Clinical Trials /

Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma

NCT03839498

Description:

Primary Objective: To determine the response rate (RR) of metastatic or locally advanced pheochromocytoma/paraganglioma to axitinib administered daily. Secondary Objectives: - Determine the progression-free survival. - In an exploratory manner examine the extent of activation of the VEGFR pathway in pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry assay and examine the relationship with response to therapy. - Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline DNA examination.

Related Conditions:
  • Adrenal Gland Pheochromocytoma
  • Paraganglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
  • Official Title: Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

Clinical Trial IDs

  • ORG STUDY ID: AAAR5314
  • NCT ID: NCT03839498

Conditions

  • Pheochromocytoma
  • Paraganglioma

Interventions

DrugSynonymsArms
AxitinibAG-013736Axitinib (AG-013736)

Purpose

Primary Objective: To determine the response rate (RR) of metastatic or locally advanced pheochromocytoma/paraganglioma to axitinib administered daily. Secondary Objectives: - Determine the progression-free survival. - In an exploratory manner examine the extent of activation of the VEGFR pathway in pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry assay and examine the relationship with response to therapy. - Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline DNA examination.

Detailed Description

      The long-term survival for malignant pheochromocytoma/paraganglioma (PHEO/PGL) may be limited
      because of its hormonal effects as well as its aggressive behavior and dissemination,
      particularly in some hereditary PHEO/PGL. Although several therapeutic modalities have been
      used to palliate malignant PHEO/PGL, a continued search for new agents to address the
      malignancy is needed to improve outcomes. One approach is to utilize drugs that target
      signaling pathways leading to decreased proliferation and survival of cancer cells. Some data
      in the literature suggests that in malignant PHEO/PGL, VEGF seems to play a role in the
      biology of the cancer and thus, its inhibition could reduce tumor growth. Sunitinib and
      imatinib has been used in a limited number of malignant pheochromocytomas with varying
      responses. Axitinib was designed to inhibit VEGFR that participates in tumor angiogenesis. In
      order to determine the activity of axitinib in tumor and hormonal responses in malignant
      PHEO/PGL, it will be used as a single agent in this study. The combination of
      cyclophosphamide; vincristine and dacarbazine have been shown to produce partial responses in
      malignant PHEO/PGL. The majority of the patients may have already received this combination
      or will receive this combination chemotherapy in the future. The goal is to develop multiple
      lines of effective treatments for this disease.
    

Trial Arms

NameTypeDescriptionInterventions
Axitinib (AG-013736)ExperimentalSubjects with Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma will receive 16 weeks of therapy (Axitinib), and be seen in clinic every 4 weeks to monitor therapy.
  • Axitinib

Eligibility Criteria

        Inclusion Criteria

        Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by a
        CUMC/NYPH laboratory when such tissue is available to confirm.

        In the event that outside tissue is not available:

        An outside pathology report confirms the diagnosis of Pheo/PGL, AND the patient has nuclear
        medicine imaging studies that would only be positive in an adult patient with a diagnosis
        of Pheo/PGL (F-DOPA, Dotatate, F-Dopamine or MIBG)

          -  Imaging confirmation of metastatic disease

          -  Measurable disease at the time of enrollment as per RECIST 1.1.

          -  A life expectancy of at least 3 months and ECOG performance status ≤ 2

          -  Age ≥ 18 years

          -  Information available or pending regarding possible genetic alterations that can
             explain the patient's pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL
             genes)

          -  Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the
             case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was
             received as part of a "phase 0" or "exploratory IND" trial. Last surgery more than 4
             weeks prior to enrollment, to allow for wound healing. Core biopsies or FNA will not
             require any waiting period

          -  Last radiotherapy treatment ≥ 4 weeks prior to starting treatment with this protocol
             and there must be sites of measurable disease that did not receive radiation

          -  Prior therapeutic MIBG is allowed

          -  Organ and marrow function as defined below:

          -  Total bilirubin ≤ 1.5 x ULN (upper limit of normal), unless the patient meets the
             criteria for Gilbert's Syndrome. The upper limit value for bilirubin for subjects with
             Gilbert's Syndrome is less than 3 mg/dl.

             o Note: A diagnosis of Gilbert's disease will be made in the presence of (1)
             unconjugated hyperbilirubinemia noted on several occasions; (2) normal results from
             CBC count, reticulocyte count, and blood smear; (3) normal liver function test
             results; and (4) an absence of other disease processes that can explain the
             unconjugated hyperbilirubinemia.

