Clinical Trials /

Pazopanib Hydrochloride With or Without Ascorbic Acid in Treating Patients With Kidney Cancer That Is Metastatic or Cannot Be Removed by Surgery

NCT03334409

Description:

This randomized phase II trial studies how well pazopanib hydrochloride with or without ascorbic acid work in treating patients with kidney cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ascorbic acid may help pazopanib hydrochloride stop tumor growth and improve treatment survival. Giving pazopanib hydrochloride and ascorbic acid may work better in treating patients with kidney cancer.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pazopanib Hydrochloride With or Without Ascorbic Acid in Treating Patients With Kidney Cancer That Is Metastatic or Cannot Be Removed by Surgery
  • Official Title: Randomized, Phase II Trial of Intravenous Ascorbic Acid (Vitamin C) as an Adjunct to Pazopanib in the First-Line or Post-Immunotherapy Setting for Metastatic or Unresectable Clear Cell Renal Cell Carcinoma (ccRCC)

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-GU-1703
  • SECONDARY ID: NCI-2017-01998
  • SECONDARY ID: ACCRU-GU-1703
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03334409

Conditions

  • Clear Cell Renal Cell Carcinoma
  • Metastatic Clear Cell Renal Cell Carcinoma
  • Stage III Renal Cell Cancer AJCC v8
  • Stage IV Renal Cell Cancer AJCC v7
  • Unresectable Renal Cell Carcinoma

Interventions

DrugSynonymsArms
Ascorbic Acid2-(1,2-dihydroxyethyl)-4,5-dihydroxy-furan-3-one, Asorbicap, C Vitamin, C-Long, Ce-Vi-Sol, Cecon, Cenolate, Cetane, Cevalin, L-Ascorbic Acid, VIT C, Vitamin C, Vitamin-CArm A (pazopanib hydrochloride, ascorbic acid)
Pazopanib HydrochlorideGW786034B, VotrientArm A (pazopanib hydrochloride, ascorbic acid)

Purpose

This randomized phase II trial studies how well pazopanib hydrochloride with or without ascorbic acid work in treating patients with kidney cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ascorbic acid may help pazopanib hydrochloride stop tumor growth and improve treatment survival. Giving pazopanib hydrochloride and ascorbic acid may work better in treating patients with kidney cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate and compare treatment failure-free rate at 40 weeks from randomization of
      patients with unresectable/metastatic clear cell renal cell carcinoma (ccRCC) receiving one
      of the following regimens: Arm A: pazopanib hydrochloride (pazopanib) 800 mg daily plus
      intravenous (IV) ascorbic acid 1g/kg 3 times/week and Arm B: pazopanib 800 mg daily.

      SECONDARY OBJECTIVES:

      I. To estimate and compare the overall survival (OS) in patients receiving pazopanib with or
      without IV ascorbic acid.

      II. To estimate and compare the progression-free survival (PFS) in patients receiving
      pazopanib with or without IV ascorbic acid.

      III. To estimate and compare the overall response rate (ORR) in patients receiving pazopanib
      with or without IV ascorbic acid.

      IV. To estimate and compare the duration on pazopanib treatment in patients receiving
      pazopanib with or without IV ascorbic acid.

      V. To assess the adverse events (AE) profile and safety of each treatment arm using the
      Common Terminology Criteria for Adverse Events (CTCAE).

      CORRELATIVE RESEARCH:

      I. Correlation between 5 mC, 5 hmC and H3K27me3 expression (as determined by
      immunohistochemistry [IHC]), as well as MeDIP/hMeDIP sequencing (seq), and response to
      combination of IV ascorbic acid and pazopanib.

      II. Correlation between iron content in tumor microenvironment (as determined by Prussian
      blue staining) and response to combination of IV ascorbic acid and pazopanib combination.

      III. Correlation between HIF-1alpha and HIF-2alpha expression (as determined by
      immunohistochemistry [IHC]) and response to combination of IV ascorbic acid and pazopanib
      combination.

      IV. Correlation between GLUT1 expression (as determined by IHC) and response to combination
      of IV ascorbic acid and pazopanib.

      V. Correlation between PDL1 expression (as determined by IHC) and response to combination of
      IV ascorbic acid and pazopanib.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28 and
      ascorbic acid IV three times per week. Treatment repeats every 28 days for up to 10 cycles in
      the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every
      28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 8 weeks for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (pazopanib hydrochloride, ascorbic acid)ExperimentalPatients receive pazopanib hydrochloride PO QD on days 1-28 and ascorbic acid IV three times per week. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.
  • Ascorbic Acid
  • Pazopanib Hydrochloride
Arm B (pazopanib hydrochloride)Active ComparatorPatients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity.
  • Pazopanib Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of clear cell renal cancer

