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Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus

Primary Purpose

Renal Cell Carcinoma

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Neoadjuvant Lenvatinib
Neoadjuvant Pembrolizumab
Radical nephrectomy, IVC thrombectomy, retroperitoneal lymph node dissection
Adjuvant Pembrolizumab
Sponsored by
University of Texas Southwestern Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring Renal Cell Carcinoma, IVC tumor thrombus, Neoadjuvant therapy, Immunotherapy, Nephrectomy

Eligibility Criteria

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

Inclusion Criteria:

  • Male/female participants who are at least 18 years of age
  • Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus
  • The primary tumor and thrombus may be assessed to be resectable or unresectable at the time of enrollment
  • Male participants: A male participant must agree to use a protocol-approved contraception during the 120 day neoadjuvant treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
  • 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 protocol-approved contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment.
  • The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
  • Have 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.
  • Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
  • 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 as defined in the following table. Specimens must be collected within 10 days prior to the start of study intervention.
  • Absolute neutrophil count (ANC): ≥1500/µL
  • Platelets: ≥100 000/µL
  • Hemoglobin: ≥9.0 g/dL or ≥ 5.6 mmol/La
  • Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
  • Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN
  • AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
  • International normalized ratio (INR) OR prothrombin time (PT) OR Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
  • ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
  • Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
  • Creatinine clearance (CrCl) should be calculated per institutional standard.
  • Note: This includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria:

  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • 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).
  • Has received prior systemic anti-cancer therapy including investigational agents prior to allocation.
  • 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 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  • Has received a live vaccine within 30 days prior to the first dose of study drug. 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. 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. COVID-19 vaccines are permitted provided they are not live attenuated vaccines.
  • 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.
  • 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.
  • Has a known additional malignancy that is progressing or has required active treatment within the past year. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer, bladder in situ) that have undergone potentially curative therapy are not excluded.
  • Has known active CNS metastases and/or carcinomatous meningitis. 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 study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
  • Has more than three different sites of metastatic renal cell carcinoma.
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and lenvatinib and/or any of its excipients.
  • 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 and is allowed.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current 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 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.
  • 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 study, starting with the screening visit through 120 days after the last dose of trial treatment.
  • Has had an allogenic tissue/solid organ transplant.
  • Has prolongation of QTcF interval to >480 ms.
  • Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
  • Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
  • Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+>1+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
  • Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.

Sites / Locations

  • University of Texas Southwestern Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment Arm

Arm Description

Patients receive neoadjuvant lenvatinib (20 mg PO daily) for 12 weeks and pembrolizumab (200 mg IV every 3 weeks for four doses) prior to surgical resection of locally advanced RCC with IVC tumor thrombus. Following surgery, patients will receive adjuvant pembrolizumab (200 mg IV every 3 weeks for up to thirteen doses).

Outcomes

Primary Outcome Measures

Disease Control Rate
Evaluation of changes in size of primary tumor and size and level of IVC tumor thrombus on imaging due to neoadjuvant therapy prior to surgery.
Local and Metastatic Progression Rate
Evaluation of local or metastatic progression on imaging prior to surgery following neoadjuvant therapy.
90 Day Post-Operative Complications
Assessment of 90 day post-operative safety and morbidity of neoadjuvant therapy by evaluating the incidence of 90 day post-operative grade 3-5 adverse events.

Secondary Outcome Measures

Estimated blood loss
Estimated blood loss in mL during surgery
Operative time
Operative time in minutes of surgery, length of stay, and intra-operative and post-operative complications
Length of stay
Length of stay of hospital stay for surgery in days, and intra-operative and post-operative complications
Intra-operative complications
Complications that occur during surgery
Post-operative complications
Complications that occur in the post-operative period
Survival Outcomes
Evaluation of post-operative survival outcomes including recurrence-free survival and overall survival.

Full Information

First Posted
March 23, 2022
Last Updated
February 6, 2023
Sponsor
University of Texas Southwestern Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT05319015
Brief Title
Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus
Official Title
Safety and Efficacy of Neoadjuvant Lenvatinib and Pembrolizumab in Patients With Renal Cell Carcinoma and IVC Tumor Thrombus
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 6, 2023 (Actual)
Primary Completion Date
August 2024 (Anticipated)
Study Completion Date
August 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Texas Southwestern Medical Center

4. Oversight

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

5. Study Description

Brief Summary
This study will be evaluating safety and efficacy of the combination of lenvatinib and pembolizumab neoaadjuvant therapy prior to surgical resection of locally advanced renal cell carcinoma with IVC tumor thrombus.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma
Keywords
Renal Cell Carcinoma, IVC tumor thrombus, Neoadjuvant therapy, Immunotherapy, Nephrectomy

