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Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Sarcoma and Kidney Cancer

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ClinicalTrials.gov Identifier: NCT02795819
Recruitment Status : Terminated (Study drug no longer being clinically developed by manufacturer)
First Posted : June 10, 2016
Last Update Posted : April 3, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
This phase 1 study will identify recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when given in combination for subsequent clinical trials and may potentially identify candidate pharmacodynamic and predictive biomarkers.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Soft Tissue Sarcoma Metastatic Disease Drug: AR-42 Drug: Pazopanib Phase 1

Detailed Description:

This study is a single-arm, open-label, phase 1 trial to determine the RP2Ds of AR-42 and pazopanib when given in combination to patients with advanced Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS). Eligible patients will have recurrent, unresectable, or metastatic RCC or STS for which pazopanib is an appropriate therapy.

AR-42 will be taken orally once per day on 3 non-consecutive days each week during the first 3 weeks of each 4-week cycle. Pazopanib will be taken by mouth once daily continuously during each cycle.

A modified 3+3 dose-escalation design will be followed until the maximum tolerated doses (MTDs) have been determined. Additional patients will be enrolled until a total of 12 patients have been treated at the MTDs. The maximum number of patients needed is 51 with an expected sample size of 29-35 patients enrolled over a period of about 15-35 months.

Correlative studies will be conducted using samples of tumor that were archived following the most recent surgery or biopsy.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Soft Tissue Sarcoma and Renal Cell Carcinoma
Study Start Date : July 8, 2016
Actual Primary Completion Date : November 24, 2016
Actual Study Completion Date : March 14, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Pazopanib

Arm Intervention/treatment
Experimental: Pazopanib + AR42
  • AR-42 will be taken orally once per day on 3 non-consecutive days each week during the first 3 weeks of each 4-week cycle. Pazopanib will be taken by mouth once daily continuously during each cycle.
  • A modified 3+3 dose-escalation design will be followed until the maximum tolerated doses (MTDs) have been determined. Different doses of AR-42 and pazopanib will be given to several study participants. Two different Pazopanib doses of 600 mg and 800 mg will be used. The AR-42 will continue to be increased for each group of participants until side effects occur that require dose of one study drug to be lowered.
Drug: AR-42
AR-42 tablets will be taken orally once per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle. If treatment must be interrupted during the cycle, the cycle may be extended.
Other Names:
  • HDAC-42
  • OSU-HDAC42

Drug: Pazopanib
Pazopanib tablets will be taken orally once daily continuously during each 4-week treatment cycle. There are no scheduled breaks in pazopanib therapy.
Other Name: Votrient




Primary Outcome Measures :
  1. The recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when given in combination. [ Time Frame: 1 month ]
    To determine the recommended phase 2 doses (RP2Ds) for AR-42 and pazopanib that are the same as or less than the maximum tolerated doses (MTDs). The dose-limiting toxicity (DLT) evaluation period will be the first treatment cycle. Patients must have taken a minimum of 6 AR-42 doses and a minimum of 21 pazopanib doses during cycle 1 to be considered evaluable for DLT, if DLT has not been observed at the delivered dose. Patients' treatment dose level, dose modification, evaluability for DLT, and DLTs will be listed and summarized by basic descriptive statistics such as frequency and proportion. The maximum tolerated dose(MTDs)/recommended phase 2 doses (RP2Ds) will be found based on the criteria in the protocol.


Secondary Outcome Measures :
  1. Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment, AR-42 and pazopanib combination. [ Time Frame: 5 months ]
    The safety and toxicity of AR-42 and pazopanib when given in combination. Adverse Events (AEs) characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) to determine the safety and toxicity of the combination of AR-42 and pazopanib. All AEs regardless of grade will be recorded from the beginning of the study procedures through 30 days following the end of study treatment.

  2. The antitumor effects of the AR-42 and pazopanib treatment regimen in patients with advanced Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS). [ Time Frame: 5 months ]
    Tumor response based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The clinical response (complete response [CR] + partial response[PR]) rate will be calculated along with its 95% confidence interval.



Information from the National Library of Medicine

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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:

  • Recurrent, unresectable, or metastatic Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS) (any histologic type) for which pazopanib is an appropriate therapy
  • Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
  • Age ≥ 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Adequate bone marrow function as defined below:

    • Absolute neutrophil count (ANC) ≥ 1200/mm3
    • Platelets ≥ 120,000/mm3
    • Hemoglobin ≥ 9.5 g/dL
  • Adequate renal function as defined below:

    • Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance ≥ 60 mL/min
    • Proteinuria ≤ 2+ [100 mg/dL] (using a random urine sample or < 3.0 gm using a 24-hour sample) (Note: If urine sample indicates ≥ 2+ [100 mg/dL]), a 24-hour urine sample must be collected and tested; urine protein in the 24-hour sample must be < 3.0 gm/24 hours.)
  • Adequate hepatic function as defined below:

