SLM + Axitinib for Clear Cell RCC | NCT02535533

NCT02535533

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Pfizer	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Study Treatment	Experimental	During the Dose-Escalation Part 1, patients will receive SLM twice daily for 14 days followed by SLM once daily in combination with axitinib 5 mg twice daily with titration according to package insert. Treatment will continue until disease progression or unacceptable toxicity. During the Expansion Part 2, patients will be treated at the maximum tolerated dose (MTD) of SLM determined as 4000 mcg SLM. SLM will be given 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. Treatment will continue until disease progression or unacceptable toxicity. During the Pilot Phase, dosing will begin at dose level 3 (4000, 5000, or 6000 mcg SLM calculated based on patients' BSA). SLM will be given orally twice daily for 14 days. Each cohort will enroll 2 evaluable patients.	Drug: Selenomethionine (SLM) Drug: Axitinib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Selenomethionine (SLM)	Drug	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

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Incidence of Adverse Events (AE) Per CTCAE 4.03	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.	After 2 cycles (28 days)
Pilot Phase - Determine Dose-concentration Relationship and Estimate the Effective Dose of SLM (Informed by Preclinical Data) Using the Continual Reassessment Method (CRM).	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%.	14 days

Secondary Outcomes

Measure	Description	Time Frame
Overall Response Rate	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.

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Mohammed Milhem, MBBS	University of Iowa Hospitals & Clinics	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Iowa Hospitals and Clinics		Iowa City	Iowa	52242	United States

Arm/Group Information

ID	Title	Description
FG000	Dose Escalation Phase 1: SLM 2500mcg / Axitinib 5mg	SLM administrated orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.
FG001	Dose Escalation Phase 1: SLM 3000mcg / Axitinib 5mg	SLM administrated orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.
FG002	Dose Escalation Phase 1: SLM 4000mcg / Axitinib 5mg	SLM administrated orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.
FG003	Dose Expansion Phase 2: SLM 4000mcg / Axitinib 5mg	In this expansion phase, participants will be treated at the maximum tolerated dose (MTD) of SLM determined in the Escalation Phase 1. It will be given orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.
FG004	Pilot Cohort-Dose Level 3 (BSA-adjusted)	A pilot group 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. Participants receive selenium at Dose Level 3, adjusted for body surface area (BSA): BSA 1.50-1.79 m² → 4000 mcg BID BSA 1.80-2.19 m² → 5000 mcg BID BSA 2.20-2.49 m² → 6000 mcg BID Administered BID on Days 1-14, then daily until progression.
FG005	Pilot Cohort-Level 4 Dose (BSA-adjusted)	A pilot group 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. Participants receive selenium at Dose Level 4, adjusted for body surface area (BSA): BSA 1.50-1.79 m² → 5000 mcg BID BSA 1.80-2.19 m² → 6000 mcg BID BSA 2.20-2.49 m² → 7000 mcg BID Administered BID on Days 1-14, then daily until progression.

ID	Title	Description
BG000	Dose Escalation Phase 1: SLM 2500mcg / Axitinib 5mg	SLM administrated orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.
BG001	Dose Escalation Phase 1: SLM 3000mcg / Axitinib 5mg

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Incidence of Adverse Events (AE) Per CTCAE 4.03

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.

Number of participants who received study drug and assessed for adverse events

Posted

Count of Participants

Participants

After 2 cycles (28 days)

ID	Title	Description
OG000	Dose-Escalation Phase I: SLM 2500mcg / Axitnib 5mg	SLM will be given twice daily for 14 days followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma. Treatment will continue until disease progression or unacceptable toxicity.
OG001

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Period 1: Phase 1: SLM 2500	SLM administrated orally twice daily for 14 days, followed by once daily dosing in combination with axitinib twice daily with titration according to package insert in patients with advanced renal cell carcinoma.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Dec 28, 2022	Jul 3, 2024	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	May 15, 2023	Jul 3, 2024	ICF_001.pdf

ID	Term
D014571	Urologic Neoplasms
D014565	Urogenital Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms

ID	Term
D016566	Organoselenium Compounds
D009930	Organic Chemicals
D008715	Methionine
D000603	Amino Acids, Sulfur