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Trial record 1 of 1 for:    NCT03546582
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SBRT +/- Pembrolizumab in Patients With Local-Regionally Recurrent or Second Primary Head and Neck Carcinoma (KEYSTROKE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03546582
Recruitment Status : Recruiting
First Posted : June 6, 2018
Last Update Posted : March 23, 2021
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
RTOG Foundation, Inc.

Brief Summary:
This phase II trial with a safety run-in component will evaluate whether the addition of pembrolizumab to Stereotactic Body Radiation Therapy (SBRT) re-irradiation will improve the progression-free survival for patients with recurrent or new second primary Head and Neck Squamous Cell Carcinoma (HNSCC).

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma (HNSCC) Drug: Pembrolizumab Radiation: Stereotactic Body Radiation Therapy (SBRT) Phase 2

Detailed Description:

Safety Run-In:

To evaluate the safety of the addition of pembrolizumab (anti PD-1 immunotherapy) to re-irradiation with SBRT for patients with recurrent or new second primary head and neck squamous cell carcinoma (HNSCC).

Phase II:

To compare progression-free survival (PFS) for patients with recurrent or new second primary head and neck squamous cell carcinoma with SBRT re-irradiation with or without pembrolizumab.


Safety Run-In: Patients receive SBRT over 2 weeks and then receive pembrolizumab every 3 weeks for up to 2 years.

Phase II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive SBRT over 2 weeks and then receive pembrolizumab every 3 weeks for up to 2 years.

ARM II: Patients receive SBRT over 2 weeks. Arm II patients who experience progressive disease within 2 years after the start of SBRT will be allowed to cross over to receive pembrolizumab for up to 2 years.

After the completion of study treatment, patients are followed up every 6 months for 3 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: KEYSTROKE: A Randomized Phase II Study of Pembrolizumab (KEYTRUDA®) Plus Stereotactic Re-irradiation Versus SBRT Alone for Locoregionally Recurrent or Second Primary Head and Neck Carcinoma
Actual Study Start Date : November 14, 2018
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2026

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Arm I
Patients receive Stereotactic Body Radiation Therapy (SBRT) over 2 weeks and then receive pembrolizumab every 3 weeks for up to 2 years.
Drug: Pembrolizumab
Anti-PD-1 targeted immunotherapy
Other Name: Keytruda

Radiation: Stereotactic Body Radiation Therapy (SBRT)
High-precision radiotherapy
Other Name: SBRT

Arm II
Patients receive Stereotactic Body Radiation Therapy (SBRT) over 2 weeks. Arm II patients who experience progressive disease within 2 years after the start of SBRT will be allowed to cross over to receive pembrolizumab for up to 2 years.
Radiation: Stereotactic Body Radiation Therapy (SBRT)
High-precision radiotherapy
Other Name: SBRT

Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Assessed up to 5 years ]
    The time from randomization to the first documented progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever comes first.

Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Assessed up to 5 years ]
    The time from randomization to death due to any cause.

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

Inclusion Criteria:

  • Pathologically (histologically or cytologically) confirmed diagnosis of locoregional recurrent or any new primary squamous cell carcinoma of the head and neck (including of the nasopharynx or paranasal sinus) that is not amenable to curative resection.

    • Patients for whom curative resection would be medically contraindicated and/or would impose excessive surgical risk are eligible.
    • Patients who are medically and surgically resectable but for whom surgery would be associated with undue surgical morbidity are eligible.
    • For purposes of this protocol, undue surgical morbidity would include total glossectomy; carotid artery resection; laryngectomy or pharyngolaryngectomy; and major ablative resection requiring free flap reconstruction. Patients with primary tumors that can be resected without the forgoing are ineligible.
    • The principal investigators are available to review these criteria on a case by case basis if helpful to the enrolling institution.

A new primary HNSCC is defined where any one of the following criteria are met:

  • Metachronous invasive SCC developing ≥ 6 months after an index HNSCC, more than 3 cm from the index lesion;
  • SCC developing in the same region as the index SCC if ≥ 36 months after the index diagnosis and if within 3 cm of a site where disease was completely resected or complete response was documented;
  • New SCC that is cytologically or molecularly distinct from index SCC (e.g. new HPV negative SCC with prior index SCC that was HPV positive).