          -  Documented metastatic or unresectable disease and at least one measurable lesion by
             Response Evaluation Criteria in Solid Tumors (RECIST) criteria; NOTE: Nephrectomy or
             ablation of the primary tumor is allowed prior to enrollment

          -  No prior systemic therapy for clear cell renal cancer or have progressed after
             immunotherapy such as ipilimumab plus nivolumab in the first line; other
             immunotherapies (e.g. interleukin-2) or additional lines of immunotherapy may be
             allowed after discussion with the principal investigator

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 21 days prior to
             registration)

          -  Platelet (PLT) >= 100,000/mm^3 (obtained =< 21 days prior to registration)

          -  Hemoglobin (Hgb) >= 9.0 g/dL (obtained =< 21 days prior to registration); NOTE:
             Subjects may not have had a transfusion =< 7 days of registration

          -  Total Bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 21 days prior to
             registration)

               -  NOTE: For bilirubin elevation 1 to 1.5 x ULN, alanine aminotransferase (ALT)
                  above 1.5 x ULN (upper limit of normal) is not permitted

               -  NOTE: For bilirubin elevation 1 to 1.5 x ULN, aspartate aminotransferase (AST)
                  above 1.5 x ULN (upper limit of normal) is not permitted

          -  Alanine amino transferase (ALT) < 2.5 X ULN, with normal bilirubin (obtained =< 21
             days prior to registration); NOTE: Concomitant elevations in bilirubin and ALT above
             1.5 x ULN (upper limit of normal) is not permitted

          -  Aspartate aminotransferase (AST) < 2.5 X ULN, with normal bilirubin (obtained =< 21
             days prior to registration); NOTE: Concomitant elevations in bilirubin and AST above
             1.5 x ULN (upper limit of normal) is not permitted

          -  Creatinine =< 1.5 mg/dl OR creatinine > 1.5 mg/dl, estimated creatinine clearance must
             be >= 55 mL/minute by Cockcroft Gault formula (obtained =< 21 days prior to
             registration)

          -  International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
             =< 1.5 x ULN (obtained =< 21 days prior to registration); NOTE: This applies only to
             patients who are not receiving therapeutic anticoagulation; patients receiving
             therapeutic anticoagulation should be on a stable dose

          -  Individuals of non-childbearing potential, or individual of childbearing potential
             with negative serum pregnancy test =< 7 days prior to randomization and willing to
             practice total abstinence or use a highly effective method of contraception, as
             outlined below:

               -  Non-childbearing potential (i.e., physiologically incapable of becoming
                  pregnant), including any female individual who has had the following:

                    -  A hysterectomy

                    -  A bilateral oophorectomy (ovariectomy)

                    -  A bilateral tubal ligation

                    -  Is post-menopausal

                    -  NOTE: Subjects not using hormone replacement therapy (HRT) must have
                       experienced total cessation of menses for >= 1 year and be greater than 45
                       years in age, OR, in questionable cases, have a follicle stimulating hormone
                       (FSH) value > 40 mIU/mL and an estradiol value < 40 pg/mL (< 140 pmol/L);
                       subjects using HRT must have experienced total cessation of menses for >= 1
                       year and be greater than 45 years of age OR have had documented evidence of
                       menopause based on FSH and estradiol concentrations prior to initiation of
                       HRT

               -  Childbearing potential, including any individual who has had a negative serum
                  pregnancy test, =< 7 days prior to randomization

               -  Agrees to use adequate contraception; acceptable contraceptive methods, when used
                  consistently and in accordance with both the product label and the instructions
                  of the physician, are as follows:

                    -  Complete abstinence from sexual intercourse for 14 days before exposure to
                       investigational product, through the dosing period, and for at least 21 days
                       after the last dose of investigational product

                    -  Oral contraceptive, either combined or progestogen alone

                    -  Intrauterine device (IUD) or intrauterine system (IUS) with a documented
                       failure rate of less than 1% per year

                    -  Male partner sterilization (vasectomy with documentation of azoospermia)
                       prior to the female subject's entry into the study, and this male is the
                       sole partner for that subject

                    -  Double barrier method: condom and an occlusive cap (diaphragm or
                       cervical/vault caps) with a vaginal spermicidal agent
                       (foam/gel/film/cream/suppository)

          -  Provide informed written consent

          -  Willing to provide archive tissue samples for correlative research purposes

        Exclusion Criteria:

          -  Any of the following:

               -  Individuals/or persons who are nursing

               -  Individual/or persons who are pregnant

               -  Individuals/or persons of childbearing potential who are unwilling to employ
                  adequate contraception

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Immunocompromised patients (other than that related to the use of corticosteroids)
             including patients known to be human immunodeficiency virus (HIV) positive

          -  Prior history of receiving pazopanib or any other tyrosine kinase inhibitor treatments
             for malignancy

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Chronic ongoing or active infection

