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Title RTOG3507: A randomized Phase II study of re-irradiation of SBRT plus anti-PD-1 antibody Pembrolizumab (Keytruda®) versus SBRT Kalone for locoregionally recurrent or second primary head and neck carcinoma

IRB RFI1318

CC 19-560

Hospital Main Campus

Stage Recurrent/Relapsed

Phase Phase 2

Disease Squamous Cell Carcinoma of Head and Neck

Drug Pembrolizumab

Description

Primary Objective for Run-In Component

• 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

Primary Objective for Phase II Trial

• 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

Secondary Objectives for Phase II Trial (11-MAR-2019)

• To compare overall survival (OS) for patients with recurrent or new second primary head and neck squamous cell carcinoma with SBRT re-irradiation with or without pembrolizumab;
• To compare safety and toxicity in patients treated with SBRT re-irradiation with or without pembrolizumab;
• To determine the radiographic response rate, PFS and OS in patients who receive cross-over treatment to pembrolizumab following disease progression on SBRT alone;
• Correlative: Tumor biopsy specimens will be used to examine:
  • the presence of high density of tumor infiltrating immune cells defined by the multiplex immunohistochemical staining;
  • the presence of "T cell-inflamed phenotype" defined by the 12-gene cytokine signature;
  • the presence of a genetic alteration profile that associates with PD-1 inhibitor sensitivity.

Inclusion Criteria

1. Pathologically (histologically or cytologically) confirmed diagnosis of locoregional recurrent or any new primary squamous cell carcinoma of the head and neck that is not amenable to curative resection. 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 (eg new HPV negative SCC with prior index SCC that was HPV positive).
2. 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 performed and documented at the time of enrollment from either the new primary tumor or the recurrent cancer.
3. Patients must have had prior radiotherapy (RT) to the head and neck (minimum of 30 Gy) with overlap of at least 25% of the current PTV with the previously treated area. Obtaining and reviewing prior radiation treatment plans is strongly encouraged. In the event that they are unavailable, and the area in question was clearly in the previous radiation field (e.g. in a conventional 3 field arrangement), that patient will be considered eligible for trial.
4. 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
   • A primary site recurrence in the oropharynx with a concurrent level 2 nodal mass, or a laryngeal recurrence with a level 3 nodal mass
   • Multiple nodes in the same (level 2) or adjacent nodal levels (levels 2 and 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.
5. 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, Dr. John Ridge (drew.ridge@fccc.edu) for determination of eligibility. The operative report, pathology report and radiographic image(s) of the preoperative and postoperative target lesion must be included in the email along with the eligibility inquiry. These will be addressed within 3 business days.
   • Patients eligible for study must have cutaneous wounds healed for 4-6 weeks prior to the initiation of SBRT.
6. The following diagnostic evaluation is required:
   • History/physical examination within 56 days prior to registration
     • Examination by a Radiation Oncologist and Medical Oncologist within 56 days prior to registration; [Note: Baseline dental assessment is strongly recommended prior to start of therapy but is not required for eligibility (See Section 4)]
   • Contrast enhanced CT or MRI, of the tumor and neck within 56 days prior to registration.
   • Chest CT scan or full body PET/CT within 56 days prior to registration; 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;
7. Zubrod Performance Status 0-1 within 28 days prior to registration;
8. Age ≥ 18;
9. The trial is open to all genders;
10. Adequate bone marrow, liver function, renal function, and laboratory parameters within 28 days prior to registration defined as follows:
    • 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 xULN
    • 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]
11. Negative serum pregnancy test within 14 days prior to registration 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)
12. The patient or legally authorized representative must provide study-specific informed consent prior to study entry.

Exclusion Criteria

1. Patients with distant metastases;
2. Tumors that involve more than 180 degrees of the carotid artery on diagnostic CT or MRI of the neck within 56 days prior to registration. 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 registration.
3. 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 per Section 5.2.8 can be achieved without the use of bolus;
4. 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;
5. Patients for whom the maximal total tumor dimension (GTV) is >7.5cm
6. Prior radiation to primary tumor within 6 months of registration
7. Prior systemic therapy, investigational agent or investigational device within 28 days of start of study treatment.
8. 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, please email the Surgical Co-PI, Dr. John Ridge (drew.ridge@fccc.edu) for determination of eligibility. The operative report, pathology report and radiographic image(s) of the postoperative target lesion must be included in the email along with the eligibility inquiry. These will be addressed within 3 business days.
9. No concurrent treatment with other investigational agent or investigational device
10. Prior therapy with a checkpoint inhibitor (eg anti-CTLA-4, anti-PD-1 or anti-PD-L1 therapy);
11. Severe, active co-morbidity defined as follows:
    • Patients with immunodeficiency, or receiving systemic steroid, or any form of immunosuppressive therapy at the time of registration (eg 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 (ie with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg 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 (eg 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 registration. 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 registration.
12. 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;
13. 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.