Advanced Metastatic Clear Cell Renal Cell Carcinoma (CCRCC)
Conditions
Keywords
Kidney cancer, Selenium (Se)
Brief summary
This phase I trial studies the side effects and best dose of L-selenomethionine when given together with axitinib in treating patients with clear cell renal cell carcinoma that has spread from the primary site (place where it started) to other places in the body and usually cannot be cured or controlled with treatment (advanced metastatic). L-selenomethionine may stop the growth of tumor cells by blocking the growth of new blood vessels necessary for tumor growth. Axitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving L-selenomethionine together with axitinib may be a better treatment for advanced metastatic clear cell renal cell carcinoma.
Detailed description
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): 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.
Interventions
SLM administrated orally twice daily for 14 days followed by SLM once daily in combination with Axitinib 5 mg twice daily with titration according to package insert
DRUGAxitinib
Following SLM administrated orally twice daily for 14 days, SLM once daily in combination with Axitinib 5 mg twice daily with titration according to package insert
Sponsors
Mohammed Milhem
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: * Patients with prior malignancies of the same or different tumor type in the last 5 years and patients with concurrent malignancies of the same or different tumor type UNLESS the natural history of the disease or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AE) Per CTCAE 4.03 | After 2 cycles (28 days) | The AEs will be summarized and classified by body system and by treatment group. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated. |
| Pilot Phase - Determine Dose-concentration Relationship and Estimate the Effective Dose of SLM (Informed by Preclinical Data) Using the Continual Reassessment Method (CRM). | 14 days | Dose escalation for this pilot study will be conducted using a CRM in which the probability of exceeding a blood selenium concentration of 45 µM on Day 14 is being modeled. Prior probabilities of exceeding a blood selenium concentration of 45 µM on Day 14 were estimated based on preclinical and preliminary data from the initial trial. A one parameter logistic model with intercept set at 3 and an initial value of 1 for the slope will be used to estimate the dose-concentration relationship through sequential recursive Bayesian assessment. The target probability of exceeding 45 µM is ≤20%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From treatment initiation to treatment end, up to 3 years | The overall response rate is the percentage of patients with a confirmed complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression-Free Survival | From treatment initiation up to 2 years | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Overall Survival | From treatment initiation up to 3 years | Overall survival is defined as the time from study treatment initiation to death due to any cause. Patients still alive were censored at the last date known to be alive. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMohammed Milhem, MBBS
University of Iowa Hospitals & Clinics
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 44 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 5 | 5 / 7 | 16 / 20 | 5 / 8 | 2 / 2 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 7 / 7 | 20 / 20 | 8 / 8 | 2 / 2 |
| serious Total, serious adverse events | 1 / 3 | 4 / 5 | 7 / 7 | 5 / 20 | 4 / 8 | 0 / 2 |
Outcome results
None listed