    • Total bilirubin ≤ 1.5 x ULN for the laboratory (Note: Patients with known Gilbert's Syndrome are not eligible for this study)
    • Aspartate aminotransferase (AST) ≤ 2.5 x ULN for the laboratory
    • Alanine aminotransferase (ALT) ≤ 2.5 x ULN for the laboratory
  • Non-hematologic toxicities from previous cancer therapies resolved to ≤ grade 1
  • International normalized ratio (INR) ≤ 1.5
  • Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN for the laboratory
  • Left ventricular ejection fraction (LVEF) assessment (eg, echocardiogram, MUGA scan, first-pass technique) performed within 3 months prior to initiation of study treatment indicates an LVEF of ≥ 50%
  • A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age and has not had a hysterectomy, must have a documented negative serum pregnancy test within 7 days prior to initiating study treatment
  • A WCBP and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment
  • Ability to understand and willingness to sign the consent form

Exclusion Criteria:

  • Symptomatic or untreated brain metastasis
  • Leptomeningeal metastasis
  • Any investigational agent within 4 weeks prior to initiating study treatment
  • Previous therapy with pazopanib
  • Inability to swallow medication
  • Known or suspected malabsorption condition or obstruction
  • Contraindication to antiangiogenic agents, including:

    • Serious non-healing wound, non-healing ulcer, or bone fracture
    • Major surgical procedure or significant traumatic injury within 4 weeks prior to initiating study treatment; other surgical procedures within 2 weeks prior to initiating study treatment
    • Pulmonary hemorrhage/bleeding event ≥ grade 2 within 12 weeks prior to initiating study treatment
    • Any other hemorrhage/bleeding event ≥ grade 3 within 12 weeks prior to initiating study treatment
  • History of organ allograft including corneal transplant
  • Evidence of bleeding diathesis or coagulopathy
  • Documented Gilbert's Syndrome
  • Resting systolic blood pressure (BP) < 100 mmHg
  • Hypertension defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg despite optimal medical management
  • QTc interval > 450 ms on screening 12-lead electrocardiogram (ECG)

    • If baseline QTc on screening ECG meets exclusion criteria:

      • Check calcium, potassium, and magnesium serum levels.
      • Correct any identified hypocalcemia, hypokalemia, and/or hypomagnesemia and repeat ECG to confirm exclusion of patient due to prolonged QTc interval.
    • For patients with heart rate (HR) 60-100 bpm, manual read of QTc is not required.
    • For patients with a baseline HR < 60 bpm or > 100 bpm, manual read of the QT interval by a cardiologist is required, with Fridericia correction applied to determine QTc (ie, QTcF).
  • Active or clinically significant cardiac disease including any of the following:

    • Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment
    • Myocardial infarction within 6 months prior to initiating study treatment
    • Cardiac arrhythmias currently requiring anti-arrhythmic therapy other than beta blockers
  • Any documented history of clinically significant thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism necessitating therapeutic anticoagulation within 6 months prior to initiating study treatment (Note: Patients with a tumor-associated thrombus of locally-involved vessels should not be excluded from participating in the study.)
  • Active infection requiring treatment or chronic infection requiring suppressive therapy
  • Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy
  • Pleural effusion or ascites that causes respiratory compromise (eg, ≥ grade 2 dyspnea)
  • Required ongoing treatment with other drugs thought to potentially have adverse interactions with either of the medications included in the study treatment; if such medications have been used, patients must have discontinued these agents at least 1 week prior to initiating study treatment. Examples include:

    • Strong CYP3A4 inhibitors and/or strong CYP3A4 inducers; the reference list of CYP isozymes and classification of strong, moderate, and weak interactions are available through the Food and Drug Administration (FDA website.
    • Strong inhibitors of P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP); the reference list of strong inhibitors of P-gp and BCRP.
    • Simvastatin and other HMG-CoA reductase inhibitors (ie, statins)
    • Drugs that raise gastric pH including proton pump inhibitors and H2-blockers (Note: Short-acting antacids, in place of PPIs and H2-blockers, are permitted.)
    • HDAC inhibitors
  • Pregnancy or breastfeeding
  • Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirement

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): NCT02795819


Locations
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United States, Virginia
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Andrew S Poklepovic, MD Massey Cancer Center

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT02795819     History of Changes
Other Study ID Numbers: MCC-14-10774
NCI-2016-00851 ( Registry Identifier: NCI CTRP )
P30CA016059 ( U.S. NIH Grant/Contract )
First Posted: June 10, 2016    Key Record Dates
Last Update Posted: April 3, 2019
Last Verified: April 2019

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

Additional relevant MeSH terms:
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Sarcoma
Neoplasm Metastasis
Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective and Soft Tissue
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Neoplastic Processes
Pathologic Processes