This phase I trial is to find out the best dose, possible benefits and/or side effects of
NHS-IL12 given together with bintrafusp alfa and radiation therapy in treating patients with
hormone receptor positive, HER2 negative breast cancer that has spread to other places in the
body (metastatic). Immunotherapy with NHS-IL12, may induce changes in body's immune system
and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with
bintrafusp alfa, a bifunctional fusion protein composed of the monoclonal antibody avelumab
and TGF-beta, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill
tumor cells and shrink tumors. Giving NHS-IL12, bintrafusp alfa, and radiation therapy may
kill more tumor cells.
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of bintrafusp alfa (M7824) in combination with
immunocytokine NHS-IL12 (NHS-IL-12) and radiation therapy in patients with metastatic hormone
receptor positive (HR+)/HER2- breast cancer.
II. To determine the recommended phase II dose (RP2D) of NHS-IL-12 in combination with M7824
and radiation therapy in patients with metastatic HR+/HER2- breast cancer.
SECONDARY OBJECTIVES:
I. To assess immunologic/molecular responses, specifically percent (%) change in tumor
infiltrating lymphocytes (TIL) pre and post therapy to M7824 in combination with NHS-IL-12
and radiation therapy in patients with HR+/HER2- metastatic breast cancer.
II. To explore preliminary progression free survival (PFS) and overall survival (OS) to power
future definitive trial.
III. To evaluate the in-field and abscopal effect of treatment with M7824 in combination with
NHS-IL-12 and radiation therapy.
EXPLORATORY OBJECTIVES:
I. To characterize circulating immune cell populations and cytokine profiles in tumor and
circulation following treatment with M7824.
II. To conduct tissue-based ribonucleic acid sequencing (RNAseq), RNA scope, whole exome
sequencing (WES) targeted sequencing.
III. To correlate dosimetry to response (assessed by degree of radiation fibrosis).
IV. To evaluate the pharmacokinetics of NHS-IL-12 in combination with M7824.
OUTLINE: This is a dose-escalation study of immunocytokine NHS-IL12.
Patients receive bintrafusp alfa intravenously (IV) over 1 hour on days 1 and 14 and
immunocytokine NHS-IL12 subcutaneously (SC) on day 14. Beginning on day 14 of cycle 1,
patients undergo radiation therapy once daily (QD) for up to 4 days. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:
- Is willing and able to provide written informed consent for the trial and has signed
the appropriate written informed consent form, approved by the investigator's
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the
performance of any trial activities
- Is age >= 18 years at time of study entry
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Women of childbearing potential must be using an adequate method of contraception to
avoid pregnancy throughout the study and for up to 8 weeks after the last dose of
investigational product in such a manner that the risk of pregnancy is minimized. Men
on study also must be using contraception. Women of childbearing potential (WOCBP) are
women who have not been postmenopausal greater than 1 year or undergone a hysterectomy
or bilateral oophorectomy
- Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease.
Eligible patients must have estrogen receptor (ER) and/or progesterone (PR) expression
10% or greater by immunohistochemistry (IHC). HER2 negative or nonamplified is
determined by the current American Society of Clinical Oncology- College of American
Pathologists (ASCO-CAP) criteria which are as follows: HER2 testing by IHC as 0 or 1+.
If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if:
- IHC 3+ based on circumferential membrane staining that is
- Complete, intense
- ISH positive based on:
- Single-probe average HER2 copy number >= 6.0 signals/cell
- Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0
signals/cell
- Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0
signals/cell
- Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0
signals/cell
- Has at least 2 identified sites of metastatic disease. This can include areas of
metastatic disease to the bone, but one additional of the sites of metastatic disease
must be amenable to biopsy
- Has measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST)
criteria
- Has received no more than 5 previous lines of chemotherapy and has received at least
one line of therapy with an endocrine therapy or endocrine therapy combination
- Hemoglobin >= 10.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not
apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only upon treating physician, principle
investigator (PI) or co-PI approval
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x ULN
- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits, examinations, and assessments
(including follow up)
- Protocol participation is such that the treatment will be administered as an
outpatient. Inpatient status is not required and change in status does not necessitate
removal from protocol
- Has not had major surgery within 28 days prior to starting study treatment. Central
venous access surgeries and/or placements would not be considered as major surgery
Exclusion Criteria:
- Anticancer treatment within 14 days before the start of trial treatment (e.g.
cytoreductive therapy, radiotherapy etc.), or surgery within 4 weeks of start of trial
treatment
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =< 3
years before the first dose of study drug and of low potential risk for
recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ
- QT interval corrected for heart rate (QTc) >= 470 ms
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of M7824 or NHS-IL-12, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are not to
exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
with vitiligo, hypo- or hyperthyroid disease, or psoriasis not requiring systemic
treatment are not excluded
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)
- Significant acute or chronic infections including, among other:
- Known history of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome
- Active hepatitis B virus (HBV surface antigen positive) or hepatitis C virus (HCV
antibody positive and/or HCV RNA positive)
- Subjects with known active tuberculosis (history of exposure or history of
positive tuberculosis test plus presence of clinical symptoms, physical or
radiographic findings)
- History of allogeneic organ transplant
- History of hypersensitivity to M7824 or NHS-IL-12 or any excipient of either compound
- History of uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or
gastritis, active bleeding diatheses including any subject known to have evidence of a
psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed consent
- Known history of previous clinical diagnosis of tuberculosis
- Subjects with active central nervous system (CNS) metastases causing clinical symptoms
or metastases that require therapeutic intervention, including leptomeningeal disease,
are excluded. Subjects with a history of treated CNS metastases (by surgery or
radiation therapy) are not eligible unless they have demonstrated no progression for
at least 1 month, and do not require continued steroid therapy.
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving study drugs
- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control
- Any condition, including chronic medical condition, that, in the opinion of the
investigator, would interfere with evaluation of study treatment or interpretation of
patient safety or study results
- Subjects with uncontrolled seizures
- Any absolute contraindication to protocol specified radiotherapy based on prior
radiotherapy (determined by radiation oncologist)
