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Neoadjuvant Study of PD-1 Inhibitor Pembrolizumab in PD-1 Naive Cutaneous Squamous Cell Carcinoma (cSCC)

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.
 
ClinicalTrials.gov Identifier: NCT04808999
Recruitment Status : Recruiting
First Posted : March 22, 2021
Last Update Posted : June 23, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Diwakar Davar, University of Pittsburgh

Brief Summary:
This phase II single-arm two-stage neoadjuvant study of pembrolizumab in patients with PD-1 naïve high-risk resectable cutaneous squamous cell carcinoma (cSCC) will be conducted over a 52-week period. The study will include patients who have not undergone surgery to remove disease, to formally evaluate whether both biologically and clinically high-risk disease may benefit from neoadjuvant anti-PD-1 therapy. Response to neoadjuvant anti-PD-1 therapy will be evaluated for association with improved landmark Relapse-free Survival (RFS).

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma Drug: Pembrolizumab Injection Phase 2

Detailed Description:
Patients with high-risk resectable cSCC who have yet to undergo definitive surgery will be eligible to enroll. Patients with nodal and/or in-transit relapse including those who have received prior adjuvant RT are eligible to enroll. This trial excludes patients who have received either nivolumab or pembrolizumab or other anti-PD-(L)1 therapy. Suitable patients will be identified pre-operatively. Patients will undergo a 28-day screening evaluation consisting of systemic staging scans, tumor biopsy, and blood studies to confirm suitability. Once enrolled, patients will receive pembrolizumab peri-operatively for 6 weeks (200mg Q3Wq3; 2 cycles) prior to definitive surgery (Neoadjuvant Phase). Following peri-operative therapy, patients will undergo restaging scans and surgical evaluation followed by definitive surgical resection (Surgical Phase). Post-operatively, patients will receive 15 further cycles of pembrolizumab over a 45-week period (200mg q3Q3W) (Adjuvant Phase). In the post-operative period, if patients are deemed eligible for RT, this will be administered concurrently with pembrolizumab. The total duration of pembrolizumab therapy is 1 year (52 weeks).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Neoadjuvant Study of PD-1 Inhibitor Pembrolizumab in PD-1 Naive Cutaneous Squamous Cell Carcinoma (cSCC)
Actual Study Start Date : May 28, 2021
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : October 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab
Neoadjuvant Phase: 200 mg IV infusion, every 3 weeks (Day 1 of each 3-week cycle, 2 cycles) Adjuvant Phase: Day 1 of each 3-week cycle, 15 cycles
Drug: Pembrolizumab Injection
200 mg IV infusion
Other Name: Keytura




Primary Outcome Measures :
  1. Pathologic Complete Response (pCR) [ Time Frame: From start of treatment, up to 24 months ]
    The proportion of patients with pathologic complete response (pCR) per Immune-Related Pathologic Response Criteria' (irPRC) criteria: 0% residual viable tumor (RVT)] remaining in post-therapy specimen (no signs of cancer) in tissue samples removed during surgery.


Secondary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Up to 60 months ]
    The median length of time from initiation of study drug(s) until disease relapse (disease progression) as defined by RECIST v1.1, or death. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  2. 1-year PRS [ Time Frame: Up to 12 months ]
    The proportion of patients whose disease does not progress/relapse (as defined by RECIST v1.1), or cease to breath at 1 year after the initiation of treatment. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  3. 6-month PFS [ Time Frame: Up to 6 months ]
    The proportion of patients whose disease does not progress/relapse (as defined by RECIST v1.1), or cease to breath at 6 months after the initiation of treatment. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  4. 2-year PFS [ Time Frame: Up to 24 months ]
    The proportion of patients whose disease does not progress (as defined by RECIST v1.1), or cease to breath at 2 years after the initiation of treatment. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  5. 3-year PFS [ Time Frame: Up to 36 months ]
    The proportion of patients whose disease does not progress/relapse (as defined by RECIST v1.1), or cease to breath at 3 years after the initiation of treatment. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  6. Overall Survival (OS) [ Time Frame: Up to 84 months ]
    The median length of time from initiation of study treatment that patients remain alive.

  7. 1-year OS [ Time Frame: Up to 12 months ]
    The proportion of patients alive at 1 year after the initiation of treatment.

  8. 2-year OS [ Time Frame: Up to 24 months ]
    The proportion of patients alive at 2 years after the initiation of treatment.

  9. Pathologic Response [ Time Frame: From start of treatment, up to 24 months ]
    Number of patients with response per Immune-Related Pathologic Response Criteria (irPRC) criteria: major pathologic response (<0 to ≤10% RVT); partial pathologic response (<10 to ≤50% RVT).



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
Criteria

Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of high-risk localized or locooregional cSCC as defined below may be enrolled in this study.

  1. NOTE: Patients are eligible for this trial either at initial presentation for cSCC with locally advanced and/or concurrent regional nodal metastasis; or at the time of recurrence with locally advanced and/or concurrent regional nodal metastasis assuming following criteria are met per the cSCC-specific AJCC UICC 8th edition staging classification

i. T2 and Nx and M0 (tumor >2 cm and ≤4 cm in greatest dimension) OR;

ii. T3 and Nx and M0 (tumor >4 cm or minor bone erosion or perineural invasion or deep invasion) OR;

  1. Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor).
  2. Perineural invasion is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.

    iii. T4 and Nx and M0 (tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion if deemed surgically resectable) OR;

    iv. Tx and N1-3 and M0 (if deemed surgically resectable) OR;

    b. NOTE:

    i. If T2, tumors must possess ≥2 NCCN/BWH clinical or pathologic risk factor(s) as stated below.

    ii. NCCN/BWH clinical risk factors:

1. Tumors ≥20 mm on trunk or extremities (excluding pretibia, hands, feet, nail units, and ankles).

2. Tumors ≥10 mm on cheeks, forehead, scalp, neck, or pretibial areas.

iii. NCCN/BWH pathologic risk factors:

  1. Poorly defined borders.
  2. Recurrent tumors.
  3. Neurologic symptoms to suggest perineural invasion.
  4. High-risk histologic subtypes including: poorly differentiated tumor, acantholytic (adenoid), adenosquamous, desmoplastic, or metaplastic (carcinosarcomatous) subtypes (as stated in the pathology report or written documentation by Mohs surgeon).
  5. Histopathologically documented perineural, lymphatic, or vascular involvement (as stated in the pathology report or written documentation by Mohs surgeon).

    c. NOTE: Tumors of any size on the "mask areas" of the face [central face, eyelids, eyebrows, periorbital nose, lips (cutaneous and vermilion) are not eligible.

    d. NOTE: Tumors of any size on genitalia, hands, and feet may be eligible at the discretion of the treating surgical oncologist.

    e. NOTE: Patients with tumors that arise in the setting of chronic inflammation (Marjolin's ulcer) such as chronic wounds and/or scars are excluded.

    f. NOTE: Determination of surgical resectability must be made before enrollment by the treating surgical oncologist (or ENT surgeon or equivalent).

2. Male participants: A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

3. Female participants:

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

  1. Not a woman of childbearing potential (WOCBP)

    OR

  2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.

    4. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

    5. Have at least a single site of measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

    6. Willing to undergo pre-treatment biopsies.

  1. Prior archival tumor tissue sample are not permitted.
  2. Minimum tissue requirements: core (16G or 18G, 6 cores; preferred), punch or excisional biopsy of a tumor lesion that has not been previously irradiated.

    7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

a. ECOG evaluation should be performed at Screening and repeated on Cycle 1 Day 1.

8. Have adequate organ function, per protocol criteria

Exclusion Criteria:

  1. Diagnosis of immunodeficiency, immunosuppression and/or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
  3. Prior chemotherapy, targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
  4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  5. 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 intervention.
  6. A WOCBP who has a positive urine pregnancy test at Screening. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  7. Has received a live vaccine within 30 days prior to the first dose of study drug.

    1. 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 (BCG), and typhoid vaccine.
    2. 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.
  8. 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 14 days prior to the first dose of study drug.
  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).

    1. Note: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
  10. Concurrent non-hematologic malignancy other than cSCC within 3 years of data of first planned dose of therapy except for tumors with a negligible risk of metastasis and/or death as defined below:

    a. Adequately treated non-invasive malignancies including but not limited to melanoma in situ (MIS), BCC, CIS of cervix, or DCIS of breast may be enrolled.

    b. Low-risk early stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score ≤6 and PSA ≤10 ng/mL) for which the management plan is active surveillance, or prostate adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of > 12 months for which the management plan is active surveillance may be enrolled.

    c. Indolent hematologic malignancies for which the management plan is active surveillance including but not limited to CLL/indolent lymphoma may be enrolled.

    i. Patients with high-risk hematologic malignancies (CML, ALL, AML, Hodgkin's or non- Hodgkin's lymphoma) are excluded even if the management plan is active surveillance.

  11. Has known active CNS metastases and/or carcinomatous meningitis.

    a. Note: Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during Screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.

  12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
  13. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  14. Has an active infection requiring systemic therapy.
  15. Has a known history of Human Immunodeficiency Virus (HIV) infection.
  16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) and/or known active Hepatitis C virus (defined as anti-HCV reactive) infection.

    a. Patients with treated Hepatitis B/C with no evidence of active infection may be enrolled.

  17. Has a known history of active TB (Bacillus Tuberculosis).
  18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  20. 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 trial treatment.
  21. Has had an allogenic tissue/solid organ transplant.

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 ClinicalTrials.gov identifier (NCT number): NCT04808999


Contacts
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Contact: Amy Rose, RN, BSN 412-647-8587 kennaj@upmc.edu
Contact: Rachel Piecuch, RN, BSN 412-864-7893 piecuchre@upmc.edu

Locations
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United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Amy Rose, RN, BSN    412-647-8587    kennaj@upmc.edu   
Contact: Rachel Piecuch, RN, BSN    412-864-7893    piecuchre@upmc.edu   
Principal Investigator: Diwakar Davar, MD, M.Sc         
Sponsors and Collaborators
Diwakar Davar
Merck Sharp & Dohme LLC
Investigators
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Principal Investigator: Diwaker Davar, MD, M.Sc UPMC Hillman Cancer Center
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Responsible Party: Diwakar Davar, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04808999    
Other Study ID Numbers: HCC 20-300
First Posted: March 22, 2021    Key Record Dates
Last Update Posted: June 23, 2022
Last Verified: June 2022
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
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Diwakar Davar, University of Pittsburgh:
PD-1 inhibitor
neoadjuvant
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents