Clinical trial NCT06487481: Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma
Official title: A Phase I Dose-escalation Study of Preoperative Radiation Therapy in Participants With Resectable Recurrent Abdominal Adrenocortical Carcinoma
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Adrenocortical Carcinoma (ACC)
Recurrent Adrenocortical Carcinoma (ACC)
Recurrent Abdominal Adrenocortical Carcinoma (ACC)
Carcinoma, Adrenocortical
Carcinoma, Adrenal Cortical
Keywords: external beam radiation therapy (EBRT)
abdominal adrenocortical carcinoma (ACC)
preoperative radiation
Mitotane
Maximum Tolerated Dose (MTD)
Surgical Resection
in-field intraabdominal progression-free survival (PFS)
out-of-field intraabdominal progression-free survival (PFS)
DNA damage repair markers
oxidative stress response
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2024-07-05
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal glands. ACC often returns after tumors are removed with surgery. Less than 35% of people with ACC survive 5 years after diagnosis.

Objective:

To test a new type of radiation therapy (external beam radiation therapy \[EBRT\]) before surgery in people with ACC.

Eligibility:

People aged 18 years and older with ACC that came back after treatment but may be safely removed with surgery.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function. They will have imaging scans. A small sample of tumor tissue may be collected if one is not available. They will undergo laparoscopy: Small incisions will be made in the abdomen so that a thin tube with a light and camera can be inserted to view the organs.

EBRT comes from a machine that aims radiation at tumors. Participants will receive EBRT 5 days a week for 2 to 3 weeks. Visits will last 30 to 60 minutes.

Participants will undergo surgery to remove their tumors 4 to 8 weeks after they finish EBRT. They will stay in the hospital 1 to 3 weeks after surgery.

Participants will have follow-up visits for 10 years after surgery.

Detailed description: Background:

* Although surgical resection is the treatment of choice in participants with localized or regionalized primary and recurrent abdominal adrenocortical carcinoma (ACC), loco-regional recurrence following complete resection of ACC occurs in 50-80% of the participants, most commonly in the first five years postoperatively.
* Retrospective single institutional series report improvement in local control with postoperative adjuvant radiotherapy (RT) in selected participants with ACC.
* Preoperative RT is used in several abdominal and retroperitoneal malignancies to improve local control. There is no prospective data available for the use of this treatment approach for participants with resectable ACC.
* We hypothesize that preoperative RT alone is safe and can result in a lower loco-regional recurrence in participants with resectable recurrent ACC with no peritoneal carcinomatosis. Thus, this phase I dose-escalation trial aims to evaluate the safety and feasibility of preoperative radiation in participants with resectable recurrent ACC.
* Health-related quality of life (QOL) is a well-accepted tool to measure the outcome of cancer treatments. SF-36 v2 questionnaire has been frequently used to evaluate the QOL in participants with cancer. There is no study evaluating the difference in QOL in participants with resectable recurrent ACC undergoing preoperative RT and surgery.

Objectives:

-To determine the maximum tolerated dose and the safety and toxicity profile of preoperative external beam radiation therapy (EBRT) with or without standard of care mitotane, before surgical resection in participants with resectable ACC

Eligibility:

* Age \>= 18 years
* Pathological confirmation of ACC with clinical evidence of abdominal recurrence
* ECOG 0-2
* Surgically resectable disease at presentation with no or limited extra-abdominal disease and without ACC peritoneal carcinomatosis based on a diagnostic laparoscopy at screening.
* The last dose of chemotherapy treatment except for mitotane more than 4 weeks prior to starting treatment with this protocol, and participants must have recovered from chemotherapy.
* No prior abdominal radiation
* No contraindication to abdominal radiotherapy

Design:

* This study will enroll up to 24 evaluable participants as follows:

  * Participants will be enrolled in Cohort 1 or 2 based on mitotane use or serum level. Up to 6-18 evaluable participants per these cohorts (i.e., resectable ACC with and without mitotane use) will be enrolled to assess the safety of 3-level dose-escalating preoperative EBRT.
  * Participants will be enrolled in Cohort 3 regardless of mitotane use or serum level, and will only start enrollment when we observe no DLTs in \> 1 participant in Cohort 1 at Dose Level 1. Up to 12 evaluable participants will be enrolled in this cohort.
* Preoperative assessment of QOL using a standardized questionnaire (SF-36 v2) will be obtained at baseline.
* Participants will be treated with preoperative external beam radiation therapy (EBRT) daily 5 days/week (M-F), followed by a planned surgical resection, 6-8 weeks after the completion of EBRT.
* A standard 3 + 3 design will be used to determine the MTD of dose-escalated EBRT, with 3 dose levels (DL1- 30 Gy delivered in 10 fractions, DL2-36 Gy in 12 fractions, DL3-42 Gy in 14 fractions).
* Postoperative surveillance imaging studies and laboratory tests will be performed every 3 months in the first 3 years, then every 6 months thereafter in years 4-10. FDG-PET scan will be performed every 6 months postoperatively in the first 3 years, then every year in years 4-10. Additional assessments may be performed if clinically indicated.

