Clinical Trials /

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

NCT04576091

Description:

This phase I trial evaluates the side effects and best dose of BAY1895344 and radiation therapy when given together with pembrolizumab and to see their effect 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 and radiation therapy in combination with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than the usual approach alone.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, BAY1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer
  • Official Title: Phase I Trial of BAY1895344 ATR Inhibitor Combined With Stereotactic Body Radiation Therapy and Pembrolizumab for Recurrent Head and Neck Squamous Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-07522
  • SECONDARY ID: NCI-2020-07522
  • SECONDARY ID: 10405
  • SECONDARY ID: 10405
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT04576091

Conditions

  • 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

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor BAY1895344ATR Inhibitor BAY1895344, BAY 1895344, BAY-1895344, BAY1895344Treatment (pembrolizumab, BAY1895344, SBRT)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, BAY1895344, SBRT)

Purpose

This phase I trial evaluates the side effects and best dose of BAY1895344 and radiation therapy when given together with pembrolizumab and to see their effect 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 and radiation therapy in combination with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than the usual approach alone.

Detailed 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).

      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 for a total of 9 doses during cycle
      2. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, BAY1895344, SBRT)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Starting on day 7, patients also receive BAY1895344 PO BID on days 7-9 and 14-16 during cycle 1, and before and after each SBRT treatment for a total of 9 doses during cycle 2. 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.
  • ATR Kinase Inhibitor BAY1895344
  • Pembrolizumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-tolerated dose of ATR kinase inhibitor BAY1895344 and stereotactic body radiation therapy (Dose Escalation Phase)
Time Frame:Within 90 days of treatment initiation
Safety Issue:
Description:Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:Will be assessed per CTCAE version 5. The frequency and percentage of adverse events will be provided overall and by dose level for any grade and attribution as well as for grade 3 or greater adverse events, at least possibly related to treatment.
Measure:Locoregional control
Time Frame:Up to 2 years
Safety Issue:
Description:A competing risk analysis will be conducted with local failure, distal failure, and death as competing events. The cumulative incidence and 95% confidence interval for local failure will be estimated. Time to each event will be measured from the start of treatment regimen (day 1 pembrolizumab).
Measure:Progression-free survival
Time Frame:From the start of treatment regimen (day 1 pembrolizumab) until documented local or distal failure or death from any cause, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Overall response will be defined as a complete response or partial response based on the Response Evaluation Criteria in Solid Tumors 1.1 criteria. The proportion of patients responding to the treatment regimen and corresponding 95% confidence interval estimates will be calculated.
Measure:1-year overall survival
Time Frame:From the start of treatment regimen (day 1 pembrolizumab) until death from any cause, assessed up to 1 year
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier.
Measure:Quality of life
Time Frame:Up to 12 months
Safety Issue:
Description:Will be assessed by the Functional Assessment of Cancer Therapy for Patients With Head and Neck Cancer, version 4. The frequency and percentage of responses to the quality of life questionnaire will be summarized at 3, 6, and 12 months post-treatment and interpreted descriptively.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 3, 2020