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Surgery and Heated Chemotherapy for Adrenocortical Carcinoma

Primary Purpose

Adrenocortical Carcinoma, Peritoneal Carcinomatosis

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

About this trial

This is an interventional treatment trial for Adrenocortical Carcinoma focused on measuring Synergy for Cisplatin and Hyperthermia, Rare Tumor, Poor Prognosis

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA
  • Histologically proven Adrenocortical carcinoma (ACC) with the majority of disease confined to the peritoneal cavity and resectable or amenable to radiofrequency ablation
  • Disease evaluable by computed tomography (CT) or positron emission tomography (PET) imaging

  • All disease should be deemed resectable based on imaging studies e.g.:

    • Hepatic metastases (unilateral or bilateral less than or equal to 5 lesions, less than or equal to 15 cm total diameter)
    • Note: Hepatic lesions must be amenable to complete resection
    • Primary peritoneal metastases (small disease load less than or equal to P2 disease) without massive ascites or intestinal obstruction
    • Lung metastases (less than or equal to 3 unilateral/bilateral, 9 cm total diameter)
    • Note: lung lesions must be amenable to complete resection
    • Note: Patients with both pulmonary and hepatic metastases will be enrolled at the discretion of the principal investigator (PI)
    • Note: In situations where resection to Completeness of Cytoreduction Score (CC) 0 or 1 is uncertain, patients may undergo diagnostic laparoscopy prior to enrollment to determine feasibility of resection.
  • Greater than or equal to 18 years of age
  • Able to understand and sign the Informed Consent Document
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) less than or equal to 2
  • Life expectancy of greater than three months
  • Patients of both genders must be willing to practice birth control during and for four months after receiving chemotherapy

  • Hematology:

    • Absolute neutrophil count greater than 1500/mm^3 without the support of Filgrastim.
    • Platelet count greater than 75,000/mm^3.
    • Hemoglobin greater than 8.0 g/dl.

  • Chemistry:

    • Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine clearance is greater than 60 mL/min/1.73 m2
    • serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within 5 times the upper limit of normal and a total serum bilirubin of less than 3 times the upper limit of normal, both of which define the upper limit of grade 2 treatment related toxicities.
    • Prothrombin time (PT) within 2 seconds of the upper limit of normal (international normalized ratio (INR) less than or equal to 1.8)
  • Recovered from any toxicity to grade 2 or less from all prior chemotherapy, immunotherapy or radiotherapy and be at least 30 days past the date of their last treatment with the exception of mitotane which may be continued.
  • Able to understand their disease and the exploratory nature of combining surgery and Heated Intraperitoneal Peritoneal Chemotherapy (HIPEC) for this histology.

EXCLUSION CRITERIA

  • Concomitant medical problems that would place the patient at unacceptable risk for a major surgical procedure.
  • History of congestive heart failure and/or an left ventricular ejection fraction (LVEF) less than 40%

Note: Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g., greater than 65yo, diabetes, history of hypertension, elevated low-density lipoproteins (LDL), first degree relative with coronary artery disease) will undergo full cardiac evaluation and will not be eligible if they demonstrate significant irreversible ischemia on stress thallium or an ejection fraction less than 40%.

- Significant Chronic Obstructive Pulmonary Disease (COPD) or other chronic pulmonary restrictive disease with pulmonary function test (PFTs) indicating an forced expiratory volume 1 (FEV1) less than 50% or a Carbon monoxide diffusing capacity (DLCO) less than 40% predicted for age

Note: Patients who have shortness of breath with minimal exertion or who are at risk for pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will not be eligible if their FEV1 is less than 50% of expected.

  • Grade 2 or greater neuropathy
  • Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the chemotherapy on the fetus or infant.
  • Brain metastases or a history of brain metastases
  • Childs B or C cirrhosis
  • Evidence of severe portal hypertension by history, endoscopy, or radiologic studies

Note: Any diagnosis of portal hypertension or clinical stigmata of such including but not limited to gastric or esophageal varices, umbilical vein varices or telangiectasias.

  • Weight less than 30 kg
  • Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cytoreductive surgery followed by HIPEC

Arm Description

Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin

Outcomes

Primary Outcome Measures

Intraperitoneal Progression Free Survival (PFS)
Amount of time subject survives without intraperitoneal disease progression after treatment. Disease progression is defined as imageable tumor nodules or increasing ascites persistent on computed tomography (CT) scan as interpreted by the official interpretation of the imaging studies.

