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Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC

Primary Purpose

Head and Neck Squamous Cell Carcinoma

Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Pembrolizumab
Lenvatinib
Sponsored by
Universität des Saarlandes
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Head and Neck Squamous Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

  1. Male/female participants who are at least 18 years of age on the day of signing informed consent
  2. Pathologically proven new diagnosis of squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx or supraglottic larynx stage III-IVB according to TMM 8th edition
  3. PD-L1 combined positive score (CPS) ≥1 (in sample prior to radiochemotherapy) by central pathology review
  4. Completed definitive radiochemotherapy up to at least 68Gy with at least 200mg/m² body surface area concomitant Cisplatin.
  5. No progression during radiochemotherapy. Study screening CT has to be compared to radiochemotherapy baseline CT. (Study screening CT may be performed before the end of radiochemotherapy, whereas a minimum radiation dose of 50Gy has to be administered at the time point of the study screening CT.)
  6. Male participants:

    A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab or lenvatinib, whichever is administered last) and refrain from donating sperm during this period. In addition, contraception has to be used for 180 days after the last dose of cisplatin.

  7. 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: a. Not a woman of childbearing potential (WOCBP) OR b. 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 (pembrolizumab or lenvatinib, whichever is administered last). In addition, contraception has to be used for 180 days after the last dose of cisplatin.

  8. The participant provides written informed consent for the trial.
  9. Have measurable disease based on RECIST 1.1.
  10. Have provided archival tumor tissue sample with sufficient tumor content. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
  11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
  12. Have adequate organ function. Specimens must be collected within 10 days prior to the start of study intervention.

Exclusion Criteria:

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

  1. Have tumor infiltration/perforation of the skin or cervical fistula (either at timepoint of study inclusion or prior to radiochemotherapy)
  2. Have radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90-degree abutment or encasement of a major blood vessel.
  3. Had prior radical surgery for the head and neck cancer under study or induction chemotherapy with more than one cycle prior to definitive radiochemotherapy. Patients with single cycle induction chemotherapy prior radiochemotherapy can be included.
  4. WOCBP who have a positive urine or serum pregnancy test within 72 hours prior to. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  5. Have 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).
  6. Have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study drug administration (except from cisplatin concomitant to radiochemotherapy).
  7. Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
  8. Are currently participating in or have participated in a study of an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study intervention.
  9. Have 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.
  10. Have a known additional malignancy that is progressing or have required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous 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.
  11. Have distant metastases.
  12. Have severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients.
  13. Have 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 and is allowed.
  14. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  15. Have an active infection requiring systemic therapy.
  16. Have a known history of Human Immunodeficiency Virus (HIV) infection.
  17. Have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
  18. Have 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.
  19. Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  20. Are 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. (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).
  21. Have had an allogenic tissue/solid organ transplant.
  22. Have uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
  23. Have clinically relevant electrolyte abnormalities that have not been corrected.
  24. Have significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
  25. Have/had bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
  26. Have > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.

Sites / Locations

  • University Hospital Ulm, Otolaryngology & Head and Neck Surgery
  • University Hospital Regensburg, Clinic and Polyclinic for RadiotherapyRecruiting
  • University Hospital Augsburg, Radiation Oncology
  • University Hospital Erlangen, Radiation Oncology
  • University Hospital Frankfurt/M, Center for RadiologyRecruiting
  • University Hospital Düsseldorf, Radiation Oncology
  • Saarland University Medical Center and Saarland University Faculty of Medicine, Clinic for Radiotherapy and RadiooncologyRecruiting
  • Hospital Chemnitz, Radiation Oncology
  • Gemeinschaftspraxis Hämatologie-OnkologieRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment Arm

Arm Description

combined pembrolizumab (200mg q3w) and lenvatinib treatment (20mg once daily)

Outcomes

Primary Outcome Measures

Event-free survival (EFS) rate
To study efficacy of pembrolizumab/lenvatinib maintenance therapy after definitive radiochemotherapy of locally advanced HNSCC to prolong the event-free survival (EFS) rate at 2 years

Secondary Outcome Measures

Event-free survival (EFS) (continuous)
Pembrolizumab/lenvatinib maintenance therapy will improve further efficacy endpoints compared to historic control
Locoregional control
Locoregional progression will be evaluated by RECIST 1.1 criteria
Toxicity of Pembrolizumab/lenvatinib
Toxicity will be evaluated according to CTCAE v5.0 criteria

Full Information

First Posted
June 15, 2022
Last Updated
September 14, 2023
Sponsor
Universität des Saarlandes
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1. Study Identification

Unique Protocol Identification Number
NCT05433116
Brief Title
Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC
Official Title
Combined Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC in PD-L1 Positive Patients (CPS≥1)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 25, 2023 (Actual)
Primary Completion Date
September 2025 (Anticipated)
Study Completion Date
September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universität des Saarlandes

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Open-label, single-arm, prospective multicenter phase II clinical trial to determine the efficacy and safety combined pembrolizumab and lenvatinib as maintenance therapy after definitive radiochemotherapy of locally advanced head and neck squamous cell carcinoma (HNSCC).
Detailed Description
This is an open-label, single-arm, prospective multicenter phase II clinical trial to determine the efficacy and safety combined pembrolizumab and lenvatinib as maintenance therapy after definitive radiochemotherapy of locally advanced head and neck squamous cell carcinoma (HNSCC). The trial will be conducted in conformance with Good Clinical Practices and subjects will be enrolled into the trial by signing the informed consent form (ICF). Only subjects with PD-L1 positive (CPS≥1) tumors according to centralized reference pathologic assessment can be enrolled. Subjects without disease progression in the study screening CT (compared to radiochemotherapy baseline CT) that fulfil all further eligibility criteria can enter the trial after completion of definitive radiochemotherapy. Sites will be required to submit tissue samples for translational research to central pathology. After confirmed study inclusion, patients will receive combined pembrolizumab and lenvatinib treatment. Pembrolizumab will be administered intravenously at a dose of 200mg q3w and lenvatinib at a dose of 20mg once daily orally. The first dose of pembrolizumab has to be administered within 14 days after completion of radiochemotherapy. Treatment with lenvatinib will start concomitant to cycle 2 of pembrolizumab. Treatment will be continued until disease progression, unacceptable adverse event(s) or until the subject has received 12 months of treatment (i.e. 17 doses of pembrolizumab). Afterwards patients will enter follow-up until 24months since study inclusion. It is planned to enroll 47 patients. Primary endpoint of the trial is the event-free survival (EFS) rate at 2 years. The aim of the trial is to achieve a 2-year EFS rate of 70% (compared to 55% in the historic controls). This improvement is considered to be a clinically relevant advantage.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Head and Neck Squamous Cell Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
47 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
combined pembrolizumab (200mg q3w) and lenvatinib treatment (20mg once daily)
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda
Intervention Description
i.v., 200mg absolute, q3w, starting within 14 days after completion of radiochemotherapy
Intervention Type
Drug
Intervention Name(s)
Lenvatinib
Other Intervention Name(s)
Lenvima
Intervention Description
20mg once daily orally, start concomitant to cycle 2 of pembrolizumab
Primary Outcome Measure Information:
Title
Event-free survival (EFS) rate
Description
To study efficacy of pembrolizumab/lenvatinib maintenance therapy after definitive radiochemotherapy of locally advanced HNSCC to prolong the event-free survival (EFS) rate at 2 years
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Event-free survival (EFS) (continuous)
Description
Pembrolizumab/lenvatinib maintenance therapy will improve further efficacy endpoints compared to historic control
Time Frame
2 years
Title
Locoregional control
Description
Locoregional progression will be evaluated by RECIST 1.1 criteria
Time Frame
Restaging 12-13 weeks after completion of radiotherapy; Follow-up every 24 weeks
Title
Toxicity of Pembrolizumab/lenvatinib
Description
Toxicity will be evaluated according to CTCAE v5.0 criteria
Time Frame
until safety follow-up (1 year treatment + 30 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Male/female participants who are at least 18 years of age on the day of signing informed consent Pathologically proven new diagnosis of squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx or supraglottic larynx stage III-IVB according to TMM 8th edition PD-L1 combined positive score (CPS) ≥1 (in sample prior to radiochemotherapy) by central pathology review Completed definitive radiochemotherapy up to at least 68Gy with at least 200mg/m² body surface area concomitant Cisplatin. No progression during radiochemotherapy. Study screening CT has to be compared to radiochemotherapy baseline CT. (Study screening CT may be performed before the end of radiochemotherapy, whereas a minimum radiation dose of 50Gy has to be administered at the time point of the study screening CT.) Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab or lenvatinib, whichever is administered last) and refrain from donating sperm during this period. In addition, contraception has to be used for 180 days after the last dose of cisplatin. 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: a. Not a woman of childbearing potential (WOCBP) OR b. 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 (pembrolizumab or lenvatinib, whichever is administered last). In addition, contraception has to be used for 180 days after the last dose of cisplatin. The participant provides written informed consent for the trial. Have measurable disease based on RECIST 1.1. Have provided archival tumor tissue sample with sufficient tumor content. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Have adequate organ function. Specimens must be collected within 10 days prior to the start of study intervention. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Have tumor infiltration/perforation of the skin or cervical fistula (either at timepoint of study inclusion or prior to radiochemotherapy) Have radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates >90-degree abutment or encasement of a major blood vessel. Had prior radical surgery for the head and neck cancer under study or induction chemotherapy with more than one cycle prior to definitive radiochemotherapy. Patients with single cycle induction chemotherapy prior radiochemotherapy can be included. WOCBP who have a positive urine or serum pregnancy test within 72 hours prior to. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Have 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). Have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study drug administration (except from cisplatin concomitant to radiochemotherapy). Have received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed. Are currently participating in or have participated in a study of an investigational agent or have used an investigational device within 4 weeks prior to the first dose of study intervention. Have 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. Have a known additional malignancy that is progressing or have required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous 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. Have distant metastases. Have severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their excipients. Have 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 and is allowed. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. Have an active infection requiring systemic therapy. Have a known history of Human Immunodeficiency Virus (HIV) infection. Have a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Have 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. Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Are 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. (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). Have had an allogenic tissue/solid organ transplant. Have uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication. Have clinically relevant electrolyte abnormalities that have not been corrected. Have significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening. Have/had bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. Have > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wiebke Pirschel, M. Sc.
Phone
+49684116
Ext
24606
Email
wiebke.pirschel@uks.eu
First Name & Middle Initial & Last Name or Official Title & Degree
Markus Hecht, Prof.
Phone
+49684116
Ext
24606
Email
markus.hecht.clinicaltrials@uks.eu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Markus Hecht, Prof.
Organizational Affiliation
Saarland University Medical Center, Clinic for Radiotherapy and Radiooncology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Antoniu-Oreste Gostian, MD
Organizational Affiliation
University Hospital Straubing, Clinic for Otolaryngology, Head and Neck and Facial Plastic Surgery
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Henning Kahl, MD
Organizational Affiliation
University Hospital Augsburg, Radiation Oncology
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Rainer Fietkau, Prof.
Organizational Affiliation
University Hospital Erlangen, Radiation Oncology
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Udo Gaipl, Prof.
Organizational Affiliation
University Hospital Erlangen, Radiation Oncology
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Markus Eckstein, MD
Organizational Affiliation
University Hospital Erlangen, Pathology
Official's Role
Study Chair
Facility Information:
Facility Name
University Hospital Ulm, Otolaryngology & Head and Neck Surgery
City
Ulm
State/Province
Baden-Württemberg
ZIP/Postal Code
89070
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Hospital Regensburg, Clinic and Polyclinic for Radiotherapy
City
Regensburg
State/Province
Bavaria
ZIP/Postal Code
93053
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Hospital Augsburg, Radiation Oncology
City
Augsburg
State/Province
BY
ZIP/Postal Code
86156
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Hospital Erlangen, Radiation Oncology
City
Erlangen
State/Province
BY
ZIP/Postal Code
91054
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
University Hospital Frankfurt/M, Center for Radiology
City
Frankfurt
State/Province
Hesse
ZIP/Postal Code
60590
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Hospital Düsseldorf, Radiation Oncology
City
Düsseldorf
State/Province
Northrhine-Westphalia
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Saarland University Medical Center and Saarland University Faculty of Medicine, Clinic for Radiotherapy and Radiooncology
City
Homburg
State/Province
Saarland
ZIP/Postal Code
66421
Country
Germany
Individual Site Status
Recruiting
Facility Name
Hospital Chemnitz, Radiation Oncology
City
Chemnitz
State/Province
Saxony
ZIP/Postal Code
09116
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Gemeinschaftspraxis Hämatologie-Onkologie
City
Dresden
State/Province
Saxony
ZIP/Postal Code
01307
Country
Germany
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

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Pembrolizumab and Lenvatinib After Definitive Chemoradiation of Locally Advanced HNSCC

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