    • Tumor tissue testing for p16 status is required for base of tongue, soft palate, and tonsil cancer. If a p16 testing has been previously performed on an oropharynx cancer that has recurred, then repeat testing for p16 status is not required. Participants whose first cancer was an unknown primary must have p16 testing from either the new primary tumor or the recurrent cancer.
    • Prior radiotherapy (RT) to the head and neck (30 Gy minimum)
    • Disease must be limited to a single site or adjacent sites that can be treated in a single contiguous target volume for which the maximum total tumor dimension (GTV) must be <7.5cm. Examples of eligible patients include:

      1. A primary site recurrence in the oropharynx with a concurrent level 2 nodal mass, or a laryngeal recurrence with a level 3 nodal mass
      2. Multiple nodes in the same (level 2) or adjacent nodal levels (levels 2 and 3)
      3. Skull base recurrence with a lateral pharyngeal or high level 2 node

Note: These cases will be eligible provided that the maximum total tumor dimension is <7.5cm. For cases in which a tumor biopsy was performed and there is a biopsy/tumor debulking bed adjacent to the gross residual disease, all of the preoperative radiographic abnormalities must be included in the GTV and meet the <7.5cm maximal dimension criteria to meet eligibility.

Note: Patients who meet these criteria only after surgical removal of a portion of the patient's disease (e.g. removal of level 4 nodal mass in a patient with a tongue base primary; or of a contralateral nodal mass in an N2c patient) are ineligible.

  • Patients who have undergone a recent biopsy (e.g. incisional) are eligible. Any preceding surgical procedure beyond a biopsy (e.g. debulking) must be reviewed as follows:

    • Patients rendered free of gross disease are not eligible.
    • Patients with gross residual disease postoperatively, must be reviewed by the Surgical Co-PI for determination of eligibility.
    • Patients eligible for study must have cutaneous wounds healed for 4-6 weeks prior to the initiation of SBRT.
  • History/physical examination within 56 days prior to entry
  • Examination by a Radiation Oncologist and Medical Oncologist within 56 days prior to entry; [Note: Baseline dental assessment is strongly recommended prior to start of therapy but is not required for eligibility]
  • Contrast enhanced CT or MRI, of the tumor and neck within 56 days prior to entry.
  • Chest CT scan or full body PET/CT within 56 days prior to entry; patients with equivocal pulmonary nodules that are < 1.5 cm, that cannot be safely biopsied, or that are negative on PET/CT imaging are eligible.
  • Zubrod Performance Status of 0-1 within 28 days prior to entry.
  • Age ≥ 18
  • Trial is open to all genders
  • Hematologic: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3, Platelets ≥ 100,000 cells/mm3, Hemoglobin ≥ 9 g/dL
  • Hepatic: Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN, AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
  • Creatinine ≤ 1.5 x ULN, OR measured or calculated creatinine clearance > 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN [NOTE: Calculated creatinine per institutional standard; GFR may be used in place of creatinine or CrCl]
  • Coagulation: International normalized ratio (INR), OR prothrombin time (PT), and Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
  • Negative serum pregnancy test within 14 days prior to entry for women of childbearing potential. (Note: A pregnancy test must be repeated within 3 days prior to the administration of the first dose of pembrolizumab)
  • The patient or legally authorized representative must provide study-specific informed consent prior to study entry.

Exclusion Criteria:

  • Distant metastases.
  • Tumors that involve more than 180 degrees of the carotid artery on diagnostic CT or MRI of the neck within 56 days prior to entry. Investigators are encouraged to review the CT simulation imaging and ensure that tumor progression has not occurred whereby patients who were initially eligible based on diagnostic imaging, would be rendered ineligible based on CT simulation imaging (e.g. tumor size >7.5cm, skin involvement, >180 degrees of carotid encasement by tumor). If this does occur, the patient should be removed from the study and the Radiation Oncology Co-PIs should be notified via email. Note: It is strongly recommended that CT simulation be performed prior to entry.
  • Patients with gross skin involvement (i.e. tumor ulceration through the skin) are excluded. Patients with tumor approaching the skin but in which the overlying skin remains intact are eligible, providing that planning constraints can be achieved without the use of bolus.
  • Disease that requires two or more discontiguous target volumes will be ineligible. Examples of such cases include:

    • Bilateral nodal targets
    • Level 2 and level 4 nodes
    • An oropharyngeal recurrence with a low level 4 node;
  • Patients for whom the maximal total tumor dimension (GTV) is >7.5cm
  • Prior radiation to primary tumor within 6 months of entry
  • Prior systemic therapy, investigational agent or investigational device within 28 days of start of study treatment.
  • Surgical resection of the qualifying cancer is not permitted. (Patients who have undergone biopsies are eligible). Patients without radiographically apparent gross tumor are ineligible. For cases where an operation more extensive than a biopsy was performed but radiographically apparent gross residual tumor remains, will be reviewed by the Surgical Co-PI for determination of eligibility.
  • No concurrent treatment with other investigational agent or investigational device.
  • Prior therapy with a checkpoint inhibitor (eg anti-CTLA-4, anti-PD-1 or anti-PD-L1 therapy).
  • Patients with immunodeficiency, or receiving systemic steroid, or any form of immunosuppressive therapy at the time of registration (e.g. history of human immunodeficiency virus - HIV). Use of physiologic doses corticosteroids may be approved with consultation with study chairs.
  • 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. thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a form of systemic therapy
  • Known active hepatitis B (positive test for virus surface antigen - HBsAg) or hepatitis C virus (e.g. positive HCV RNA qualitative test).
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  • Treatment with a live vaccine within 30 days of entry. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed
  • Unstable angina and or congestive heart failure requiring hospitalization in the last 6 months.
  • Transmural myocardial infarction within the last 6 months.
  • Active bacterial or fungal infection requiring intravenous antibiotic at the time of registration; Note: If the infection resolves and the patient is on p.o. and still within, the required registration timeframe, then the patient is eligible
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of entry.
  • Other significant medical, surgical or psychiatric conditions or requirements for any medication or treatment that in the opinion of the investigator may interfere with compliance, make administration of anti-PD-L1 therapy hazardous, or obscure interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
  • Pregnancy, nursing females, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

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 identifier (NCT number): NCT03546582

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Contact: Stuart J. Wong, MD 414-805-4621

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United States, Arizona
University of Arizona Cancer Center - North Campus Recruiting
Tucson, Arizona, United States, 85719
Contact: Alysha Zeoli    520-694-9056   
Principal Investigator: Jared Robbins, MD         
United States, Florida
Cleveland Clinic - Weston Recruiting
Weston, Florida, United States, 33331
Contact: Holly Sasak    216-445-5256   
Principal Investigator: Shlomo Koyfman, MD         
United States, Kentucky
University of Louisville, James Graham Brown Cancer Center Recruiting
Louisville, Kentucky, United States, 40202
Contact: Teresa Roberts, RN, BSN    502-333-6943   
Principal Investigator: Neal Dunlap, MD         
United States, Massachusetts
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Annie Jose    617-638-8213   
Principal Investigator: Michael Dyer, MD         
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: John Gaggin, RN    313-916-3731   
Principal Investigator: Eleanor Walker, MD         
United States, Missouri
Washington University St. Louis Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Wade Thorstad, MD    314-362-8516   
Principal Investigator: Wade Thorstad, MD         
United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Ellen Perme    216-844-2512   
Principal Investigator: Min Yao, MD         
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Holly Sasak    216-445-5256   
Principal Investigator: Shlomo Koyfman, MD         
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Tiffany Elsea    614-685-8966   
Principal Investigator: Dukagjin Blakaj, MD         
United States, Pennsylvania
University of Pittsburgh Medical Center Shadyside Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Karen Holeva    412-623-1275   
Principal Investigator: David Clump, MD, PhD         
United States, Texas
University of Texas Southwestern Recruiting
Dallas, Texas, United States, 75390
Contact: Jiffin John    214-645-8527   
Principal Investigator: David Sher, MD         
United States, Wisconsin
Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Kay Lieb, RN    414-805-5153   
Contact: Matthew Lasowski    414-805-8375   
Principal Investigator: Stuart Wong, MD         
Canada, Alberta
Cross Cancer Institute Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Contact: Holly Toker    780-432-8711   
Principal Investigator: Brock Debenham, MD         
Canada, Quebec
Centre Hospitalier de l'université de Montréal Recruiting
Montréal, Quebec, Canada, H2X 3E4
Contact: Mom Phat, RN    514-890-8000 ext 11171   
Principal Investigator: Phuc Felix Nguyen-Tan, MD         
McGill University Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Marianna Perna, CCRP, CCRC    514-934-1934 ext 43191    marianna.perna@muhc.mcg   
Principal Investigator: George Shenouda, MD         
CHU de Quebec - Universite Laval Recruiting
Québec, Quebec, Canada, G1R 2J6
Contact: Josee Allard    418-691-5790   
Principal Investigator: Andre Fortin, MD         
Sponsors and Collaborators
RTOG Foundation, Inc.
Merck Sharp & Dohme Corp.
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Principal Investigator: Stuart J. Wong, MD RTOG Foundation
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Responsible Party: RTOG Foundation, Inc. Identifier: NCT03546582    
Other Study ID Numbers: RTOG 3507
First Posted: June 6, 2018    Key Record Dates
Last Update Posted: March 23, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by RTOG Foundation, Inc.:
Head and Neck Squamous Cell Carcinoma
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Antineoplastic Agents, Immunological
Antineoplastic Agents