Secondary Outcome Measures

Number of Patients With Treatment Related Morbidity Following the Heated Intraperitoneal Peritoneal Chemotherapy (HIPEC) Procedure
Patients who died following the HIPEC procedure. The HIPEC is a surgical procedure in which two large bore catheters are inserted in the abdominal wall over the liver and pelvis. The physician closes the abdominal fascia and the catheters are connected to a perfusion circuit. The temperature of the catheters is carefully monitored while the physician ensures the perfusion is distributed properly by manually moving the abdomen.
Percentage of Participants Who Survived 5-years Post Treatment
Percentage of participants who are alive after treatment.
The Functional Assessment of Cancer Therapy-Colorectal Quality of Life (FACT-G) (QOL) Score Prior to Surgery, 6 Weeks After Surgery, and 3 Months After Surgery
QOL characteristics were collected using The Functional Assessment of Cancer Therapy-Colorectal Quality of Life (QOL) questionnaire version 4, a validated survey that interrogates physical, emotional, functional, and social well being in cancer related issues on a 5-point scale. Scores range from 0 to 108 points. Higher scores are consistent with a better outcome.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Full Information

First Posted
April 12, 2013
Last Updated
July 10, 2019
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01833832
Brief Title
Surgery and Heated Chemotherapy for Adrenocortical Carcinoma
Official Title
Phase II Trial of Surgical Resection and Heated Intraperitoneal Peritoneal Chemotherapy (HIPEC) for Adrenocortical Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
April 12, 2013 (Actual)
Primary Completion Date
August 9, 2018 (Actual)
Study Completion Date
August 9, 2018 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Background: - Adrenocortical carcinoma (ACC) is a rare tumor of the adrenal gland. Few people who develop this disease live more than 5 years after being diagnosed. Those whose tumors have spread inside their abdomen may have an especially poor outcome. In these cases, traditional chemotherapy is not very effective. One possible new treatment is aggressive surgery with heated chemotherapy. This type of treatment has been more effective for other types of cancer in the abdomen. Researchers want to see this if approach can improve the outcomes of people with ACC. Objectives: - To test the safety and effectiveness of surgery and heated chemotherapy for ACC. Eligibility: - Individuals at least 18 years of age who have advanced ACC. Design: Participants will be screened with a physical exam and medical history. Blood samples will be collected. Heart function tests will be given. Imaging studies will be used to locate the surgical sites before the operation. Participants will have surgery to remove ACC tumor tissue. After the tumors have been removed, they will have heated chemotherapy with cisplatin. The heat may help weaken any remaining cancer cells and make them easier to destroy. It will also focus the treatment on the tumor sites, rather than the whole body. Participants will recover in the hospital for several days after surgery. They will have regular follow-up visits to monitor the outcome of the surgery.
Detailed Description
Background: Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5 to 2 per million people per year and has a very poor prognosis with an overall 5-year mortality rate of 75 - 90% and an average survival from the time of diagnosis of 14.5 months. The treatment of choice for a localized primary or recurrent tumor is surgical resection. For unresectable metastatic or recurrent disease, mitotane, aminoglutethimide, metapyrone, and ketoconazole are used. Cisplatin is one of the most effective chemotherapeutic agents for ACC. In the Surgery Branch we have conducted Phase I and II trials using heated intraperitoneal (IP) chemotherapy with cisplatin for primary peritoneal mesothelioma, low grade appendiceal adenocarcinoma, ovarian malignancies, and high grade adenocarcinoma of the gastrointestinal tract. Synergy has been demonstrated for cisplatin and hyperthermia. The purpose of this trial is to determine if an aggressive surgical approach with intraperitoneal administration of heated cisplatin when tumor volume is minimal, can impact and improve on progression free survival. Objectives: - To determine IP progression free survival after optimal debulking and heated IP chemotherapy with cisplatin in patients with IP spread of adrenocortical cancer Eligibility: - Histologically proven ACC evaluable by computed tomography (CT) imaging with the majority of disease confined to the peritoneal cavity and surgically resectable to a residual size of less than 1 cm or amenable to radiofrequency ablation in patients who are > 18 years of age. Design: - This is a classic phase 2 trial to determine efficacy of this therapeutic strategy in ACC. Patients will undergo cytoreductive surgery to achieve a CCR of 0 or 1. Patients who are successfully debulked will then undergo hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin. Patients will be evaluated by associate investigators in coordination with the Principal Investigator for eligibility. Due to its exploratory nature, up to 30 patients may be enrolled to obtain 24 evaluable patients. (Patients must undergo successful debulking and HIPEC to be considered evaluable.)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adrenocortical Carcinoma, Peritoneal Carcinomatosis
Keywords
Synergy for Cisplatin and Hyperthermia, Rare Tumor, Poor Prognosis