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
Patients receive neoadjuvant lenvatinib (20 mg PO daily) for 12 weeks and pembrolizumab (200 mg IV every 3 weeks for four doses) prior to surgical resection of locally advanced RCC with IVC tumor thrombus. Following surgery, patients will receive adjuvant pembrolizumab (200 mg IV every 3 weeks for up to thirteen doses).
Intervention Type
Drug
Intervention Name(s)
Neoadjuvant Lenvatinib
Intervention Description
20 mg PO daily for 12 weeks prior to surgery
Intervention Type
Drug
Intervention Name(s)
Neoadjuvant Pembrolizumab
Intervention Description
200 mg IV every 3 weeks for 4 doses prior to surgery
Intervention Type
Procedure
Intervention Name(s)
Radical nephrectomy, IVC thrombectomy, retroperitoneal lymph node dissection
Intervention Description
Resection of locally advanced RCC with IVC tumor thrombus
Intervention Type
Drug
Intervention Name(s)
Adjuvant Pembrolizumab
Intervention Description
200 mg IV every 3 weeks for up to 13 doses after surgery
Primary Outcome Measure Information:
Title
Disease Control Rate
Description
Evaluation of changes in size of primary tumor and size and level of IVC tumor thrombus on imaging due to neoadjuvant therapy prior to surgery.
Time Frame
12 weeks
Title
Local and Metastatic Progression Rate
Description
Evaluation of local or metastatic progression on imaging prior to surgery following neoadjuvant therapy.
Time Frame
12 weeks
Title
90 Day Post-Operative Complications
Description
Assessment of 90 day post-operative safety and morbidity of neoadjuvant therapy by evaluating the incidence of 90 day post-operative grade 3-5 adverse events.
Time Frame
13 weeks
Secondary Outcome Measure Information:
Title
Estimated blood loss
Description
Estimated blood loss in mL during surgery
Time Frame
1 week
Title
Operative time
Description
Operative time in minutes of surgery, length of stay, and intra-operative and post-operative complications
Time Frame
1 week
Title
Length of stay
Description
Length of stay of hospital stay for surgery in days, and intra-operative and post-operative complications
Time Frame
1 week
Title
Intra-operative complications
Description
Complications that occur during surgery
Time Frame
1 week
Title
Post-operative complications
Description
Complications that occur in the post-operative period
Time Frame
12 weeks
Title
Survival Outcomes
Description
Evaluation of post-operative survival outcomes including recurrence-free survival and overall survival.
Time Frame
3 years
Other Pre-specified Outcome Measures:
Title
Exploratory Outcomes
Description
Identify metabolic signatures in plasma that are noninvasive predictors of therapy response and identify metabolic alterations following neoadjuvant therapy in patients who do and do not respond.
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male/female participants who are at least 18 years of age Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus The primary tumor and thrombus may be assessed to be resectable or unresectable at the time of enrollment Male participants: A male participant must agree to use a protocol-approved contraception during the 120 day neoadjuvant treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period. 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: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the protocol-approved contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. Have 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. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 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 as defined in the following table. Specimens must be collected within 10 days prior to the start of study intervention. Absolute neutrophil count (ANC): ≥1500/µL Platelets: ≥100 000/µL Hemoglobin: ≥9.0 g/dL or ≥ 5.6 mmol/La Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) International normalized ratio (INR) OR prothrombin time (PT) OR Activated partial thromboplastin time (aPTT): ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. Creatinine clearance (CrCl) should be calculated per institutional standard. Note: This includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 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). Has received prior systemic anti-cancer therapy including investigational agents prior to allocation. 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 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. Has received a live vaccine within 30 days prior to the first dose of study drug. 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. 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. COVID-19 vaccines are permitted provided they are not live attenuated vaccines. 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. 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. Has a known additional malignancy that is progressing or has required active treatment within the past year. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer, bladder in situ) that have undergone potentially curative therapy are not excluded. Has known active CNS metastases and/or carcinomatous meningitis. 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 study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention. Has more than three different sites of metastatic renal cell carcinoma. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and lenvatinib and/or any of its excipients. 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 and is allowed. Has a history of (non-infectious) pneumonitis that required steroids or has current 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 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. 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 study, starting with the screening visit through 120 days after the last dose of trial treatment. Has had an allogenic tissue/solid organ transplant. Has prolongation of QTcF interval to >480 ms. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO) Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+>1+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Donna Mitchell
Phone
214-645-8787
Email
donna.mitchell@utsouthwestern.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Doreen Simonsen
Phone
214-645-8790
Email
doreen.simonsen@utsouthwestern.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vitaly Margulis, MD
Organizational Affiliation
University of Texas Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vitaly Margulis
Phone
214-648-0567
Email
vitaly.margulis@utsouthwestern.edu
First Name & Middle Initial & Last Name & Degree
MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus

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