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Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer

Primary Purpose

Adrenal Cortex Neoplasms

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Axitinib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adrenal Cortex Neoplasms focused on measuring Selective VEGF Inhibitor, Clinical Activity, Response Rate, Measurable Disease, Biological Markers, Adrenocortical Cancer

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA:

    1. Pathologic confirmation of adrenocortical cancer by the Laboratory of Pathology, National Cancer Institute (NCI).
    2. Measurable disease at presentation.
    3. A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
    4. Age greater than or equal to 18 years.
    5. 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 investigational new drug (IND) trial. Last surgery more than 4 weeks prior to enrollment, to allow for wound healing. Core biopsies or fine needle aspiration (FNA) will not require any waiting period.
    6. 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.
    7. Prior mitotane therapy is allowed. Patients with a history of a functional tumor who are receiving mitotane to control the excess hormone production may continue to receive mitotane.
    8. Organ and marrow function as defined below:
  • Total bilirubin less than or equal to 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.

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 complete blood count (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.

  • Aspartate aminotransaminase (AST) less than or equal to 2.5 times ULN, alanine aminotransaminase (ALT) greater than or equal to 2.5 times ULN
  • Amylase and lipase equal to, or less than, the institutional ULN.
  • Creatinine clearance greater than or equal to 40 ml/min (measured in a timed urine collection) or serum creatinine less than or equal to 1.6 mg/dl
  • Absolute neutrophil count greater than or equal to 1000/mm^3.
  • Platelet count greater than or equal to 100,000/ mm^3.

    9. Ability to understand and sign an informed consent document.

    10. Ability and willingness to follow the guidelines of the clinical protocol including visits to NCI, Bethesda, Maryland for treatment and follow up visits.

    11. Because the effects of chemotherapy on the developing human fetus are potentially harmful, women of childbearing potential and men 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:

  1. Patients with adrenocortical tumors potentially curable by surgical excision alone as determined by the Principal Investigator in discussions with the surgical consultants.
  2. 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.
  3. Unstable hypertension defined as a systolic blood pressure greater than 140 mm Hg or diastolic pressure greater than 90 mmHg despite optimal medical management and patients who are receiving more than 1 antihypertensive agent at trial entry, (not including spironolactone) unless the patient has Cushing's Disease with its associated hypertension and is well controlled on medications.
  4. Untreated brain metastases (or local treatment of brain metastases within the last 6 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic adverse events.
  5. Pregnancy, due to the possible adverse effects on the developing fetus.
  6. Lactating women who are breast-feeding due to the possibility of transmitting axitinib to the child.
  7. The presence of a second malignancy, other than a skin cancer 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 two years can be enrolled in this study.
  8. Patients with evidence of a bleeding diathesis.
  9. Phosphorus level equal to, or less than, the institutional lower limits of normal that cannot be corrected.
  10. Gastrointestinal abnormalities including:

    1. inability to take oral medications
    2. requirement for intravenous alimentation
    3. prior surgical procedure affecting absorption including total gastric resection
    4. treatment for active peptic ulcer disease in the past 6 months
    5. 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
    6. malabsorption syndrome
  11. Current use or anticipated need for treatment with drugs that are known potent cytochrome P450 3A4 (CYP3A4) inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).
  12. Current use or anticipated need for treatment with drugs that are known CYP3A4 inducers (i.e., carbamazepine, Phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John's wort).
  13. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
  14. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
  15. 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 6 months for deep vein thrombosis or pulmonary embolism.
  16. 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.
  17. Current use of drugs that are known inhibitors or inducers of Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptide (OATP)1B1/3 or known to affect protein binding should be used with caution and with acknowledgement of the principal investigator (PI).

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Adrenal Cortex Neoplasms

Arm Description

Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.

Outcomes

Primary Outcome Measures

Response Rate (RR) of Axitinib Administered Daily, in Patients With Recurrent, Metastatic, or Primary Unresectable Adrenocortical Cancer (ACC)
Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameter. Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: the appearance of one or more new lesions is also considered progression). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking s reference the smallest sum diameters while on study.

Secondary Outcome Measures

Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse events module.

Full Information

First Posted
December 4, 2010
Last Updated
April 25, 2013
Sponsor
National Cancer Institute (NCI)
Collaborators
Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT01255137
Brief Title
Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer
Official Title
Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2013
Overall Recruitment Status
Completed
Study Start Date
September 2010 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
Collaborators
Pfizer

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Background: - Adrenocortical carcinoma is an aggressive cancer that starts in the adrenal gland at the top of the kidneys. It has a low survival rate if standard treatment options are not effective. Axitinib is an experimental drug that is being studied to determine if it can stop tumors from growing or make them smaller. Researchers are interested in investigating axitinib in individuals with aggressive or otherwise untreatable adrenocortical cancer. Objectives: - To evaluate the effectiveness of axitinib in individuals who have adrenocortical cancer that is inoperable and has not responded to standard treatments. Eligibility: - Individuals at least 18 years of age who have been diagnosed with adrenocortical cancer that has not responded to standard treatments. Design: Participants will be screened with a full physical examination and medical history, as well as tumor imaging studies. Participants may have a tumor biopsy prior to starting axitinib. All participants will receive axitinib to take twice a day with food for 28 days (1 cycle). Participants should not drink grapefruit juice or smoke cigarettes while participating in this study. After the first cycle, the dose may be increased and additional cycles will be given if the treatment has not had serious side effects. Participants will have regular examinations while taking axitinib, including blood samples and tumor imaging studies to determine if the tumor has stopped growing. Blood pressure levels will be carefully monitored during treatment to evaluate potential risk for high blood pressure. Participants may have a second tumor biopsy 20 to 30 days after treatment begins. Treatment will continue as directed by the study researchers.
Detailed Description
Background: The response rates of recurrent, metastatic and unresectable adrenocortical cancer (ACC) to mitotane, doxorubicin, etoposide, and cisplatin are low and underscore the need for more effective systemic therapies. VEGF expression and evidence of angiogenesis has been found in many ACCs, so it is plausible that interfering with vascular endothelial growth factor(VEGF) signaling may result in anti-tumor activity in patients with ACC. Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued. Given the known clinical safety and efficacy of axitinib, an assessment of its activity in ACC and its impact on the VEGF pathway in ACC could provide valuable information. Objectives: Determine the response rate of axitinib (AG-013736) in recurrent, metastatic, or primary unresectable ACC Determine the progression-free survival Explore the relationship of potential biological markers of axitinib activity with clinical outcomes. Explore the pharmacogenetic analyses of drug metabolism and transport proteins through germline deoxyribonucleic acid (DNA) examination. Eligibility: Adults with pathologic confirmation of ACC by the Laboratory of Pathology, National Cancer Institute (NCI) Diagnosis of recurrent, metastatic, or primary unresectable ACC Measurable disease at presentation Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor Design: Phase II, open label, non-randomized trial Patients with recurrent, metastatic, or primary unresectable ACC will be given in eight weeks cycles with BID dosing of axitinib (AG-013736). Patients will be evaluated for response every eight weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Tumor biopsies are not mandatory but every attempt will be made to obtain these from patients prior to starting axitinib and again 20-30 days after treatment has begun. Approximately 40 patients will be needed to achieve the objectives of the trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adrenal Cortex Neoplasms
Keywords
Selective VEGF Inhibitor, Clinical Activity, Response Rate, Measurable Disease, Biological Markers, Adrenocortical Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Adrenal Cortex Neoplasms
Arm Type
Experimental
Arm Description
Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.
Intervention Type
Drug
Intervention Name(s)
Axitinib
Other Intervention Name(s)
AG-013736
Intervention Description
5 mg tab orally twice a day with food every 28 days
Primary Outcome Measure Information:
Title
Response Rate (RR) of Axitinib Administered Daily, in Patients With Recurrent, Metastatic, or Primary Unresectable Adrenocortical Cancer (ACC)
Description
Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameter. Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: the appearance of one or more new lesions is also considered progression). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking s reference the smallest sum diameters while on study.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse events module.
Time Frame
3/2/11 - 8/2/12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Pathologic confirmation of adrenocortical cancer by the Laboratory of Pathology, National Cancer Institute (NCI). Measurable disease at presentation. A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2. Age greater than or equal to 18 years. 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 investigational new drug (IND) trial. Last surgery more than 4 weeks prior to enrollment, to allow for wound healing. Core biopsies or fine needle aspiration (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 mitotane therapy is allowed. Patients with a history of a functional tumor who are receiving mitotane to control the excess hormone production may continue to receive mitotane. Organ and marrow function as defined below: Total bilirubin less than or equal to 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. 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 complete blood count (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. Aspartate aminotransaminase (AST) less than or equal to 2.5 times ULN, alanine aminotransaminase (ALT) greater than or equal to 2.5 times ULN Amylase and lipase equal to, or less than, the institutional ULN. Creatinine clearance greater than or equal to 40 ml/min (measured in a timed urine collection) or serum creatinine less than or equal to 1.6 mg/dl Absolute neutrophil count greater than or equal to 1000/mm^3. Platelet count greater than or equal to 100,000/ mm^3. 9. Ability to understand and sign an informed consent document. 10. Ability and willingness to follow the guidelines of the clinical protocol including visits to NCI, Bethesda, Maryland for treatment and follow up visits. 11. Because the effects of chemotherapy on the developing human fetus are potentially harmful, women of childbearing potential and men 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 adrenocortical 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 greater than 140 mm Hg or diastolic pressure greater than 90 mmHg despite optimal medical management and patients who are receiving more than 1 antihypertensive agent at trial entry, (not including spironolactone) unless the patient has Cushing's Disease with its associated hypertension and is well controlled on medications. Untreated brain metastases (or local treatment of brain metastases within the last 6 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 a skin cancer 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 two years can be enrolled in this study. Patients with evidence of a bleeding diathesis. Phosphorus level equal to, or less than, the institutional lower limits of normal that cannot be corrected. 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 cytochrome P450 3A4 (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 inducers (i.e., carbamazepine, 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 devise 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 6 months 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. Current use of drugs that are known inhibitors or inducers of Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptide (OATP)1B1/3 or known to affect protein binding should be used with caution and with acknowledgement of the principal investigator (PI).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio T Fojo, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
6088397
Citation
Plager JE. Carcinoma of the adrenal cortex: clinical description, diagnosis, and treatment. Int Adv Surg Oncol. 1984;7:329-53. No abstract available.
Results Reference
background
PubMed Identifier
2325710
Citation
Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990 Apr 26;322(17):1195-201. doi: 10.1056/NEJM199004263221705.
Results Reference
background
PubMed Identifier
3787475
Citation
Cohn K, Gottesman L, Brennan M. Adrenocortical carcinoma. Surgery. 1986 Dec;100(6):1170-7.
Results Reference
background
Links:
URL
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2010-C-0203.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer

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