Randomized Phase II Study of Immune Stimulation with Pembrolizumab and Radiotherapy in Second Line Therapy of Metastatic Head and Neck Squamous Cell Carcinoma (IMPORTANCE, Keynote-717)

Overview
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This is an open-label, randomized, prospective, multicenter phase II clinical trial of pembrolizumab with or without local radiotherapy in patients with recurrent and/or metastatic HNSCC after progression to platinum-based therapy.

All patients will receive pembrolizumab 200mg absolute dose administered every third week. Patients in treatment arm A will receive radiotherapy of one, two or three metastases with a total tumor volume of at least 10cm³ intended to induce tumor cell death acting as an in situ vaccination. Radiotherapy will be performed conventionally fractioned with single doses of 3Gy to a total dose of 36Gy. There will be a strict time schedule. Radiotherapy will always start on Wednesday. After application of the third radiation dose (Friday) the patients will receive pembrolizumab. After an interruption of radiotherapy for two days (Saturday, Sunday), radiotherapy will be continued. Pembrolizumab will be continued on an every three week schedule until confirmed disease progression according to iRECIST criteria, unacceptable toxicity, patient's wish to stop therapy or a maximal treatment time of 12 months. Tumor assessment will be performed every 9 weeks and will be evaluated according to iRECIST and RECIST. For each patient the same assessment method will be used throughout the study. Toxicity will be assessed according to CTCAE 4.0.

Programme: Radiotherapy with Pembrolizumab in Metastatic HNSCC (IMPORTANCE)

SEEK ID: https://ldh.uker.imise.uni-leipzig.de/projects/5

Public web page: Not specified

NFDI4Health PALs: No PALs for this Project

Project start date: 20th Jul 2018

Project end date: 1st Oct 2024

Extended Metadata (Nfdi4Health MDS 3.3)

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Resource classification(*)

Type of the resource : Registry

Title(s)/name(s) of the Project

Title/name : Randomized Phase II Study of Immune Stimulation with Pembrolizumab and Radiotherapy in Second Line Therapy of Metastatic Head and Neck Squamous Cell Carcinoma (IMPORTANCE, Keynote-717, EudraCT NUMBER: 2017-002122-20 )
Language of the title/name : English

Acronym(s) of the Project

Acronym : IMPORTANCE
Language of the acronym : English

Acronym : Keynote-717
Language of the acronym : English

Description(s) of the Project

Description : This is an open-label, randomized, prospective, multicenter phase II clinical trial of pembrolizumab with or without local radiotherapy in patients with recurrent and/or metastatic HNSCC after progression to platinum-based therapy. All patients will receive pembrolizumab 200mg absolute dose administered every third week. Patients in treatment arm A will receive radiotherapy of one, two or three metastases with a total tumor volume of at least 10cm³ intended to induce tumor cell death acting as an in situ vaccination. Radiotherapy will be performed conventionally fractioned with single doses of 3Gy to a total dose of 36Gy. There will be a strict time schedule. Radiotherapy will always start on Wednesday. After application of the third radiation dose (Friday) the patients will receive pembrolizumab. After an interruption of radiotherapy for two days (Saturday, Sunday), radiotherapy will be continued. Pembrolizumab will be continued on an every three week schedule until confirmed disease progression according to iRECIST criteria, unacceptable toxicity, patient's wish to stop therapy or a maximal treatment time of 12 months. Tumor assessment will be performed every 9 weeks and will be evaluated according to iRECIST and RECIST. For each patient the same assessment method will be used throughout the study. Toxicity will be assessed according to CTCAE 4.0.
Language of the description : English

Keyword(s) describing the Project

Keyword(*) : Squamous Cell Carcinoma of Head and Neck

Keyword(*) : clinical trial

Keyword(*) : phase II

Contributor(s) of the Project

Is it a personal or organisational contribution?(*) : Organisational
Details about the contributing organisation(s)/institution(s)/group(s)
Contributor type(*) : Data curator
Funding identifier(s) : Not specified
Name of the organisation/institution/group(*) : Universitätsklinikum Erlangen, Medizinisches Zentrum für Informations- und Kommunikationstechnik (MIK), Datenintegrationszentrum (DIZ)
Details about the contributing person(s)
Contributor type(*) : Not specified
Given name(*) : Not specified
Family name(s)(*) : Not specified
Digital identifier(s)
Identifier(*) : Not specified
Scheme(*) : Not specified
Email address : Forschung.MIK(at)uk-erlangen.de
Phone number : +49 9131 8549444
Organisation(s) associated with the contributor
Name(*) : Barbara Bärthlein
Address : Krankenhausstraße 12, 91052, Erlangen, Germany
Web page : https://www.mik.uk-erlangen.de/ueber-uns/datenintegrationszentrum/forschungs-it/
Digital identifier(s)
Identifier(*) : 0030f2a11
Scheme(*) : ROR

