Clinical Trials /

Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma

NCT03172754

Description:

This is a Phase I/II, open-label, multi-center study of axitinib in combination with nivolumab in patients with previously treated and untreated advanced RCC. This clinical study will be composed of a dose finding phase (Phase I) and two parallel dose expansion phases (Phase II). The dose finding phase will assess the safety of the combination and establish a recommended phase II dose (RP2D, the highest tested dose that is declared safe and tolerable by the Investigators and the Sponsor Investigator) in patients with advanced RCC who have received prior systemic therapy for metastatic disease. Phase II will evaluate the efficacy of the combination at the RP2D in two parallel expansion cohorts in both previously treated and treatment naïve patients.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma
  • Official Title: Phase I/II Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: GU-102
  • NCT ID: NCT03172754

Conditions

  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
NivolumabPhase I patients
AxitinibPhase I patients

Purpose

This is a Phase I/II, open-label, multi-center study of axitinib in combination with nivolumab in patients with previously treated and untreated advanced RCC. This clinical study will be composed of a dose finding phase (Phase I) and two parallel dose expansion phases (Phase II). The dose finding phase will assess the safety of the combination and establish a recommended phase II dose (RP2D, the highest tested dose that is declared safe and tolerable by the Investigators and the Sponsor Investigator) in patients with advanced RCC who have received prior systemic therapy for metastatic disease. Phase II will evaluate the efficacy of the combination at the RP2D in two parallel expansion cohorts in both previously treated and treatment naïve patients.

Trial Arms

NameTypeDescriptionInterventions
Phase I patientsExperimentalPhase I patients must have received at least 1 prior tyrosine kinase inhibitor for RCC.
  • Nivolumab
  • Axitinib
Phase II patients: cohort 1ExperimentalPhase II cohort 1 patients must have received at least 1 prior tyrosine kinase inhibitor for RCC.
  • Nivolumab
  • Axitinib
Phase II patients: cohort 2ExperimentalPhase II cohort 2 patients must not have received prior systemic therapy for advanced RCC.
  • Nivolumab
  • Axitinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed advanced RCC with predominantly clear cell
             subtype.

          -  Archival tumor biospecimen (when available) must be procured for correlative
             evaluation. If tumor tissue is not available or accessible despite good faith efforts,
             patient may still be treated on study.

          -  Formalin fixed, paraffin embedded [FFPE] tissue block(s) or at least 12 unbaked,
             unstained slides are required. Tissue samples taken from a metastatic lesion prior to
             the start of screening are acceptable.

          -  At least one measureable lesion as defined by RECIST version 1.1.

          -  Age > 18 years.

          -  ECOG performance status 0 or 1

          -  Adequate bone marrow, kidney, and liver function as defined by: WBC ≥ 2000/μL.
             Neutrophils ≥ 1500/μL. Platelets ≥ 100 x103/μL. Hemoglobin > 9.0 g/dL. Serum
             creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the
             Cockcroft-Gault formula): Female CrCl = (140 - age in years) x (weight in kg x
             0.85)/(72 x serum creatinine in mg/dL). Male CrCl = (140 - age in years) x (weight in
             kg x 1.00)/(72 x serum creatinine in mg/dL). AST/ALT ≤ 3 x ULN. Total Bilirubin ≤ 1.5
             x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0
             mg/dL).

          -  No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline
             blood pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP
             readings must be ≤ 150 mm Hg, and the baseline diastolic BP readings must be ≤ 90 mm
             Hg

          -  Patients enrolled to the prior treatment arm of the expansion cohort must have been
             exposed to a TKI for metastatic disease. Exposure to TKI as part of (neo)adjuvant
             treatment that completed within 1 year of study qualifies as prior exposure as well.

        Exclusion Criteria:

          -  Prior therapy with axitinib

          -  Prior systemic therapy directed at advanced RCC is not allowed for patients enrolled
             to the expansion cohort, treatment naïve arm. If prior (neo)adjuvant treatment given
             as part of a clinical trial, this would be allowed as long as last dose was > 1 year
             prior to start of treatment

          -  Patients enrolled to the prior treatment arm of the dose escalation cohort must not
             have received anti-cancer therapy less than 14 days prior to the first dose of study
             drug or palliative, focal radiation therapy less than 14 days prior to the first dose
             of study drug.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other
             antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

          -  Patients are excluded if they have active, symptomatic brain metastases or
             leptomeningeal metastases. Subjects with known brain metastases are eligible if
             metastases have been treated and there is no magnetic resonance imaging (MRI) evidence
             of progression for four weeks (after treatment is complete and within 28 days prior to
             study drug administration.

