Details

Details

Title A Phase 3 Study of Pembrolizumab Versus Placebo Following Surgery and Radiation in Participants with High-risk Locally Advanced Squamous Cell Carcinoma of the Skin (KEYNOTE-630; MK-3475-630).

IRB MRK1619

CC 19-776

Hospital Main Campus

Phase Phase 3

Disease Head and Neck, Squamous Cell Carcinoma of Head and Neck

Drug Pembrolizumab

Description

Description

Primary Objective:

  • To compare the recurrence-free survival (RFS), as assessed by the investigator and confirmed by biopsy, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy.

Secondary Objectives:

  • To compare overall survival (OS) in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy.
  • To compare mean change from baseline in health-related quality of life (HRQoL) scores from the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy.
  • To determine the safety and tolerability of pembrolizumab as adjuvant therapy in study participants.

Secondary/Exploratory Objectives:

  • To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of pembrolizumab and other treatments.
  • To compare changes from baseline in HRQoL scores from the Skindex-16 questionnaire, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy.
  • Characterize utilities using EuroQol-5 Dimensions (EQ-5D).
Inclusion Criteria

Inclusion Criteria

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

  1. Participants must have histologically confirmed cSCC as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted).
    Note: Participants for whom the primary site of squamous cell carcinoma was anogenital area (penis, scrotum, vulva, perianal region) are not eligible. Participants with tumors arising on cutaneous non-glabrous (hair-bearing) lip with extension onto vermillion (dry red lip) may be eligible after communication and approval from the clinical director. Participants for whom the primary site is the nose may be eligible after communication and approval from the clinical director if the primary site is skin, not nasal mucosa with outward extension to skin.
  2. Participant must have undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins. Surgery may consist of 1 or a combination of the following:
    • Resection of the primary lesion (Note: If a primary lesion is present, it must be completely resected as above)
    • Any type of neck dissection(s)
    • Any type of parotidectomy (superficial, total, partial)
  3. Participant must have histologically confirmed LA cSCC with a high-risk feature(s) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted). High-risk features include at least 1 of the following:
    • Histologically involved nodal disease that has at least 1 of the following features:
      • Any extracapsular extension
      • =3 regional lymph nodes per primary site (affected regional sites and associated draining lymph nodes)
      • 1-2 involved lymph nodes with any node =3 cm in greatest diameter, independent of extracapsular extension
    • Any index tumor with =2 of the following high risk features:
      • Tumor =4 cm with a depth >6 mm
      • Multi-focal perineural invasion for nerves of <0.1 mm diameter or any involved nerve =0.1 mm diameter
      • Invasion beyond subcutaneous fat
      • Poor differentiation and/or sarcomatoid and/or spindle cell histology
      • Recurrent disease (any cSCC that recurs within 3 years in the previously surgically or topically treated area)
    • Any gross cortical bone invasion or skull base invasion and/or skull base foramen invasion.
    • Any index tumor that is resected with microscopic residual positive surgical margins.
  4. Participant must have completed adjuvant RT for LA cSCC with last dose of RT =4 weeks and =16 weeks from randomization.
  5. Participant must have completed at least 50 Gy 25 fractions of adjuvant RT for LA cSCC prior to study entry.
  6. Participant is disease-free as assessed by the investigator with complete radiographic staging assessment =28 days from randomization.
  7. Demographics: Participant is male or female and at least 18 years of age at the time of signing the informed consent.
  8. Female Participants: Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Is not a woman of childbearing potential (WOCBP) OR
      • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
      • A WOCBP must have a negative highly sensitive pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention.
      • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 5.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  9. 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. Note: Eligible participants must provide additional informed consent for participation in post-study cross-over/retreatment.
  10. Participant provides a tumor tissue sample adequate for PD-L1 testing as determined by central laboratory testing. This tissue sample may be obtained from either the surgical resection, or a prior archival tissue specimen not previously irradiated. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
    • Note: Participants from whom PD-L1 testing cannot be performed due to infeasibility of testing of the tissue sample will not be eligible. Participants will not be excluded if tissue was initially thought to be adequate but a PD-L1 result was unable to be reported for whatever reason.
    • Note: Central pathological review for PD-L1 will not be performed before randomization.
  11. Participant has a life expectancy of greater than 3 months.
  12. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to treatment initiation.
  13. Participant has 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

Exclusion Criteria

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

Medical Conditions

  1. Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease before randomization.
  2. Has any other histologic type of skin cancer other than invasive cSCC, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen's disease, MCC, melanoma.
  3. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study treatment.

Prior/Concomitant Therapy

  1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another costimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
  2. Has received prior systemic anticancer therapy including investigational agents for cSCC within 4 weeks prior to randomization.
    • Note: Participants must have recovered from all AEs due to previous therapies to =Grade 1 or baseline. Participants with =Grade 2 neuropathy may be eligible.
    • Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  3. Participant must have recovered from all radiation-related toxicities, not have required corticosteroids, and not have had radiation pneumonitis.
  4. Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), 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

  1. 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 Assessment

  1. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
  2. Has a diagnosed and/or treated additional malignancy within the past 5 years prior to randomization.
    • Note: Participants with basal cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
    • Note: Participants with low risk early-stage prostate cancer, defined as below are not excluded: Stage T1c or T2a with a Gleason score =6 and a prostate-specific antigen (=10 ng/ml) either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation.
  3. Has known active central nervous system metastases and/or carcinomatous meningitis.
  4. Has severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients (refer to the Investigator's Brochure for a list of excipients).
  5. 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.
  6. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  7. Has an active infection requiring systemic therapy.
  8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
  9. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected) infection.
    • Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
  10. 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.
  11. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
  12. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.
  13. Has had an allogeneic tissue/solid organ transplant.