Axitinib Given on an Individualized Schedule for Metastatic Renal Cell Cancer

Primary objective To determine whether axitinib given on an individualized dose/schedule for
metastatic renal cell carcinoma following immunotherapy with PD-1 and PD-L1 Inhibitors leads
to improved PFS.

Secondary objectives:

1. To characterize the objective response rates in patients given axitinib on an
individualized dose/schedule.

2. To evaluate the tolerability and safety of an alternative method of axitinib titration.

3. To characterize the anti-tumor effect, as measured by change in tumor burden per RECIST
1.1, of axitinib titration performed after initial RECIST PD on axitinib.

Inclusion Criteria:

- Histologically confirmed, locally recurrent or metastatic clear cell renal cell
carcinoma

- Has received one prior systemic therapy regimen for mRCC directed against PD-1 and/or
PD-L1 which must have been the most recent regimen

- Prior high-dose interleukin-2 therapy is permitted in addition to anti-PD(L)1
therapy, but is not required

- Prior bevacizumab or VEGF TKI is permitted either in combination with anti-PD(L)1
therapy OR as monotherapy when given PRIOR to anti-PD(L)1 therapy

- Prior treatment with combined ipilimumab and nivolumab is permitted

- Prior axitinib in any setting is not permitted

- A minimum of two weeks since last dose of most recent renal cell cancer therapy
assuming resolution of clinically significant treatment-related toxicities to
grade 1, baseline, or controlled with supportive medications

- Evidence of measurable disease per RECIST 1.1.

- Karnofsky performance status ≥ 70 %.

- Adequate organ function as defined by:

- Absolute neutrophil count (ANC) ≥1,000/μL

- Platelets ≥100,000/μL

- Hemoglobin ≥9.0 g/dL

- Serum calcium ≤12.0 mg/dL

- Serum creatinine ≤2.0 x ULN

- Total serum bilirubin ≤1.5 x ULN

- SGOT≤2.5 x ULN and SGPT ≤2.5x ULN

- Signed informed consent and willingness/ability to comply with scheduled visits,
treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

- Non clear cell RCC

- Major surgery within 4 weeks of starting the study treatment.

- Radiation therapy within 2 weeks of starting the study treatment. Prior palliative
radiotherapy to metastatic lesion(s) is permitted, provided there is at least one
measurable lesion that has not been irradiated.

- NCI CTCAE Version 4.03 grade 3 hemorrhage within 4 weeks of starting the study
treatment.

- Any of the following within the 6 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident or transient
ischemic attack.

- Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.03 grade ≥2. Controlled atrial
fibrillation is permitted.

- Uncontrolled hypertension (>160/100 mm Hg despite optimal medical therapy)

- Concurrent treatment on another clinical trial. Supportive care trials or
non-treatment trials, e.g. QOL, and imaging trials, are allowed.

- Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum) prior to enrollment. Male subjects must be surgically sterile
or must agree to use effective contraception during the period of therapy. The
definition of effective contraception will be based on the judgment of the principal
investigator or a designated associate

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the subject inappropriate for entry into
this study.

- Uncontrolled CNS metastases. Patients are considered to have controlled CNS metastases
(and thus eligible) if they have completed local therapy (XRT and/or surgery) and are
off steroids with clinical and radiographic stability 3 months from the end of
CNS-directed therapy.