               -  Symptomatic anemia

               -  Uncontrolled hypertension (defined as systolic blood pressure [SBP] of >= 160
                  mmHg or diastolic blood pressure [DBP] of >= 100 mmHg)

               -  Symptomatic congestive heart failure as defined by the New York Heart Association
                  (NYHA) (does not exclude class III congestive heart failure [CHF])

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Evidence of active bleeding or bleeding diathesis

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Any other serious uncontrolled medical disorders in the opinion of the
                  investigator

          -  History of a major thromboembolic event =< 6 months prior to randomization, including
             cerebrovascular accident, transient ischemic attack (TIA), myocardial infarction,
             symptomatic pulmonary embolism (PE) or untreated deep venous thrombosis (DVT), or
             coronary artery bypass graft surgery; NOTE: Subjects with recent DVT or asymptomatic
             PE who have been treated with therapeutic anticoagulating agents for at least 6 weeks
             are eligible

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Other active malignancy =< 5 years prior to randomization; EXCEPTIONS: Nonmelanoma
             skin cancer or carcinoma-in-situ of the cervix, or cancers with low metastatic
             potential (e.g. Gleason score 6 prostate cancer) treated with curative therapy; NOTE:
             If there is a history or prior malignancy, they must not be receiving other specific
             treatment for their cancer

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis, except for individuals who have previously treated CNS
             metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure
             medication for =< 6 months prior to randomization; Note: Screening with CNS imaging
             studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required
             only if clinically indicated or if the subject has a history of CNS metastases

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including, but not limited to:

               -  Active peptic ulcer disease

               -  Known intraluminal metastatic lesion/s with risk of bleeding

               -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn?s disease), or other
                  gastrointestinal conditions with increased risk of perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
                  abscess =< 28 days prior to randomization

               -  Clinically significant gastrointestinal abnormalities that may affect absorption
                  of investigational product including, but not limited to:

                    -  Malabsorption syndrome

                    -  Any prior major resection of the stomach or small bowel

          -  Corrected QT interval (QTc) > 480 msecs using Bazett?s formula

          -  Receiving any medications or substances with risk of Torsades de Pointes; Note:
             medications or substances on the list ?Drugs with Risk of Torsades de Pointes? are
             prohibited; medications or substances on the list ?Drugs with Possible or Conditional
             Risk of Torsades de Pointes? may be used while on study with extreme caution and
             careful monitoring

          -  Treatment with any of the following anti-cancer therapies =< 14 days prior to
             registration:

               -  Radiation therapy

               -  Surgery or tumor embolization

               -  Chemotherapy, immunotherapy

               -  Biologic therapy

               -  Investigational therapy

               -  Hormonal therapy

          -  Prior autologous or allogeneic organ or tissue transplantation

          -  Elective or planned major surgery to be performed during the course of the trial

          -  Receiving any medications or substances that are strong or moderate inhibitors of
             CYP3A4; use of strong or moderate inhibitors are prohibited =< 7 days prior to
             randomization

          -  Receiving any medications or substances that are inducers of CYP3A4; use of inducers
             are prohibited =< 7 days prior to randomization

          -  Glucose-6-phosphate dehydrogenase (G6PD) deficiency (i.e. below normal limits)

          -  End-stage renal disease (estimated glomerular filtration rate [GFR] < 55 ml/min/body
             surface area [BSA]), unless the estimated creatinine clearance by Cockcroft Gault is
             >= 55 ml/min prior to randomization

          -  History of calcium oxalate stones

          -  History of iron overload

          -  Unable to swallow oral medications

          -  History of myocardial infarction =< 6 months, current symptomatic CHF or left
             ventricular ejection fraction (LVEF) < 40% or > grade 2 diastolic dysfunction, with no
             symptoms or signs of heart failure
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Treatment failure-free rate
Time Frame:At 40 weeks
Safety Issue:
Description:Treatment failure is defined as any of the following: radiographic disease progression, off-protocol treatment due to adverse event, initiation of alternative therapy (except metastasectomy post clinical benefit (complete response [CR], partial response [PR], or stable disease [SD] per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 to treatment), and death due to any cause.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From randomization to death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier and be compared using log rank tests.
Measure:Progression free survival
Time Frame:From start of study therapy to documentation of disease progression or death, whichever comes first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Defined to be a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors 1.1. Will be compared using a Chi-Square test.
Measure:Duration of time on pazopanib hydrochloride
Time Frame:From initial dose of pazopanib hydrochloride until the date the patient is considered off-treatment for pazopanib hydrochloride or death, whichever comes first, assessed up to 3 years
Safety Issue:
Description:Will be described using descriptive statistics.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events and toxicities will be evaluated using all patients who have received any study treatment as well as summarizing those who have been included in the efficacy analyses. The overall adverse event rates for grade 3 or higher adverse events, will be compared using Chi-Square tests between the 2 treatment arms.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Academic and Community Cancer Research United

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