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SLM + Axitinib for Clear Cell RCC

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ClinicalTrials.gov Identifier: NCT02535533
Recruitment Status : Recruiting
First Posted : August 28, 2015
Last Update Posted : September 16, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Yousef Zakharia, University of Iowa

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.

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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 2022
Estimated Study Completion Date : June 2023


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




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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02535533


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

Locations
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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
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Principal Investigator: Yousef Zakharia, MD University of Iowa Hospitals & Clinics
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Responsible Party: Yousef Zakharia, Clinical Assistant Professor, University of Iowa
ClinicalTrials.gov Identifier: NCT02535533    
Other Study ID Numbers: 201507716
First Posted: August 28, 2015    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic 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
Nutrients
Growth Substances