          -  AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN

          -  Amylase and lipase equal to, or less than, the institutional ULN.

          -  Creatinine clearance ≥ 40 ml/min (estimated or measured creatinine clearance) or serum
             creatinine ≤ 1.6 mg/dl

             o Random urine protein < 20 mg/dL. If ≥ 20 mg/dL then a 24-hour urine protein
             collection will be performed to accurately demonstrate that the 24-hour total is <1000
             mg, the level acceptable for enrollment on study

          -  Absolute neutrophil count ≥ 500/mm3

          -  Platelet count ≥ 50,000/ mm3

          -  Ability to understand and sign an informed consent document.

          -  Ability and willingness to follow the guidelines of the clinical protocol.

          -  Because the effects of chemotherapy on the developing human fetus are potentially
             harmful, women of childbearing potential and men who participate in the study must
             agree to use adequate contraception (hormonal or barrier methods) before, during the
             study and for a period of 3 months after the last dose of chemotherapy.

        Exclusion Criteria

          -  Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical
             excision alone as determined by the Principal Investigator in discussions with the
             surgical consultants

          -  Patients who have large abdominal masses impinging on bowel or pulmonary masses with
             encroached vessels and a potential to bleed will be considered on case by case basis
             after careful consultation with multiple disciplines such as radiologists and surgeons
             with main intent being patient safety.

          -  Unstable hypertension defined as a systolic blood pressure >150 mm Hg or diastolic
             pressure > 90 mmHg despite optimal medical management.

          -  Untreated brain metastases (or local treatment of brain metastases within the last 3
             months) due to the poor prognosis of these patients and difficulty ascertaining the
             cause of neurologic adverse events.

          -  Pregnancy, due to the possible adverse effects on the developing fetus.

          -  Lactating women who are breast-feeding due to the possibility of transmitting axitinib
             to the child.

          -  The presence of a second malignancy, other than squamous cell carcinoma of the skin or
             in situ cervical cancer because it will complicate the primary objective of the study.
             Cancer survivors who have been free of disease for at least one year can be enrolled
             in this study.

          -  Patients with evidence of a bleeding diathesis

          -  Patients must not have received prior therapy with a TKI. Prior TKI usage in
             pheochromocytoma affects the same pathway as axitinib.

          -  Gastrointestinal abnormalities including:

               -  Inability to take oral medications

               -  Requirement for intravenous alimentation

               -  Prior surgical procedure affecting absorption including total gastric resection

               -  Treatment for active peptic ulcer disease in the past 6 months

               -  Active gastrointestinal bleeding, unrelated to cancer, as evidenced by
                  hematemesis, hematochezia or melena in the past 3 months without evidence of
                  resolution documented by endoscopy or colonoscopy.

               -  Malabsorption syndrome

          -  Current use or anticipated need for treatment with drugs that are known potent CYP3A4
             inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
             erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir,
             nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).

          -  Current use or anticipated need for treatment with drugs that are known CYP3A4 or
             CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole,
             phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and
             St. John's wort).

          -  Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
             anticoagulants for maintenance of patency of central venous access devices or
             prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
             weight heparin is allowed.

          -  Active seizure disorder or evidence of brain metastases, spinal cord compression, or
             carcinomatous meningitis.

          -  Any of the following within 12 months prior to study drug administration: myocardial
             infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic
             congestive heart failure, cerebrovascular accident or transient ischemic attack and
             within 6 months before study drug administration for deep vein thrombosis or pulmonary
             embolism.

          -  Other severe acute or chronic medical or psychiatric condition, or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, and in
             the judgment of the investigator would make the patient inappropriate for entry into
             this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response Rate (RR)
Time Frame:Up to 16 weeks
Safety Issue:
Description:This study is designed to determine the percentage of patients whose cancer shrinks or disappears after treatment.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Duration of time from start of treatment to time of progression or death, whichever occurs first; an average of up to 12 months
Safety Issue:
Description:The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Columbia University

Trial Keywords

  • Axitinib

Last Updated