Cabozantinib in Advanced Adrenocortical Carcinoma

NCT03612232 | Unknown Phase 2 FDA Drug

• 1 other identifier: CaboACC
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 2

Brief Summary

Adrenocortical carcinoma is an orphan malignant disease that has a dismal prognosis in advanced stages. Mitotane is the only approved treatment but is limited by severe toxicity. Efficacy of mitotane is unsatisfactory with an objective response rate of ≈20% in monotherapy in selected patients (Megerle et al., JCEM 2018). Cytotoxic chemotherapy with etoposide, doxorubin and cisplatin (EDP) or streptozotocin (Sz) in addition to mitotane (Fassnacht et al., N Engl J Med 2012) succeeded in a progression-free survival of 5.6 months and 2.2 months, respectively in patients with advanced ACC. Objective response rates were 23 and 9%. EDP plus mitotane is therefore considered as standard treatment of ACC. Results by Phan et al. (Cancer Research 2015) demonstrated expression of c-MET and its ligand HGF in ACC and provide a rationale to therapeutically target c-MET in ACC. In a case series of 16 patients with advanced ACC refractory to mitotane (with the exception of one case) and 3 (median, range 0-8)further lines of therapy, single agent treatment with cabozantinib off label resulted in three partial responses and five additional cases of disease stabilization for four months or longer (Kroiss et al., J Clin Endocrinol Metab 2020).

Conditions

Adrenocortical Carcinoma

Keywords

adrenal cancer; adrenal cortex neoplasm; adrenal cortical carcinoma; cabozantinib; c-MET

Outcome Measures

Primary Outcomes (1)

• progression free survival at 4 months

  4 months

Secondary Outcomes (7)

• Objective Response Rates (ORR)

  12 months

• Duration of response (DR)

  12 months

• progression-free survival

  12 months

• overall survival

  12 months

• best percentage change in size of target lesions

  12 months

Study Arms (1)

Cabozantinib

EXPERIMENTAL

oral cabozantinib as tablets continuously (60 mg single dose, tablets)

Drug: Cabozantinib-s-malate

Interventions

Cabozantinib-s-malate DRUG

oral cabozantinib-S-malate 60 mg as a daily single oral dose continuously

Cabozantinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological confirmation of ACC based on either:
• i) Weiss Score of ≥ 3 in patients who had earlier surgical resection (Lin-Weiss-Bisceglia system will be used for oncocytic ACC) OR ii) biopsy results compatible with ACC in the context of clinical setting highly suggestive of ACC (adrenal mass \> 4 cm invading surrounding organs or associated with distant metastases).
• Locally advanced or metastatic disease not amenable to surgery with curative intent with measurable disease per RECIST 1.1 37 as determined by the investigator based on an assessment of all known disease sites by computerized tomography (CT) scan or magnetic resonance imaging (MRI) of chest/abdomen/pelvis within 28 days before the first dose of cabozantinib
• Received prior treatment with mitotane and platinum containing chemotherapy. Patients in whom mitotane and/or platinum containing chemotherapy is contraindicated or who refused treatment with mitotane and/or platinum containing chemotherapy are eligible for the study.
• Documented progressive disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy
• Life expectancy of at least 3 months
• Adequate organ and bone marrow function and laboratory values as follows within 14 days prior to the first dose of cabozantinib:
• Absolute neutrophil count (ANC) ≥ 1500/μL without colony stimulating factor support, white blood cell count ≥ 2500/μL.
• Platelets ≥ 100,000/μL without transfusion
• Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL
• Serum albumin ≥ 2.8 g/dl
• (PT)/INR or partial thromboplastin time (PTT) test \< 1.3 x the laboratory ULN

You may not qualify if:

• Received cytotoxic chemotherapy, or targeted therapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies), or other investigational agent within 14 days before study treatment.
• Prior treatment with cabozantinib or other cMET inhibitors
• Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 6 weeks before first dose of study treatment.
• Subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy.
• \- Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis).
• Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Corticosteroid replacement treatment is allowed with dose at the discretion of the investigator.
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• The use of strong CYP3A4 inhibitors (with the exception of ketoconazole).
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose of study treatment. b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment.
• Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment.
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.

Sponsors & Collaborators

• Wuerzburg University Hospital: lead

Study Sites (2)

University Hospital Munich, Department of Internal Medicine IV

München, 80336, Germany

Location

University Hospital Würzburg

Würzburg, 97080, Germany

Location

Related Publications (2)

• Phan LM, Fuentes-Mattei E, Wu W, Velazquez-Torres G, Sircar K, Wood CG, Hai T, Jimenez C, Cote GJ, Ozsari L, Hofmann MC, Zheng S, Verhaak R, Pagliaro L, Cortez MA, Lee MH, Yeung SC, Habra MA. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma. Cancer Res. 2015 Oct 1;75(19):4131-42. doi: 10.1158/0008-5472.CAN-14-3707. Epub 2015 Aug 17.

  PMID: 26282167 BACKGROUND

• Kroiss M, Megerle F, Kurlbaum M, Zimmermann S, Wendler J, Jimenez C, Lapa C, Quinkler M, Scherf-Clavel O, Habra MA, Fassnacht M. Objective Response and Prolonged Disease Control of Advanced Adrenocortical Carcinoma with Cabozantinib. J Clin Endocrinol Metab. 2020 May 1;105(5):1461-8. doi: 10.1210/clinem/dgz318.

  PMID: 31900481 BACKGROUND

Related Links

• Wuerzburg University Hospital

MeSH Terms

Conditions

Adrenocortical Carcinoma; Adrenal Gland Neoplasms; Adrenal Cortex Neoplasms

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Adrenal Cortex Diseases; Adrenal Gland Diseases; Endocrine System Diseases

Study Officials

• Matthias Kroiss, MD, PhD

  Wuerzburg University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2018
• First Posted: August 2, 2018
• Study Start: June 4, 2019
• Primary Completion: December 31, 2024
• Study Completion: April 30, 2025
• Last Updated: August 19, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

DE (2)