Alternative identifiers

Type of the registry(*) : NCT (ClinicalTrials.gov)
Identifier(*) : NCT03386357

Type of the registry(*) : EudraCT
Identifier(*) : 2017-002122-20

Characteristics of the Project

Is it an interventional or non-interventional Project? : Interventional
Specification of the type of the Project
Interventional Project type : Parallel
Non-interventional Project type : []
Primary health condition(s) or disease(s) considered in the Project
Primary health condition or disease name(*) : Squamous Cell Carcinoma of Head and Neck
Terminology/classification(*) : ICD-10
Code of the health condition or disease : C44.42
Groups of diseases or conditions(*)
Which groups of diseases or conditions were the data collected on? : Neoplasms (II)
On which diseases or conditions were the data collected? : []
Collects mortality data? : Yes, with cause of death
Administrative information about the Project
Status of the ethics committee approval : Not specified
Overall Project status : Not specified
Participants enrolled by invitation? : Not specified
Start date : Not specified
End date : Not specified
Mono- or multicentric? : Not specified
Number of centers : Not specified
One or more data providers? : One data provider
Number of data providers : Not specified
Primary subject(*) : Person
Eligibility criteria for Project participants
Eligibility criteria: Minimum age
Minimum eligible age(*) : 18
Unit of age(*) : Years
Eligibility criteria: Maximum age
Maximum eligible age(*) : 100
Unit of age(*) : Years
Eligible gender : Male, Female, Diverse
Inclusion criteria : Be willing and able to provide written informed consent/assent for the trial. - Kriterium 1; Be >18 years of age on day of signing informed consent. - Kriterium 2; Metastatic HNSCC (at least two distinct lesions: Lesion planned for radiotherapy with ≥10 ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥10 ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥10ml) OR Locally recurrent HNSCC not suitable for curative local treatment within or outside the previously irradiated tissue (at least two distinct lesions: Lesion planned for radiotherapy with ≥10 ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥10 ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥10ml). - Kriterium 3; Progression to first line platinum-based or any second/third line chemotherapy OR Progression within 6 months after platinum-based radiochemotherapy of locally advanced disease - Kriterium 4; Histological confirmation of HNSCC - Kriterium 5; Have at least one measurable lesion according to iRECIST that receives less than 10% of the prescribed dose of the irradiated lesion(s) (not considering doses from previous radiotherapy) - Kriterium 6; Have a performance status of 0-1 on the ECOG Performance Scale. - Kriterium 7; Demonstrate adequate organ function - Kriterium 8; 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. - Kriterium 9; Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. - Kriterium 10; Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. - Kriterium 11
Exclusion criteria : 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. - Kriterium 1; Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. - Kriterium 2; Has a known history of active TB (Bacillus Tuberculosis) - Kriterium 3; Hypersensitivity to pembrolizumab or any of its excipients. - Kriterium 4; 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. - Kriterium 5; Has had prior chemotherapy, targeted small molecule therapy, or radiation 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. Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the 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. - Kriterium 6;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. - Kriterium 7; 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. - Kriterium 8; 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. - Kriterium 9; History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis - Kriterium 10; Has an active infection requiring systemic therapy. - Kriterium 11; 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. - Kriterium 12; Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. - Kriterium 13; 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. - Kriterium 14; Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. - Kriterium 15; Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). - Kriterium 16; Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected). - Kriterium 17; Has received a live vaccine within 30 days of planned start of study therapy. 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. - Kriterium 18; Have a performance status of ≥2 on the ECOG Performance Scale. - Kriterium 19
Population of the Project(*)
Coverage : National
Country(ies) : Germany
Region(s) and/or city(ies) : Bochum, Dresden, Erlangen, Frankfurt/Main, Homburg, Regensburg
Interventions of the Project
Name of the intervention(*) : Not specified
Type of the intervention : Not specified
Additional information about the intervention : Not specified
Name(s) of the arm(s) associated with the given intervention : Not specified
Exposures of the Project
Name of the exposure : Immune stimulation with Pembrolizumab and radiotherapy
Type of the exposure : Combination product (combining a drug and device, a biological product and device; a drug and biological product; or a drug, biological product, and device)
Additional information about the exposure : Pembrolizumab (200mg absolute, q3w) combined with radiotherapy (12x3Gy) of one, two or three metastases.
Name(s) of the group(s) associated with the given exposure : Experimental: A (pembrolizumab+RT)
Name of the exposure : Immune stimulation with Pembrolizumab
Type of the exposure : Drug (including placebo)
Additional information about the exposure : Pembrolizumab (200mg absolute, q3w) without radiotherapy
Name(s) of the group(s) associated with the given exposure : Active Comparator: B (pembrolizumab)
Outcome measures in the Project
Name of the outcome measure(*) : Best response according to iRECIST criteria
Description of the outcome measure : Local radiotherapy will significantly improve the overall response rate according to iRECIST
Type of the outcome measure : Primary
Time point(s) of assessment : Endpoint is the best response during pembrolizumab treatment (restaging every 9 weeks up to 12 months)
Name of the outcome measure(*) : Response rate according to RECIST
Description of the outcome measure : RECIST 1.1 criteria
Type of the outcome measure : Secondary
Time point(s) of assessment : restaging every 9 weeks up to 12 months
Name of the outcome measure(*) : Assessment of target lesion
Description of the outcome measure : changes of the size of a (not irradiated) target lesion will be measured (%)
Type of the outcome measure : Secondary
Time point(s) of assessment : restaging every 9 weeks up to 12 months
Name of the outcome measure(*) : Assessment of the duration of response
Description of the outcome measure : The duration of the response will be evaluated in responding patients.
Type of the outcome measure : Secondary
Time point(s) of assessment : restaging every 9 weeks up to 12 months
Name of the outcome measure(*) : Assessment of the progression free survival
Description of the outcome measure : progression free survival (in months)
Type of the outcome measure : Secondary
Time point(s) of assessment : restaging every 9 weeks up to 12 months
Name of the outcome measure(*) : Assessment of the overall survival
Description of the outcome measure : Overall survival (in months)
Type of the outcome measure : Secondary
Time point(s) of assessment : restaging every 9 weeks up to 12 months
Name of the outcome measure(*) : Assessment of toxicity of the combination of pembrolizumab and radiotherapy
Description of the outcome measure : Toxicity will be evaluated according to CTCAE 4.0
Type of the outcome measure : Secondary
Time point(s) of assessment : at every pembrolizumab administration (q3w) (up tp 12 months)
Name of the outcome measure(*) : Assessment of changes of the immunophenotype in peripheral blood after pembrolizumab without and with radiotherapy (longitudinal analysis)
Description of the outcome measure : Assessment of predictive value of PD-L1 in combination with tumor-infiltrating lymphocytes
Type of the outcome measure : Other
Time point(s) of assessment : week 1, at pembrolizumab administration 2, 4, 8, 12 and through study completion an average of 1 year
Additional information about the Project : Not specified
Additional assessments/measurements in the Project : []
Data sharing strategy of the Project(*)
Is it planned to share the data?(*) : No, there is no plan to make data available
Supporting documents available in addition to the data : []
When and for how long will the data be available? : Not specified
Criteria for data access : Not specified
Additional information about data sharing : Not specified
DataSHIELD/Opal infrastructure available? : Not specified
Link to data request application : Not specified
Web page with additional information about data sharing : Not specified
Record linkage possible? : false
Non-interventional aspects of the Project
Temporal design : []
Target follow-up duration of the Project
Target follow-up duration(*) : Not specified
Unit of time(*) : Not specified
Number of follow-ups conducted : Not specified
Biosamples retained in a biorepository : []
Specific types of retained biosamples : Not specified
Interventional aspects of the Project
Numerical phase : Not specified
Masking of intervention(s) assignment
Masking implemented? : Not specified
Who is masked? : []
Additional information about masking : Not specified
Type of allocation of participants to an arm : Not specified
Off-label use of a drug product : Not specified

Annotated Properties

Topic annotations

Preclinical and clinical studies

Randomized Phase II Study of Immune Stimulation with Pembrolizumab and Radiotherapy in Second Line Therapy of Metastatic Head and Neck Squamous Cell Carcinoma (IMPORTANCE, Keynote-717)

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