Eligibility criteria: * INCLUSION CRITERIA:
* Age \>= 18 years
* Pathological confirmation of ACC by the Laboratory of Pathology, NCI. Note: Confirmation may be done from archival sample; fresh tissue is not required unless otherwise acquired for clinical purposes.
* Measurable disease by RECISTv1.1. criteria at enrollment
* Evidence of recurrent ACC amenable to surgical resection that can be performed at NIH Clinical Center (CC)
* Must be suitable for external beam radiotherapy AND surgery in the opinion of the treating investigator (e.g., based on clinical history and imaging)
* Participants with metastatic ACC outside the area(s) to be exposed to investigational treatments (e.g., liver parenchyma, lung\[s\], or bone\[s\]) must have disease that is amendable for a complete resection and/or catheter-based and/or radiation-based ablation.
* Mitotane therapy- Participants may be receiving mitotane currently, have received it in the past, or never have received mitotane. However, participants will be evaluated in separate cohorts based on mitotane use and, as enrollment is sequential, not all participants may be eligible for the study at all times. Note: Participants with a history of mitotane use may continue on study at the discretion of the treating investigator. Participants will not initiate mitotane on study.
* Participants must agree to undergo tumor biopsy of easily accessible tumor sites prior to study treatment.
* Performance Status (ECOG) 0-2
* Adequate organ function, including:

  * Hemoglobin \>= 9.0 gm/dL
  * ANC \>= 1,500/mm\^3
  * Platelets \>= 75,000/mm\^3
  * AST and ALT \<= 3 x Upper Limit Normal (ULN)
  * Bilirubin \<= 2 x ULN
  * Creatinine within normal institutional limits or creatinine clearance \>60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal calculated using eGFR.
* Individuals of childbearing potential must agree to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to and for 4 months following cytoreduction surgery.
* Nursing (including breastfeeding) participants must agree to discontinue nursing until 4 months following cytoreductive surgery.
* Ability of participant to understand and willingness to sign a written informed consent document
* Participants must agree to co-enroll in tissue collection protocol 09C0242 "Prospective comprehensive molecular analysis of endocrine neoplasms."

EXCLUSION CRITERIA:

* Primary ACC or suspicious/indeterminate adrenal tumor without pathological confirmation
* Prior abdominal radiation therapy
* Participants who have received chemotherapy, immunotherapy, investigational therapy, or radiotherapy treatment within the last 4 weeks prior to starting treatment and/or have not recovered from toxicities to less than grade 2 CTCAE.
* Infection requiring parenteral antibiotics
* Suspected or proven ACC peritoneal metastasis
* Pre-existing known or suspected radiation sensitivity syndromes
* Prohibitive condition(s) to diagnostic laparoscopy
* Participants who have an unacceptable risk for a major surgical procedure such as participants with high risks for major cerebro-cardiovascular (such as those who had doxorubicin exposure as based on screening echocardiogram and ECG) and pulmonary complications and those with estimated perioperative mortality greater than 15% per ACS NSQIP Surgical Risk calculator.
* Participants receiving other investigational therapies
* Participant pregnancy
* Active systemic infections, coagulation disorders, or other major medical illnesses such as uncontrolled diabetes mellitus, uncontrolled hypertension (persistently grade 2 or worse), active severe cerebro-cardio-pulmonary diseases, and acute major organ dysfunction.
* Acute intraabdominal conditions such as obstruction or peritonitis at the time of the evaluation or surgery.
* Evidence at screening of or currently active CNS metastasis within 6 months of EBRT; participants with history of treated brain metastases with intracranial recurrence within 6 months prior to treatment. Note: Participants with any signs or symptoms suggestive of previously undiagnosed brain metastasis at screening or with a history of brain metastasis should receive imaging at screening; otherwise, imaging is not required.
* HIV-positive participants with CD4 below 200 or who are not on anti-retroviral therapy
* Participants who have a history of another primary malignancy from which the participant has been disease-free for \< 3 years at the time of enrollment.

Primary outcomes:
measure: Determine the maximum tolerated dose (MTD) and safety and toxicity profile of preoperative external beam radiation therapy (EBRT) with or without standard-of-care mitotane, before surgical resection
timeFrame: from the start of EBRT and for 30 days after its completion
Secondary outcomes:
measure: Assess quality of life measured by Short Form-36 Health Survey version 2.0 (SF-36 v2) questionnaire
timeFrame: baseline, 6 weeks after EBRT, and then 2 weeks, 6 weeks, 6 months and 12 months after surgery
measure: Determine overall survival (OS) through 10 years postoperatively
timeFrame: baseline, every 3-6 months after cytoreductive surgery for up to 10 years after surgery
measure: Assess in-field intraabdominal progression-free survival (PFS)
timeFrame: baseline, every 3-6 months after cytoreductive surgery for up to 10 years after surgery
measure: Determine the objective response of ACC in the field of radiation per RECIST criteria
timeFrame: baseline, every 3-6 months after cytoreductive surgery for up to 10 years after surgery
measure: Determine the 6 weeks postoperative complications per Clavien-Dindo classification
timeFrame: baseline, until 6 weeks after cytoreductive surgery
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Naris Nilubol, M.D.
role: PRINCIPAL_INVESTIGATOR
References: