This phase I trial evaluates the best dose, possible benefits and/or side effects of
combination therapy with BAY1895344, stereotactic body radiation, and pembrolizumab in
treating patients with head and neck squamous cell cancer that has come back (recurrent) and
cannot be removed by surgery (unresectable). BAY1895344 may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy uses
special equipment to position a patient and deliver radiation to tumors with high precision.
This method may kill tumor cells with fewer doses over a shorter period and cause less damage
to normal tissue. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help
the body's immune system attack the cancer, and may interfere with the ability of tumor cells
to grow and spread. Giving BAY1895344, stereotactic body radiation therapy in combination
with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than
treatment with radiation and immunotherapy without BAY1895344.
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of ATR kinase inhibitor BAY1895344 (BAY1895344)
with concurrent head and neck stereotactic body radiation therapy (SBRT) reirradiation and
pembrolizumab.
II. To determine the recommended phase 2 dose (RP2D) of BAY 1895344 in combination with
concurrent head and neck SBRT and pembrolizumab.
SECONDARY OBJECTIVE:
I. To observe and record anti-tumor activity (overall response rate, progression-free
survival, and overall survival) of BAY 1895344, SBRT, and pembrolizumab for recurrent head
and neck squamous cell carcinoma (HNSCC).
EXPLORATORY OBJECTIVE:
I. To identify predictive biomarkers of response to BAY 1895344, SBRT, and pembrolizumab,
including, but not limited to the following: genetic alterations of ATM and other
deoxyribonucleic acid (DNA) damage response genes, tumor mutational load, circulating tumor
DNA, baseline tumor ATM expression, tumor PD-L1 expression, and change in circulating Ki67+
CD8+ T-cells relative to baseline.
OUTLINE: This is a dose-escalation study of BAY1895344 and stereotactic body radiation
therapy (SBRT) given with fixed-dose pembrolizumab.
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Starting on day
7, patients also receive BAY1895344 orally (PO) twice daily (BID) on days 7-9 and 14-16
during cycle 1, and before and after each SBRT treatment during cycle 2 for a total of 9
doses. Beginning cycle 2, patients undergo SBRT starting between days 2 and 8 for 3 fractions
with 2-3 days between fractions. Treatment repeats every 21 days for up to 2 cycles in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up quarterly for 2 years or until
death, whichever occurs first.
Inclusion Criteria:
- Patients must have histologically confirmed recurrent, unresectable head and neck
squamous cell carcinoma, including oral cavity, oropharynx, larynx, hypopharynx, or
cervical lymphadenopathy. Unresectable refers both to patients who have declined
surgery and patients deemed unresectable by otolaryngology
- Patients must have recurrent disease within a previously irradiated area (radiotherapy
to dose >= 40 Gy, i.e., in-field recurrence)
- Patients must have competed prior radiotherapy >= 6 months prior to enrollment
- Patients must have received prior cisplatin chemotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
and a life expectancy of >= 3 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL or 5.6 mmol/L without transfusion or erythropoietin dependency
(within 7 days of assessment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (If total bilirubin
> 1.5 x ULN, direct bilirubin must be < ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (=< 5 x ULN for patients with liver metastases)
- Creatinine OR measured or calculated creatinine clearance (CrCl) < 1.5 x institutional
ULN OR glomerular filtration rate (GFR) > 60 mL/min/1.73 m^2
- CrCl should be calculated per institutional standard
- Albumin > 2.5 mg/dL
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
- Patients must have measurable disease (at least one measurable lesion) as per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Patients must have no contraindications to pembrolizumab, including no history of
organ allograft transplantation or active autoimmune disease (active defined as having
autoimmune disease-related symptoms and detectable autoantibodies) that has required
systemic treatment in the past 2 years (i.e., use of disease-modifying agents,
corticosteroids, or immunosuppressive drugs)
- Human immunodeficiency virus (HIV)-infected patients may participate IF they meet the
following eligibility requirements:
- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective
- They must have a CD4 count of greater than 250 cells/mcL
- They must not be receiving prophylactic therapy for an opportunistic infection
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy (e.g., not hepatitis B surface
antigen [HBsAg] reactive), if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load (e.g., HCV ribonucleic acid [RNA]
[qualitative] is not detected)
- 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 magnetic resonance imaging [MRI] or computed
tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment
and any neurologic symptoms have returned to baseline), have no evidence of new or
enlarging brain metastases, and are not using steroids for at least 7 days prior to
trial treatment
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this trial, patients should be class 2B or better
- Enrolling site must submit an evaluable archival tumor tissue sample for PD-L1
biomarker analysis
- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. The effects of BAY 1895344 on the developing human fetus are
unknown. For this reason and because DNA-damage response inhibitors as well as other
therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception prior to
study entry, for the duration of study participation, and for 6 months after
completion of BAY 1895344 therapy or 4 months after completion of pembrolizumab
therapy, whichever is later. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 6 months after completion of BAY 1895344 therapy or 4 months after
completion of pembrolizumab therapy, whichever is later
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients with cutaneous, nasopharynx, paranasal sinus, or salivary gland cancers
- Patients who have had more than one prior course of head and neck radiotherapy
- Patients who have disease surrounding >= 180 degrees of the carotid artery
- Patients who have disease involving the skin
- Patients with gross tumor involvement of the mandible
- Patients who have had chemotherapy, targeted small-molecule therapy, or radiotherapy
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- Note: Patients with =< grade 2 neuropathy or =< grade 2 alopecia are an exception
to this criterion and may qualify for the study
- Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy
- Patients who are currently participating and receiving study therapy or have
participated in a study of an investigational agent and received study therapy or used
an investigational device within 4 weeks of the first dose of treatment
- Has received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including granulocyte colony-stimulating
factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or
recombinant erythropoietin) within 4 weeks prior to study day 1
- Has a 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. The use of physiologic doses of corticosteroids may be approved after
consultation with the study principal investigator (PI)
- Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not
recovered (i.e., =< grade 1 or at baseline) from adverse events (AEs) due to agents
administered more than 4 weeks earlier
- Has new or progressive brain metastases, or leptomeningeal disease
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, or in situ cervical cancer
- Patients with carcinomatous meningitis should be excluded
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BAY 1893544 or pembrolizumab
- Has an 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
- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
(excluded from expansion phase only; patients who have received prior anti-PD-1,
anti-PD-L1, or anti-PD-L2 therapy may be included in the dose escalation phase)
- Patients receiving any medications that are substrates of CYP3A4 with a narrow
therapeutic window, or strong inhibitors/inducers of CYP3A4 are ineligible, if they
cannot be transferred to alternative medication. Because the lists of these agents are
constantly changing, it is important to regularly consult a frequently-updated medical
reference. As part of the enrollment/informed consent procedures, the patient will be
counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, interstitial lung disease or active, non-infectious pneumonitis,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage
response inhibitor may have the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with BAY 1895344, breastfeeding should be
discontinued if the mother is treated with BAY 1895344 and for 4 months after the end
of BAY 1895344 treatment. These potential risks may also apply to other agents used in
this study
- Has a known history of active tuberculosis (TB)
- Has received a live vaccine within 30 days of planned treatment start. Seasonal flu
vaccines that do not contain live virus are permitted
