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

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ClinicalTrials.gov Identifier: NCT04576091
Recruitment Status : Not yet recruiting
First Posted : October 6, 2020
Last Update Posted : February 5, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
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 Drug: Elimusertib Biological: Pembrolizumab Other: Quality-of-Life Assessment Radiation: Stereotactic Body Radiation Therapy Phase 1

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) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : February 15, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, BAY1895344, SBRT)
Patients 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 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.
Drug: Elimusertib
Given PO
Other Names:
  • ATR Inhibitor BAY1895344
  • ATR Kinase Inhibitor BAY1895344
  • BAY 1895344
  • BAY-1895344
  • BAY1895344

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Radiation: Stereotactic Body Radiation Therapy
Undergo SBRT
Other Names:
  • SABR
  • SBRT
  • Stereotactic Ablative Body Radiation Therapy




Primary Outcome Measures :
  1. Maximum-tolerated dose of ATR kinase inhibitor BAY1895344 and concurrent stereotactic body radiation therapy (Dose Escalation Phase) [ Time Frame: Within 90 days of treatment initiation ]
  2. Incidence of late adverse events (Dose Expansion Phase) [ Time Frame: Within 1 year of treatment initiation ]
    Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 12 months ]
    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.

  2. Locoregional control [ Time Frame: Up to 2 years ]
    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).

  3. 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 ]
    Will be estimated using the method of Kaplan-Meier.

  4. Overall response rate [ Time Frame: Up to 2 years ]
    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.

  5. 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 ]
    Will be estimated using the method of Kaplan-Meier.

  6. Quality of life [ Time Frame: At 3, 6, and 12 months from start of treatment ]
    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.


Other Outcome Measures:
  1. Potential predictive biomarkers of response [ Time Frame: Up to 2 years ]
    Will investigate the association between potential predictive biomarkers of response to treatment. Tumor mutation burden will be categorized as high (above median) or low (equal to or below median). Other biomarker expression levels will be categorized as high versus absent/reduced. The chi-square or Fisher exact test will be used to study associations between expression levels and tumor response (complete response/partial response; stable/progressive disease). Associations with time-to-event endpoints will be investigated using the log rank test. Differences in change in circulating Ki67+ CD8+ T-cells relative to baseline between levels of tumor response will be explored using the t-test or non-parametric equivalent (e.g., Mann-Whitney) if appropriate. Cox regression will be used to explore associations between change in in circulating Ki67+ CD8+ T-cells and time-to-event endpoints. Other biomarkers will be analyzed similarly.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04576091


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Yvonne M Mowery Duke University - Duke Cancer Institute LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04576091    
Other Study ID Numbers: NCI-2020-07522
NCI-2020-07522 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10405 ( Other Identifier: Duke University - Duke Cancer Institute LAO )
10405 ( Other Identifier: CTEP )
UM1CA186704 ( U.S. NIH Grant/Contract )
First Posted: October 6, 2020    Key Record Dates
Last Update Posted: February 5, 2021
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Laryngeal Neoplasms
Mouth Neoplasms
Lip Neoplasms
Oropharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Otorhinolaryngologic Neoplasms
Laryngeal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Otorhinolaryngologic Diseases
Mouth Diseases
Stomatognathic Diseases
Lip Diseases
Pharyngeal Neoplasms
Pharyngeal Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents