SLM + Axitinib for Clear Cell RCC

• ClinicalTrials.gov Identifier: NCT02535533
• Recruitment Status: Recruiting
• First Posted: August 28, 2015
• Last Update Posted: August 23, 2022
• Sponsor: Yousef Zakharia
• Collaborator: Pfizer
• Information provided by (Responsible Party): Yousef Zakharia, University of Iowa

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Metastatic Clear Cell Renal Cell Carcinoma (CCRCC)	Drug: Selenomethionine (SLM); Drug: Axitinib	Phase 1; Phase 2

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): 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Therapeutic Trial for Safety and Preliminary Efficacy of the Combination of Axitinib and Seleniomethionine (SLM) for Adult Patients With Advanced Metastatic Clear Cell Renal Cell Carcinoma (CCRCC)
• Actual Study Start Date: January 2016
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Study Treatment; 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); 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; Drug: Axitinib; 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; Drug: Selenomethionine (SLM); Maximum tolerated dose (MTD) of SLM determined in the Escalation Part 1 (4000 mcg SLM) 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; Drug: Axitinib; Following maximum tolerated dose (MTD) of SLM determined in the Escalation Part 1 (4000 mcg SLM) given orally twice daily for 14 days, SLM once daily in combination with axitinib 5 mg twice daily with titration according to package insert; Drug: Selenomethionine (SLM); 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

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events (AE) per CTCAE 4.03 [ Time Frame: 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.
2. Pilot Phase - Determine dose-concentration relationship and estimate the effective dose of SLM (informed by preclinical data) using the continual reassessment method (CRM). [ Time Frame: 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 Outcome Measures :

1. Tumor Response rate as assessed by RECIST v.1.1 [ Time Frame: After 2 cycles (28 days) ]
2. Progression free survival (PFS) [ Time Frame: 14 months ]
3. Overall survival (OS) [ Time Frame: 3 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Yousef Zakharia, MD; 319-384-8076; yousef-zakharia@uiowa.edu

Locations

United States, Iowa

University of Iowa Hospitals and Clinics; Recruiting

Iowa City, Iowa, United States, 52242

Contact: Yousef Zakharia, MD 319-384-8076 yousef-zakharia@uiowa.edu

Sponsors and Collaborators

Yousef Zakharia

Pfizer

Investigators

• Principal Investigator: Yousef Zakharia, MD; University of Iowa Hospitals & Clinics

More Information

• Responsible Party: Yousef Zakharia, Clinical Assistant Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT02535533
• Other Study ID Numbers: 201507716
• First Posted: August 28, 2015
• Last Update Posted: August 23, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yousef Zakharia, University of Iowa:

Kidney cancer; Selenium (Se)

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Selenium; Axitinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antioxidants; Protective Agents; Physiological Effects of Drugs; Trace Elements; Micronutrients