          -  Second malignancy requiring active systemic treatment

          -  Diagnosis of immunodeficiency

          -  Active, known or suspected autoimmune disease. Subjects are permitted to enroll if
             they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
             autoimmune condition only requiring hormone replacement, psoriasis not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger

          -  Patients have a condition requiring systemic treatment with either corticosteroids (>
             10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
             days of study drug administration. Inhaled or topical steroids and adrenal replacement
             doses > 10 mg daily prednisone equivalents are permitted in the absence of active
             autoimmune disease.

          -  Major surgery <4 weeks or radiation therapy <2 weeks of study entry. Prior palliative
             radiotherapy to metastatic lesion(s) is permitted, provided there is at least one
             measurable lesion that has not been irradiated.

          -  Gastrointestinal abnormalities including: Inability to take oral medication;
             Requirement for intravenous alimentation; Prior surgical procedures affecting
             absorption including total gastric resection; Treatment for active peptic ulcer
             disease in the past 6 months; Active gastrointestinal bleeding as evidenced by
             hematemesis, hematochezia or melena in the past 3 months without evidence of
             resolution documented by endoscopy or colonoscopy; Malabsorption syndromes.

          -  Evidence of inadequate wound healing.

          -  Active bleeding disorder or other history of significant bleeding episodes within 30
             days before study entry.

          -  Known prior or suspected hypersensitivity to study drugs or any component in their
             formulations.

          -  Current use or anticipated need for treatment with drugs or foods that are known
             strong CYP3A4/5 inhibitors including but not limited to atazanavir, clarithromycin,
             indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
             telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice. The
             topical use of these medications (if applicable), such as 2% ketoconazole cream, is
             allowed.

          -  Current use or anticipated need for treatment with drugs that are known strong
             CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital,
             phenytoin, rifabutin, rifampin, and St. John's wort.

          -  As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition
             to hepatotoxicity should be used with caution in patients treated with
             nivolumab-containing regimen.

          -  Known hepatitis B virus (HBV) or hepatitis C virus (HBV) infection.

          -  Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency
             syndrome (AIDS)

          -  History of any of the following cardiovascular conditions within 12 months of
             screening: Myocardial infarction, Unstable angina pectoris, Cardiac angioplasty or
             stenting, Coronary/peripheral artery bypass graft, Class III or IV congestive heart
             failure per New York Heart Association, Cerebrovascular accident or transient ischemic
             attack

          -  History of deep vein thrombosis or pulmonary embolism within 6 months of screening.
             Patients who are currently taking anticoagulation therapy for a prior history (> 6
             months from screening) of thrombosis may still be eligible.

          -  Pregnant or breast feeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment-related adverse events
Time Frame:Up to 15 months
Safety Issue:
Description:To be assessed by CTCAE v4.03. Will be used to establish recommended phase II dose (RP2D)

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 weeks
Safety Issue:
Description:DOR is the time from first partial response or complete response until progressive disease as assessed by RECIST 1.1
Measure:Progression free survival (PFS)
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 weeks
Safety Issue:
Description:PFS is the time from initiation of treatment to confirmed disease progression per RECIST 1.1
Measure:Overall survival (OS)
Time Frame:From date of initiation of treatment to death or when the patient is lost to follow up, approximately 25 months on average
Safety Issue:
Description:OS is the time from initiation of treatment to death or when the patient is lost to follow up
Measure:Safety profile as assessed by CTCAE 4.03
Time Frame:Up to 15 months
Safety Issue:
Description:Summarized by type, frequency, and severity
Measure:PD-L1 expression on tumor biospecimens
Time Frame:Up to 12 months
Safety Issue:
Description:Descriptive statistics from analysis of patient samples
Measure:Tumor infiltrating lymphocyte assessments on tumor biospecimens
Time Frame:Up to 12 months
Safety Issue:
Description:Descriptive statistics from analysis of patient samples
Measure:Pharmacodynamic effect of study treatment including cytokines
Time Frame:Up to 12 months
Safety Issue:
Description:Descriptive statistics from analysis of patient samples

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

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