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Cytoreductive surgery followed by HIPEC
Arm Type
Experimental
Arm Description
Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Other Intervention Name(s)
Platinol
Intervention Description
Patients who are successfully debulked will then undergo hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin.
Intervention Type
Procedure
Intervention Name(s)
Cytoreductive surgery
Intervention Description
Patients will undergo cytoreductive surgery to achieve a Completeness of Cytoreduction Score (CC) of 0 or 1.
Intervention Type
Drug
Intervention Name(s)
sodium thiosulfate
Intervention Description
sodium thiosulfate will be given to limit the toxicity of cisplatin
Primary Outcome Measure Information:
Title
Intraperitoneal Progression Free Survival (PFS)
Description
Amount of time subject survives without intraperitoneal disease progression after treatment. Disease progression is defined as imageable tumor nodules or increasing ascites persistent on computed tomography (CT) scan as interpreted by the official interpretation of the imaging studies.
Time Frame
Amount of time subject survives without intraperitoneal disease progression after treatment, an average of 17 months
Secondary Outcome Measure Information:
Title
Number of Patients With Treatment Related Morbidity Following the Heated Intraperitoneal Peritoneal Chemotherapy (HIPEC) Procedure
Description
Patients who died following the HIPEC procedure. The HIPEC is a surgical procedure in which two large bore catheters are inserted in the abdominal wall over the liver and pelvis. The physician closes the abdominal fascia and the catheters are connected to a perfusion circuit. The temperature of the catheters is carefully monitored while the physician ensures the perfusion is distributed properly by manually moving the abdomen.
Time Frame
Patients were assessed every 3 months up to an average of 17 months.
Title
Percentage of Participants Who Survived 5-years Post Treatment
Description
Percentage of participants who are alive after treatment.
Time Frame
5 years
Title
The Functional Assessment of Cancer Therapy-Colorectal Quality of Life (FACT-G) (QOL) Score Prior to Surgery, 6 Weeks After Surgery, and 3 Months After Surgery
Description
QOL characteristics were collected using The Functional Assessment of Cancer Therapy-Colorectal Quality of Life (QOL) questionnaire version 4, a validated survey that interrogates physical, emotional, functional, and social well being in cancer related issues on a 5-point scale. Scores range from 0 to 108 points. Higher scores are consistent with a better outcome.
Time Frame
Prior to surgery, 6 weeks post surgery, and 3 months post surgery
Title
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Description
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame
Date treatment consent signed to date off study, approximately 34 months and 28 days.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA Histologically proven Adrenocortical carcinoma (ACC) with the majority of disease confined to the peritoneal cavity and resectable or amenable to radiofrequency ablation Disease evaluable by computed tomography (CT) or positron emission tomography (PET) imaging All disease should be deemed resectable based on imaging studies e.g.: Hepatic metastases (unilateral or bilateral less than or equal to 5 lesions, less than or equal to 15 cm total diameter) Note: Hepatic lesions must be amenable to complete resection Primary peritoneal metastases (small disease load less than or equal to P2 disease) without massive ascites or intestinal obstruction Lung metastases (less than or equal to 3 unilateral/bilateral, 9 cm total diameter) Note: lung lesions must be amenable to complete resection Note: Patients with both pulmonary and hepatic metastases will be enrolled at the discretion of the principal investigator (PI) Note: In situations where resection to Completeness of Cytoreduction Score (CC) 0 or 1 is uncertain, patients may undergo diagnostic laparoscopy prior to enrollment to determine feasibility of resection. Greater than or equal to 18 years of age Able to understand and sign the Informed Consent Document Clinical performance status of Eastern Cooperative Oncology Group (ECOG) less than or equal to 2 Life expectancy of greater than three months Patients of both genders must be willing to practice birth control during and for four months after receiving chemotherapy Hematology: Absolute neutrophil count greater than 1500/mm^3 without the support of Filgrastim. Platelet count greater than 75,000/mm^3. Hemoglobin greater than 8.0 g/dl. Chemistry: Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine clearance is greater than 60 mL/min/1.73 m2 serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within 5 times the upper limit of normal and a total serum bilirubin of less than 3 times the upper limit of normal, both of which define the upper limit of grade 2 treatment related toxicities. Prothrombin time (PT) within 2 seconds of the upper limit of normal (international normalized ratio (INR) less than or equal to 1.8) Recovered from any toxicity to grade 2 or less from all prior chemotherapy, immunotherapy or radiotherapy and be at least 30 days past the date of their last treatment with the exception of mitotane which may be continued. Able to understand their disease and the exploratory nature of combining surgery and Heated Intraperitoneal Peritoneal Chemotherapy (HIPEC) for this histology. EXCLUSION CRITERIA Concomitant medical problems that would place the patient at unacceptable risk for a major surgical procedure. History of congestive heart failure and/or an left ventricular ejection fraction (LVEF) less than 40% Note: Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g., greater than 65yo, diabetes, history of hypertension, elevated low-density lipoproteins (LDL), first degree relative with coronary artery disease) will undergo full cardiac evaluation and will not be eligible if they demonstrate significant irreversible ischemia on stress thallium or an ejection fraction less than 40%. - Significant Chronic Obstructive Pulmonary Disease (COPD) or other chronic pulmonary restrictive disease with pulmonary function test (PFTs) indicating an forced expiratory volume 1 (FEV1) less than 50% or a Carbon monoxide diffusing capacity (DLCO) less than 40% predicted for age Note: Patients who have shortness of breath with minimal exertion or who are at risk for pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will not be eligible if their FEV1 is less than 50% of expected. Grade 2 or greater neuropathy Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the chemotherapy on the fetus or infant. Brain metastases or a history of brain metastases Childs B or C cirrhosis Evidence of severe portal hypertension by history, endoscopy, or radiologic studies Note: Any diagnosis of portal hypertension or clinical stigmata of such including but not limited to gastric or esophageal varices, umbilical vein varices or telangiectasias. Weight less than 30 kg Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy L Davis, 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

Plan to Share IPD
No
Citations:
PubMed Identifier
22189845
Citation
Datrice NM, Langan RC, Ripley RT, Kemp CD, Steinberg SM, Wood BJ, Libutti SK, Fojo T, Schrump DS, Avital I. Operative management for recurrent and metastatic adrenocortical carcinoma. J Surg Oncol. 2012 Jun 1;105(7):709-13. doi: 10.1002/jso.23015. Epub 2011 Dec 20.
Results Reference
background
PubMed Identifier
20348273
Citation
Leboulleux S, Deandreis D, Al Ghuzlan A, Auperin A, Goere D, Dromain C, Elias D, Caillou B, Travagli JP, De Baere T, Lumbroso J, Young J, Schlumberger M, Baudin E. Adrenocortical carcinoma: is the surgical approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol. 2010 Jun;162(6):1147-53. doi: 10.1530/EJE-09-1096. Epub 2010 Mar 26.
Results Reference
background
PubMed Identifier
14673042
Citation
Feldman AL, Libutti SK, Pingpank JF, Bartlett DL, Beresnev TH, Mavroukakis SM, Steinberg SM, Liewehr DJ, Kleiner DE, Alexander HR. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol. 2003 Dec 15;21(24):4560-7. doi: 10.1200/JCO.2003.04.150.
Results Reference
background
PubMed Identifier
30463745
Citation
Hughes MS, Lo WM, Beresnev T, Merino M, Shutack Y, Ripley RT, Hernandez JM, Davis JL. A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma. J Surg Res. 2018 Dec;232:383-388. doi: 10.1016/j.jss.2018.06.012.
Results Reference
result

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Surgery and Heated Chemotherapy for Adrenocortical Carcinoma

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