This is a Phase I/II trial for safety and preliminary efficacy of the combination of axitinib
and selenomethionine (SLM) for adult patients with advanced metastatic clear cell renal cell
carcinoma (CCRCC). This will be a two part study consisting of a dose escalation and
expansion study.
In addition, a pilot group of 10 subjects will have SLM dose calculated based on patients'
body surface area (BSA) to characterize the dose-concentration relationship and estimate the
effective administered dose of selenium necessary to achieve the target blood concentration
range informed by preclinical data.
This is a Phase I trial for safety and preliminary efficacy of the combination of axitinib
and SLM for adult patients with advanced metastatic CCRCC. This will be a two part study
consisting of a dose escalation and expansion study.
Dose-Escalation Part 1 (6-12 patients): THIS PHASE HAS BEEN COMPLETED. SLM will be given
twice daily for 14 days followed by once daily dosing in combination with axitinib 5 mg twice
daily with titration according to package insert in patients with advanced renal cell
carcinoma. Treatment will continue until disease progression or unacceptable toxicity. The
MTD was determined to be 4000 mcg SLM.
Expansion Part 2: In this phase (approximately 19 patients), will be treated at the maximum
tolerated dose (MTD) of SLM determined in the Escalation Part 1. It will be given orally
twice daily for 14 days, followed by once daily dosing in combination with axitinib 5 mg
twice daily with titration according to package insert in patients with advanced renal cell
carcinoma. Treatment will continue until disease progression or unacceptable toxicity.
A pilot group of 10 subjects will have SLM dose calculated based on patients' BSA to
characterize the dose-concentration relationship and estimate the effective administered dose
of selenium necessary to achieve the target blood concentration range informed by preclinical
data.
Inclusion Criteria:
Each patient must meet all of the following criteria to be enrolled in this study:
- Histologically and radiologically confirmed advanced metastatic CCRCC in patients who
have had at least one prior systemic therapy, which can include axitinib for the dose
escalation part. In the expansion and pilot phases, patients with prior axitinib are
allowed, as long as the last dose of axitinib was longer than 6 months ago. Written
and voluntary informed consent.
- At least one Response Evaluation Criteria In Solid Tumors (RECIST)-defined target
lesion. *Patient must have documented disease progression.
- Renal function (creatinine level within normal institutional limit, or creatinine
clearance >15 mL/min/1.73 m2 for patients with creatinine levels above institutional
normal, calculated using the Cockcroft-Gault formula).
- Liver function (AST/ALT <2.5 X institutional upper limit of normal OR < 5 x
institutional upper limit of normal in cases of liver metastases; Total bilirubin ≤
1.5 times ULN.)
- Adequate hematological lab values including;
- Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
- Platelets ≥ 100 x 109/L
- Hemoglobin ≥ 7.0 g/dL
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able
to carry on all pre-disease performance without restriction), 1 (restricted in
physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature, such as light housework or office work) or 2 (Ambulatory and capable
of all self-care but unable to carry out any work activities; up and about more than
50% of waking hours).
- Age of at least 18 years.
- Life expectancy of 12 weeks and more.
- 2 weeks or more since end of previous systemic treatment (4 weeks or more for
bevacizumab plus interferon-alfa). 3 days wash out for palliative radiation.
- Must have a safely accessible biopsy per treating physician and the provider
performing that biopsy. Patient must agree to have this biopsy done as outlined in the
calendar. If patient does not have safely accessible biopsy, the patient may still be
enrolled per investigator discretion.
Exclusion Criteria:
Patients eligible for this study must not meet any of the following criteria:
- Any other cancer from which the patient has been disease-free for less than 5 years
(except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder
cancer, or treated carcinoma in situ of the cervix, breast, or bladder and treated
localized prostate cancer with undetectable PSA for 2 years).
- Symptomatic untreated metastases in the central nervous system.
- Subject that is pregnant or lactating.
- Pre-existing uncontrolled hypertension defined as > 150/90 mm Hg with medication.
- Present use or anticipated need for cytochrome P450 (CYP) 3A4-inhibiting,
CYP3A4-inducing drugs (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and
voriconazole, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin,
phenobarbital, and St. John's wort, bosentan, efavirenz, etravirine, modafinil, and
nafcillin).Myocardial infarction, uncontrolled angina, congestive heart failure, or
cerebrovascular accident within previous 6 months. Subjects with history of deep vein
thrombosis or pulmonary embolism, at provider discretion.
- Major surgery within 4 weeks of starting study treatment.
- Known HIV or acquired immunodeficiency syndrome-related disease.
