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Immunotherapy +/- EGFR Inhibitor In Advanced/Metastatic cSCC: Tackling Primary And Secondary Resistance (I-Tackle)

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. Read our disclaimer for details. Identifier: NCT03666325
Recruitment Status : Unknown
Verified September 2018 by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano.
Recruitment status was:  Not yet recruiting
First Posted : September 11, 2018
Last Update Posted : September 11, 2018
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary:

Cutaneous Squamous Cell Cancer (Cscc, 25%) and basal cell carcinoma (BCC; 75%) are the major subtypes of non-melanoma skin cancer. Most cSCC arise in the head and neck region because it is frequently exposed to sunlight and its ensuing UV radiation-induced DNA damage, which is the major etiologic factor.

There is an urgent need to identify new therapeutic targets for patients with locally advanced or metastatic squamous Cell Cancer of the skin.

Substantial progress has recently been made in the development of immunotherapy for the treatment of cancer. In particular, the treatment with pembrolizumab alone or in conjunction with an anti epidermal growth factor receptor (EGFR) agent may reverse this condition, so performing radical surgery. Finally, the adjunct of an anti EGFR agent as cetuximab could reverse the primary and secondary resistance to pembrolizumab, with a synergistic effect able to counteract pathway redundancy (i.e. the presence of several concurrent pathways which need to be addressed together) and boosting T cell priming.

Hence, there is rationale to combine cetuximab with pembrolizumab in order to increase its effectiveness.

Condition or disease Intervention/treatment Phase
Skin Neoplasm Drug: Pembrolizumab Drug: Cetuximab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Immunotherapy Followed By EGFR Inhibitor In Locally Advanced Or Metastatic Squamous Cell Cancer Of The Skin: Tackling Primary And Secondary Resistance
Estimated Study Start Date : October 1, 2018
Estimated Primary Completion Date : October 1, 2020
Estimated Study Completion Date : October 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Skin Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab
Pembrolizumab 200 mg, IV infusion on Day 1 of each 3 week cycle. After 3 cycles patient will be evaluated. In case of disease control (SD, PR, CR) the patient will continue to receive pembrolizumab. In case of progression the patient will receive also Cetuximab (250 mg/m2 after loading dose of 400mg/m2 IV infusion every week.
Drug: Pembrolizumab
Pembrolizumab at 200 mg every 3 weeks for 9 weeks.
Other Name: Keytruda

Drug: Cetuximab
In case of first progression or no response cetuximab will be added at a weekly dose of 250 mg.
Other Name: Erbitux

Primary Outcome Measures :
  1. Cumulative response rate [ Time Frame: 15 patients will be enrolled. The first evaluation will take place when the last completes three 21-day cycles of Pembrolizumab+/-cetuximab. If we don't observe at least 5 responses (PR/CR), we will stop the recruitment and reject the hypothesis. ]
    Increase in cumulative response rate (PR + CR) obtained by single agent or by combination strategy (pembrolizumab alone or with pembrolizumab + EGFR inhibiting agent) in respect to monotherapy with anti-EGFR agent.

Secondary Outcome Measures :
  1. Compliance and safety [ Time Frame: Treatment emergent adverse events will be measured throughout the study treatment (at each 21-days cycle.). ]
    Treatment safety will be evaluated by the frequency, type and severity of adverse events, graded according to NCI-CTCAE v.4.03

  2. Best response [ Time Frame: After first evaluation (after 9 weeks), every restaging will be performed every 6 weeks ]
    Disease control (SD + PR + CR) as best response obtained by single agent or by combination

  3. PFS [ Time Frame: through study completion, an average of 4 years. PFS calculated in each patient as the time from the date of treatment start to the date of first progression or death, whichever comes first ]
    Progression free survival

  4. OS [ Time Frame: through study completion, an average of 4 years. OS, calculated for each patient as the time from the date of treatment start to the date of death. ]
    Overall survival

  5. Proportion of patients undergoing surgery [ Time Frame: Through study completion an average of 4 years ]
    Percentage of patients initially not considered for surgery due to difficulty to obtain a curative treatment that undergo surgery after the treatment (pembrolizumab alone or pembrolizumab + anti EGFR agent)

  6. percentage of responding patients [ Time Frame: Through study completion, an average of 4 years ]
    Reversal of acquired resistance to pembrolizumab obtained through the addition of cetuximab (percentage of responding patients)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • Willing and able to provide written informed consent/assent for the trial.
  • 18 years of age.
  • Histological diagnosis of squamous cell carcinoma of the skin not amenable to surgical treatment and to radiation with curative purposes or with clinical contraindication to surgery and radiation.
  • Have metastatic disease
  • Have measurable disease based on RECIST 1.1.
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion.
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  • Demonstrate adequate hematological, renal and hepatic organ function as defined in the study protocol.
  • Women of childbearing potential should have a negative pregnancy within 72 hours prior to receiving the first dose of study medication.
  • Women of childbearing potential must be willing to use an adequate method of contraception as outlined in the study protocol4
  • Men of childbearing potential must be willing to use an adequate method of contraception as outlined in the study protocol

Exclusion Criteria:

  • Current or past participation 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.
  • Previous treatment with anti-EGFR agent
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (prednisone equivalent dose > 10 mg per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Hypersensitivity to the trials drugs or their excipients.
  • 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 adverse events due to agents administered more than 4 weeks earlier.
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (≤ Grade 1 or at baseline) from adverse events.
  • Has a known additional malignancy that is progressing or requires active treatment.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years.
  • Has known history of, or any evidence of active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation, or is not in the best interest of the subject.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has previously received an organ transplant
  • Has previously received bone marrow transplantation
  • Has received a live vaccine within 30 days of planned start of study therapy.

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 identifier (NCT number): NCT03666325

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Contact: Paolo Bossi, MD +390223902150

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ASST Spedali Civili di Brescia
Brescia, BS, Italy, 25123
Contact: Francesca Consoli, MD    00390303995260   
Principal Investigator: Francesca Consoli, MD         
Azienda Ospedaliero Universitaria Careggi
Firenze, FI, Italy, 50134
Contact: Vincenzo De Giorgi, MD    0039055794111   
Principal Investigator: Vincenzo De Giorgi, MD         
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, MI, Italy, 20133
Contact: Paolo Bossi, MD    00390223902150   
Principal Investigator: Paolo Bossi, MD         
Istituto Europeo di Oncologia
Milan, MI, Italy, 20141
Contact: Emilia Cocorocchio, MD    00390257489459   
Principal Investigator: Emilia Cocorocchio, MD         
Ospedale di Circolo e Fondazione Macchi
Varese, VA, Italy, 21100
Contact: Graziella Pinotti, MD    00390332278556   
Principal Investigator: Graziella Pinotti, MD         
Istituto IRCCS AOU S. Martino
Genova, Italy, 16132
Contact: Paola Queirolo, MD    00390105600561   
Principal Investigator: Paola Queirolo, MD         
Istituto Nazionale Tumori - Fondazione IRCCS "G. Pascale"
Napoli, Italy, 80131
Contact: Paolo Ascierto, MD    00390815903236   
Principal Investigator: Paolo Ascierto, MD         
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Merck Sharp & Dohme LLC
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Principal Investigator: Paolo Bossi, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
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Responsible Party: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Identifier: NCT03666325    
Other Study ID Numbers: I-Tackle
First Posted: September 11, 2018    Key Record Dates
Last Update Posted: September 11, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
metastatic squamous cell cancer of the skin
skin neoplasm
locally advanced squamous cell cancer of the skin
Additional relevant MeSH terms:
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Neoplasms, Squamous Cell
Skin Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Skin Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action