Pembrolizumab in HNSCC With Residual Disease After Radiation

• ClinicalTrials.gov Identifier: NCT02892201
• Recruitment Status: Active, not recruiting
• First Posted: September 8, 2016
• Last Update Posted: July 12, 2022
• Sponsor: Yale University
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Barbara Burtness, Yale University

Study Description

Brief Summary:

This is a phase II study for patients with squamous cell carcinoma of the head and neck who have residual disease following definitive therapy with radiation (with or without systemic therapy). Patients must be diagnosed with residual disease within 24 weeks of completion of radiation therapy. Residual disease must be biopsy proven before the patient can consent to the trial, and can be either from lymph nodes in the neck, or from the primary tumor site. Prior to beginning study therapy patients are evaluated by an ENT to determine if they have disease amenable to surgical resection. Both resectable and unresectable patients will be eligible for participation in the study.

Condition or disease	Intervention/treatment	Phase
Head and Neck Squamous Cell Carcinoma	Drug: Pembrolizumab	Phase 2

Detailed Description:

The primary objective is to determine the overall response to pembrolizumab for patients with residual disease following radiation with or without systemic therapy for squamous cell carcinoma of the head and neck.

Hypothesis: The use of pembrolizumab in patients with residual disease following radiation with or without systemic therapy will lead to an enhanced overall response rate due to treatment-related priming of the immune response.

When initially registered, the study used a follow up assessment of 12 weeks. However, the actual study aims for the primary and secondary outcomes were updated to 168 weeks. The primary completion date was also updated to reflect the primary outcome timeline.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pembrolizumab for Patients With Head and Neck Squamous Cell Carcinoma With Residual Disease Following Definitive Chemoradiation
• Actual Study Start Date: November 2016
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: All subjects; for patients with squamous cell carcinoma of the head and neck who have residual disease following definitive therapy with radiation Pembrolizumab will be given at a constant dose of 200 mg every three weeks, for four cycles. Patients with resectable disease can then go on to surgery, and patients with unresectable disease can continue on pembrolizumab until progression or for up to 1 year.

Drug: Pembrolizumab; a constant dose of 200 mg every three weeks, for four cycles.; Other Names: Keytruda; MK-3475

Outcome Measures

Primary Outcome Measures :

1. Overall response rate [ Time Frame: 168 Weeks ]
   To determine the overall response rate based on RECIST 1.1 to pembrolizumab for patients with residual disease following radiation with or without systemic therapy for squamous cell carcinoma of the head and neck. For lesions considered too small for measurement by RECIST 1.1 a modified response criteria will be used.

Secondary Outcome Measures :

1. changes in PD-L1 expression [ Time Frame: 168 Weeks ]
   To determine changes in PD-L1 expression following irradiation
2. overall response rate [ Time Frame: 168 Weeks ]
   To determine the overall response rate as a function of PD-L1 expression
3. median progression free survival [ Time Frame: 168 Weeks ]
   To evaluate median progression free survival
4. overall survival [ Time Frame: 168 weeks ]
   To evaluate overall survival

Other Outcome Measures:

1. rate of immune related adverse events [ Time Frame: 12 weeks ]
   To determine the rate of immune related adverse events in patients receiving immunotherapy following radiation with or without systemic therapy
2. rate of distant metastases [ Time Frame: 168 Weeks ]
   To determine the rate of distant metastases

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be => 18 years of age on day of signing informed consent.
3. Biopsy proven residual disease.
4. Be willing to provide tissue from a newly obtained core biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1 and following completion of RT/CRT.
5. Have a performance status of 0 or 1 or 2 on the ECOG Performance Scale.
6. Demonstrate adequate organ function. Labs value need to be assessed within 14 days of study treatment.
7. Female subject of childbearing potential should have a negative urine or serum pregnancy 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.
8. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
9. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
10. Patients must have a history of Stage I-IVB SCC of the head and neck arising from the oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx and must have been treated with definitive intent radiation (with or without systemic therapy)
11. Patients must be at least 6 weeks (42 days) and no more than 24 weeks (168 days) from completion of radiation with or without systemic therapy at the time of biopsy confirming residual disease. Patients must receive the first dose of study medication no more than 28 weeks following completion of radiation.
12. Patients must have pathological evidence of persistent lymph node disease or persistent disease at the primary tumor site with viable tumor cells confirmed by a biopsy within 24 weeks of study treatment and no evidence of metastatic disease following primary radiation with or without systemic therapy confirmed by a CT scan within 4 weeks of study treatment. If a biopsy confirming residual disease has not been performed, this can be performed after obtaining consent during the screening procedures.
13. Persistent lymph node disease with viable tumor cells will be determined by the histological determination of tumor viability.
14. All persistent disease must have received at least 66 Gy in 1.8-2Gy fractions of radiotherapy to the area of residual disease (or a biologically equivalent dose given by the linear quadratic equation: biologically equivalent dose (BED) = nd (1 + d/( α/β), where n is the number of fractions, d dose per fraction and the α/β ratio for tumor is 10. Previous radiation records will be obtained to confirm adequate dosing.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has 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.
2. Has a diagnosis of immunodeficiency or is receiving supraphysiologic doses of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. A physiologic dose of steroids is defined as up to 10mg of prednisone daily (or its equivalent).
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from acute, non-hematological adverse events due to agents administered more than 4 weeks earlier, unless otherwise approved by the Principal Investigator.

   • Note: Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2 pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade fatigue, any grade xerostomia, and any grade dysgeusia, are an exception to this criterion and may qualify for the study. Also please note that the presence of a feeding tube to aid with nutrition does not disqualify patients from study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first protocol treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from acute, non-hematological adverse events due to a previously administered agent, unless otherwise approved by the Principal Investigator.

   • Note: Subjects with ≤ Grade 2 neuropathy, any grade dysphagia, ≤ Grade 2 pain, ≤ Grade 2 weight loss, any grade hyperpigmentation of skin, any grade fatigue, any grade xerostomia, and any grade dysgeusia, are an exception to this criterion and may qualify for the study. Also please note that the presence of a feeding tube to aid with nutrition does not disqualify patients from study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four 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. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
10. Has known history of non-infectious pneumonitis that required steroids, or current pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of the first protocol treatment. 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.
19. Any patient receiving adjuvant systemic therapy following the completion of radiation therapy is ineligible.
20. Any patient with evidence of distant metastatic disease on a CT within 4 weeks of treatment is ineligible.
21. Evidence of interstitial lung disease.

Contacts and Locations

Locations

United States, Connecticut

Yale Cancer Center

New Haven, Connecticut, United States, 06520

United States, Texas

University of Texas Southwestern Medical Center (UTSW)

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Yale University

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Barbara Burtness, MD; Yale School of Medicine

More Information

• Responsible Party: Barbara Burtness, Professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; Co-Director, Developmental Therapeutics Research Program, Yale University
• ClinicalTrials.gov Identifier: NCT02892201
• Other Study ID Numbers: 2000028047; 1602017275 ( Other Identifier: Original Yale IRB ID )
• First Posted: September 8, 2016
• Last Update Posted: July 12, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Head and Neck Neoplasms; Neoplasms by Site; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action