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Neoadjuvant Sitravatinib in Combination With Nivolumab in Patients With Clear Cell Renal Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03680521
Recruitment Status : Active, not recruiting
First Posted : September 21, 2018
Results First Posted : May 19, 2021
Last Update Posted : May 19, 2021
Sponsor:
Information provided by (Responsible Party):
Mirati Therapeutics Inc.

Brief Summary:
The study will evaluate the clinical activity of sitravatinib in combination with nivolumab in patients with locally-advanced clear cell renal cell carcinoma (ccRCC) in the neoadjuvant setting prior to nephrectomy.

Condition or disease Intervention/treatment Phase
Clear Cell Renal Cell Carcinoma Drug: Sitravatinib Drug: Nivolumab Phase 2

Detailed Description:
Sitravatinib is a receptor tyrosine kinase inhibitor (TKI) that targets multiple closely related receptor tyrosine kinase pathways including VEGFR, PDGFR, c-KIT, MET, and the TAM family of receptors (TYRO3, AXL, and MER). Nivolumab is a monoclonal antibody directed against PD-1 and blocks the interaction between PD-1 and its ligands, thereby releasing PD-1-mediated inhibition of T-cell proliferation (including cytotoxic CD8+ T-cells) and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment the efficacy of nivolumab.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Sitravatinib in Combination With Nivolumab in Patients Undergoing Nephrectomy for Locally-Advanced Clear Cell Renal Cell Carcinoma
Actual Study Start Date : October 10, 2018
Actual Primary Completion Date : April 27, 2020
Estimated Study Completion Date : May 11, 2023


Arm Intervention/treatment
Experimental: Sitravatinib and nivolumab
Sitravatinib oral capsule administered daily 2 weeks alone then in combination with nivolumab administered as 240 mg IV every 2 weeks. Total treatment duration: 6-8 weeks prior to planned nephrectomy.
Drug: Sitravatinib
Sitravatinib oral capsule administered daily for 6-8 weeks in segments 1 and 2.

Drug: Nivolumab
Nivolumab administered as 240 mg IV every 2 weeks for 4-6 weeks in segment 2.




Primary Outcome Measures :
  1. Percentage of Participants Who Achieved a Point in Time Objective Response (Either Complete or Partial Response [CR or PR]) Prior to Surgery [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
    Objective response is defined as the percent of participants documented by investigator assessment to have Complete Response (CR) or Partial Response (PR) in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR is defined as complete disappearance of all baseline target and non-target lesions with the exception of nodal disease; PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions.

  2. Point in Time Objective Response Prior to Surgery [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]

    Number and percentage of participants who experienced a response prior to surgery in accordance with RECIST 1.1.

    • CR is defined as complete disappearance of all baseline target and non-target lesions with the exception of nodal disease;
    • PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions;
    • Stable Disease (SD) is concluded when the single point in time response does not qualify for CR, PR or Progressive Disease (PD);
    • PD is defined as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing nontarget lesions.


Secondary Outcome Measures :
  1. Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Day 1 until 28 days after last dose of study drug or surgery, whichever occurred last (up to a maximum of 13 weeks) ]

    TEAEs occured after the first dose of any study treatment or any preexisting condition that increased in severity after the first dose of study treatment and prior to 28 days after last dose of study drug or surgery, whichever occurred last.

    TEAEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.


  2. Blood Plasma Concentrations of Sitravatinib [ Time Frame: Day 1 (pre-dose, and 30 minutes to 4 hours post-dose), Day 15 (pre-dose) and Day 43 (pre-dose) ]
  3. Time to Surgery [ Time Frame: Day 1 up to date of surgery (maximum time to surgery was approximately 13 weeks) ]
    Time to surgery was defined as the number of calendar days between Day 1 and the planned nephrectomy.

  4. Disease Free Survival (DFS) [ Time Frame: Up to 3 years after surgery (maximum time to surgery was approximately 13 weeks) ]
    DFS was defined as the time from date of surgery to disease recurrence or death whichever occurred first.

  5. Change From Baseline in Programmed Death Ligand 1 (PD-L1) Expression in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  6. Change From Baseline in Myeloid-derived Suppressor Cells (MDSCs) in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  7. Change From Baseline in Regulatory T-cells (Tregs) in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  8. Change From Baseline in CD4+ T-cells in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  9. Change From Baseline in CD8+ T-cells in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  10. Change From Baseline in Ratio of Type 1 to Type 2 Tumor Associated Macrophages in the Tumor [ Time Frame: Baseline to date of surgery (maximum time to surgery was approximately 13 weeks) ]
  11. Change From Baseline of Selected Cytokines in Peripheral Blood [ Time Frame: Baseline to Day 43 ]


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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. Imaging results consistent with locally-advanced RCC
  2. Candidate for partial or complete nephrectomy as part of treatment plan.
  3. Measurable disease per RECIST version 1.1.
  4. ECOG performance status 0 or 1.
  5. Adequate bone marrow and organ function.

Exclusion Criteria:

  1. Prior systemic anti-tumor treatment for RCC.
  2. Patients who are receiving any other investigational agents.
  3. Clinical status indicating that immediate surgery (within 6 weeks) is warranted regardless of whether neoadjuvant therapy is to be administered, as assessed by the treating surgeon.
  4. Inability to undergo baseline tumor biopsy.
  5. Active or prior documented autoimmune or immunocompromising conditions.
  6. Uncontrolled hypertension.

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): NCT03680521


Locations
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United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Mirati Therapeutics Inc.
  Study Documents (Full-Text)

Documents provided by Mirati Therapeutics Inc.:
Study Protocol  [PDF] May 16, 2018
Statistical Analysis Plan  [PDF] July 1, 2020

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Responsible Party: Mirati Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT03680521    
Other Study ID Numbers: 516-002
First Posted: September 21, 2018    Key Record Dates
Results First Posted: May 19, 2021
Last Update Posted: May 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mirati Therapeutics Inc.:
ccRCC
MGCD516
Antineoplastic Agents
Immunologic factors
nivolumab
Tyrosine Kinase Inhibitor
VEGFR
TAM RTKs
PD-1
PD-L1
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents