlimab and niraparib may increase the ability of the immune system to control
or destroy cancer cells throughout the body.
The research study procedures include screening for eligibility and study treatment including
evaluations and follow up visits.
Participants will receive the study drugs for up to 2 years or until their triple negative
breast cancer worsens Participants will then be followed for up to 5 years.
It is expected that about 32 people will take part in this research study.
The FDA has not approved niraparib for metastatic triple negative breast cancer, but it has
been approved for other uses.
The U.S. Food and Drug Administration (FDA) has not approved dostarlimab as treatment for any
disease.
Inclusion Criteria:
- Age ≥ 18 years.
- ECOG performance status ≤ 1
- Histologically or cytologically-confirmed TNBC (ER <1%, PR <1%, HER-2-neu 0-1+ by IHC
or non-FISH-amplified63. ER-low, PR-low (defined as ER and/or PR 1-10%) and
HER2-negative patients may also be eligible, as per treating MD discretion).
- Metastatic or recurrent TNBC.
- Prior progression on immune-checkpoint inhibitor and/or PDL1-negative. Note:
PDL1-status may be determined on tissues from either primary or mTNBC. PD-L1 status
must be determined by an FDA-approved assay approved for breast cancer, such as
PharmDx IHC (22C3) for pembrolizumab, Ventana (SP142) for atezolizumab
- No more than 2 prior lines of systemic therapy for inoperable/recurrent or metastatic
disease.
Note: Prior line of systemic therapy includes targeted or biologic agents in combination or
the absence of chemotherapy
- Radiation is clinically indicated for local control or palliation.
- At least one tumor for which RT is considered clinically appropriate.
- At least one radiographically-confirmed metastases index lesion that will not undergo
RT and is measurable based on RECIST v1.1.
- Prior therapy with targeted agents or other forms of immunotherapy is allowed
- Prior RT is permitted, provided the treating radiation oncologist deems that study RT
treatment planning guidelines can be achieved.
- Available archived tumor tissue of a metastatic tumor collected up to 28 days prior to
registration. If archival tissue is unavailable, participant willingness to provide
tissue from a newly obtained core or excisional biopsy of a tumor lesion.
Newly-obtained is defined as a specimen obtained up to 28 days prior to study
registration.
- Adequate organ function (assessed within 8 days prior to initiation of protocol
treatment, unless otherwise indicated) as follows:
- Hematology
- Absolute Neutrophil Count (ANC) ≥1500/mm3
- Platelet Count ≥100,000/mm3
- Hemoglobin ≥9.0 g/dL
- Renal Function
- Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) or
- Measured or calculated a creatinine clearance ≥ 60 mL/min for participant
with (GFR can also be used in place of creatinine creatinine levels > 1.5 X
ULN or CrCl
- Hepatic Function
- Total Bilirubin ≤ 1.5 mg/dL (Direct bilirubin ≤ ULN for participants with
total bilirubin levels > 1.5 ULN)
- INR, PT, aPTT ≤ 1.5 x ULN (participants receiving anticoagulant therapy must
have PT or PTT within therapeutic range)
- Albumin ≥ 2.5 mg/dL
- Aspartate Aminotransferase (AST) ≤ 2.5 x ULNb
- Alanine Aminotransferase (ALT) ≤ 2.5 x ULNb ULN = upper normal limit of
institution's normal range
1. Creatinine clearance should be calculated per institutional standard.
2. Participants with liver metastases may have AST and/or ALT ≤ 5 x ULN
- Female participant has a negative urine or serum pregnancy test within 7 days prior to
study treatment if a woman has child-bearing potential and agrees to abstain from
activities that could result in pregnancy from screening through 180 days after the
last dose of study treatment or is of non-childbearing potential.
Non-childbearing potential is defined as follows (by other than medical reasons):
- ≥45 years of age and has not had menses for >1 year
- Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and
oophorectomy must have a follicle stimulating hormone value in the postmenopausal
range upon screening evaluation
- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented
hysterectomy or oophorectomy must be confirmed with medical records of the actual
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical
records of the actual procedure.
- Women of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 180 days after the last dose of study medication.
Participants of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year.
Note: Abstinence is acceptable if this is the established and preferred contraception for
the patient.
- Male participant agrees to use an adequate method of contraception starting with the
first dose of study treatment through 90 days after the last dose of study treatment.
Note: Abstinence is acceptable if this is the established and preferred contraception
for the patient.
- Male subjects must not donate sperm starting with the first dose of study drug through
90 days after the last dose of study drug.
- Participant must agree not to breastfeed during the study or for 30 days after the
last dose of study treatment.
- Participant must agree to not donate blood during the study or for 90 days after the
last dose of study treatment.
- Ability to swallow (whole) and retain oral medications.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
Participants who meet any of the following criteria will be excluded:
- Known germline or somatic BRCA mutation-positive status
- Known active brain metastases or LMD (leptomeningeal disease). Note: Patients with
previously treated brain metastases may participate provided they are stable (without
evidence of progression by imaging [using the identical imaging modality for each
assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of
study treatment and any neurologic symptoms have returned to baseline), have no
evidence of new or enlarging brain metastases, and have not been using steroids for at
least 7 days prior to study treatment.
- Known additional malignancy that progressed or required treatment in the last 2 years.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Prior treatment with either a PARP inhibitor or ICI is permitted, however, prior
receipt of both therapies is excluded
- Receipt of >2 lines of chemo in the metastatic setting (including targeted or biologic
agents in combination or the absence of chemotherapy)
- Hypersensitivity to niraparib or dostarlimab components or its excipients.
- Participation in a study of an investigational agent and received study therapy or
used an investigational device within 4 weeks (or at least 5 half-lives from previous
therapy) of the first dose of study treatment.
- Receipt of prior cytotoxic therapy or targeted small molecule therapy within 2 weeks
prior to study Day 1 or who has not recovered (i.e., > Grade 1 or at baseline) from
adverse events due to a previously administered agent, including grade 2 alopecia.
Note: Participants with ≤ Grade 2 neuropathy are an exception to this criterion and may
qualify for the study.
- Patients who have undergone any major surgery within 3 weeks prior to study entry:
patients must have recovered adequately from the toxicity and/or complications from
the intervention prior to starting therapy.
- 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.
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment. Use of local corticosteroid injections (e.g. intra-articular injections),
inhaled, intranasal, ophthalmic, and topical corticosteroids, and subjects requiring
corticosteroid pre-medication for hypersensitivity reactions (e.g. CT scan
pre-medication) are allowed.
- Known history of/active, non-infectious pneumonitis requiring treatment with steroids
or has history of/active interstitial lung disease.
- Active infection requiring systemic therapy.
- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the patient's participation
for the full duration of the trial, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator.
- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
- Participant has a serious, uncontrolled medical disorder, nonmalignant systemic
disease, or active, uncontrolled infection. Examples include, but are not limited to,
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction,
uncontrolled major seizure disorder, unstable spinal cord compression.
Pregnant or breastfeeding or expecting to conceive or father children within the projected
duration of the trial, starting with the pre-screening or screening visit through 180 days
after the last dose of trial treatment.
- Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
- Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Known active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Known history of active TB (Bacillus Tuberculosis)
- Receipt of a live vaccine within 14 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
- Participant must not have received a transfusion (platelets or red blood cells) ≤ 4
weeks prior to initiating protocol therapy.
- Participant must not have received colony stimulating factors (eg, granulocyte
colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
- Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due
to prior chemotherapy that persisted > 4 weeks and was related to the most recent
treatment.
- Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with the
exception of non-clinically significant lab abnormalities.
