Axitinib and Nivolumab in Treating Patients with Advanced Kidney Cancer

Status: Active

Description

This phase I / II trial studies the side effects and best dose of axitinib when given together with nivolumab and to see how well they work in treating patients with kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving axitinib together with nivolumab may work better in treating patients with advanced kidney cancer.

Eligibility Criteria

Inclusion Criteria

  • Histologically or cytologically confirmed advanced RCC with any clear cell component; 100% sarcomatoid is permissible
  • 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 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • White blood cells (WBC) >= 2000/uL
  • Neutrophils >= 1500/uL
  • Platelets >= 100 x10^3/uL
  • Hemoglobin > 9.0 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (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 tyrosine kinase inhibitor (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 naive 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 costimulation or checkpoint pathways); prior high dose interleukin-2 is allowed and patients who received this as their only prior line of treatment for metastatic disease may be included in the treatment naïve group.
  • 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)
  • 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
  • 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

Locations & Contacts

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Michael Anthony Carducci
Phone: 410-614-3977
Email: carducci@jhmi.edu

New York

New York
NYP / Weill Cornell Medical Center
Status: Active
Contact: Ana Maria Luisa Molina
Phone: 646-962-2072
Email: amm9052@med.cornell.edu

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: Active
Contact: Matthew R. Zibelman
Phone: 215-728-3889
Email: matthew.zibelman@fccc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of axitinib and nivolumab in order to establish a recommended phase II dose (RP2D). (Phase I)

II. Assess the overall response rate of the combination in two separate cohorts of patients with treatment naive and previously treated advanced renal cell carcinoma (RCC). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the overall safety profile of the combination of axitinib and nivolumab.

II. To assess the median progression free survival (PFS) and median overall survival (OS) of axitinib in combination with nivolumab in patients with advanced RCC.

III. To explore sensitivity and resistance mechanisms to axitinib in combination with nivolumab in tumor and blood specimens.

IV. To explore the pharmacodynamic effect of axitinib in combination with nivolumab.

OUTLINE: This is a phase I, dose-escalation study of axitinib followed by a phase II study.

Patients receive axitinib orally (PO) twice daily (BID) on days 1-28and nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and annually thereafter.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Matthew R. Zibelman

Trial IDs

Primary ID GU-102
Secondary IDs NCI-2017-01090
Clinicaltrials.gov ID NCT03172754