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Active Clinical Trials

A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Active
Allegheny General Hospital
Allegheny General Hospital

Category:
Cancer - Brain
Sponsor: 
Merck Sharp & Dohme Corp
Contact: 

For more information, please contact Josh Woolford at 412-359-3826 or Josh.Woolford@ahn.org.

(MK-3475-689) A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Purpose: 

To compare the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery between participants who receive neoadjuvant therapy with pembrolizumab and participants who do not.

Male/Female participants with newly diagnosed Stage III or IVA resectable LA HNSCC of at least 18 years of age will be enrolled in this trial.

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

Type of Participant and Disease Characteristics

Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma as assessed by the investigator based on baseline imaging and clinical assessment that is either:

Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0

OR

Stage III or IVA oropharyngeal p16 negative

OR         

Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16). Note: Participants with newly diagnosed HNSCC who underwent partial surgical resection and have gross residual disease are eligible for the study if additional surgery and adjuvant treatment is required.

Note: Participants with multiple primary HNSCC tumors are eligible for the study if at least one of the tumors meets eligibility criteria based on staging after consultation with and approval by the Sponsor.

Be eligible for primary surgery based on investigator decision and per local practice.

Male/female participants who are at least 18 years of age on the day of signing informed consent

A male participant must agree to use a contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5

OR

b.    A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 180 days after the last dose of study treatment.

The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main study without participating in Future Biomedical Research.

Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator/radiology.

Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate). Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Vendor Manual).

Note: Central pathological review for PD-L1 will not be performed before inclusion.

Note: Adequacy of archival tissue sample for PD-L1 analysis will not be assessed prior to the initiation of study treatment.

Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using ‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells (please see Section 9.1.6 - Presurgery Tumor Tissue Collection for details). If HPV status was previously tested using this method, no additional testing is required.

Note: HPV stratification in this study will be performed using local testing of HPV status in participants with oropharynx cancer using the specified method.

Note: If local p16 testing results are not available, or cannot be assessed locally by the specified method, a tumor tissue sample may be submitted for p16 testing at the designated central laboratory.

Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention these tumor locations are assumed to be HPV-negative.

Have an ECOG performance status of 0 to 1 performed within 10 days of treatment initiation.

Note: investigators to confirm no deterioration prior to initiation of treatment.

Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 10 days prior to the start of study treatment.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.

Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.

A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or within 24 hours prior to the start of RT ± cisplatin (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

Prior/Concomitant Therapy

Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to randomization/allocation.

Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

Prior/Concurrent Clinical Study Experience

Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Diagnostic assessments

Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.

Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy are not excluded.

Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review.

Has Grade ≥2 audiometric hearing loss.

Note: Audiometric abnormalities without corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for exclusion.

Has Grade ≥2 neuropathy.

Has Grade 3-4 bleeding due to the underlying malignancy.

If participant has received major surgery, and the participant has not recovered adequately from the toxicity and/or complications from the intervention prior to randomization.

Has had previous allogeneic tissue/solid organ transplant.

Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients (refer to the Investigator’s Brochure for a list of excipients), RT or cisplatin or their analogs.

Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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) is not considered a form of systemic treatment and is allowed.

Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

Has an active infection requiring systemic therapy.

Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.

Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] RNA [qualitative] is detected).

Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.

Other Exclusions

Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.