Testing the Addition of an Anti-cancer Drug, BAY1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer

  • STATUS
    Recruiting
  • End date
    Apr 1, 2026
  • participants needed
    37
  • sponsor
    National Cancer Institute (NCI)
Updated on 25 April 2022

Summary

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.

Description

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.

Details
Condition Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Oral Cavity Squamous Cell Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Stage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8, Stage III Hypopharyngeal Carcinoma AJCC v8, Stage III Laryngeal Cancer AJCC v8, Stage III Lip and Oral Cavity Cancer AJCC v8, Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8, Stage IV Hypopharyngeal Carcinoma AJCC v8, Stage IV Laryngeal Cancer AJCC v8, Stage IV Lip and Oral Cavity Cancer AJCC v8, Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVA Hypopharyngeal Carcinoma AJCC v8, Stage IVA Laryngeal Cancer AJCC v8, Stage IVA Lip and Oral Cavity Cancer AJCC v8, Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVB Hypopharyngeal Carcinoma AJCC v8, Stage IVB Laryngeal Cancer AJCC v8, Stage IVB Lip and Oral Cavity Cancer AJCC v8, Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVC Hypopharyngeal Carcinoma AJCC v8, Stage IVC Laryngeal Cancer AJCC v8, Stage IVC Lip and Oral Cavity Cancer AJCC v8, Stage IVC Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Unresectable Head and Neck Squamous Cell Carcinoma, Unresectable Hypopharyngeal Squamous Cell Carcinoma, Unresectable Laryngeal Squamous Cell Carcinoma, Unresectable Oral Cavity Squamous Cell Carcinoma, Unresectable Oropharyngeal Squamous Cell Carcinoma
Treatment quality-of-life assessment, Pembrolizumab, stereotactic body radiation therapy, Elimusertib
Clinical Study IdentifierNCT04576091
SponsorNational Cancer Institute (NCI)
Last Modified on25 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must have histologically confirmed recurrent, unresectable head and neck squamous cell carcinoma, including oral cavity, oropharynx, larynx, hypopharynx, or cervical lymphadenopathy. Core needle biopsy or incisional biopsy is preferred over fine needle aspiration (FNA) for diagnosis to provide sufficient tumor tissue for correlative studies. Unresectable refers both to patients who have declined surgery and patients deemed unresectable by otolaryngology. This includes patients for whom curative resection is medically contraindicated and/or would be associated with excessive surgical risk (as deemed by the consulting otolaryngologist) or undue surgical morbidity (e.g., total glossectomy, laryngectomy, and/or major resection requiring free flap reconstruction)
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
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of BAY 1895344 with pembrolizumab in patients < 18 years of age, children are excluded from this study
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. Baseline imaging must include neck computed tomography (CT) (preferably contrast-enhanced) and chest CT or skullbase to midthigh PET/CT (preferably with contrast-enhanced neck CT if diagnostic contrast-enhanced neck CT not available). Total gross tumor volume must measure < 100 cc. Patients who have undergone surgery aside from biopsy may be included if gross disease is present within the surgical resection bed or at another site
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). 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
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
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)
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
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
surface antigen [HBsAg] reactive), if indicated
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 oligometastatic disease (5 or fewer distant metastases) may be eligible for this trial if they meet performance status inclusion criteria
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
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
Enrolling site must perform PD-L1 testing on tumor biopsy per institutional protocol (local testing or tissue sent to outside laboratory for PD-L1 immunohistochemistry (IHC) 22C3 pharmDx). Combined positive score (CPS) is recommended for PD-L1 scoring. Test result does not need to be available at the time of enrollment and treatment initiation
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
Note: Patients with =< grade 2 neuropathy or =< grade 2 alopecia are an exception to this criterion and may qualify for the study
Patients with widely metastatic disease
Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
Note: Patients with oligometastatic disease (defined as five or fewer distant metastases) may qualify for the study
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
Patients who have had chemotherapy, targeted small-molecule therapy, or radiotherapy
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
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the
History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 1893544 or pembrolizumab
study
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 who are currently participating and receiving study therapy or have
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
participated in a study of an investigational agent and received study therapy
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
or used an investigational device within 4 weeks of the first dose of
Patients with psychiatric illness/social situations that would limit compliance with study requirements
treatment
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. Similarly, COVID-19 vaccines are permitted
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