Adrenocortical CarcinomaPhase 2CaboACCNCT03612232
Cabozantinib in Advanced Adrenocortical Carcinoma
A Phase 2 study testing Cabozantinib-s-malate in people with Adrenocortical Carcinoma, run by Wuerzburg University Hospital at 2 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adrenocortical Carcinoma
- What is being tested?
- Cabozantinib-s-malate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 2 sitesGermany
- Study dates
- 4 Jun 2019to 30 Apr 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histological confirmation of ACC based on either:
- 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
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- 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
- Serum creatinine ≤ 2.0 × ULN or creatinine clearance (CrCl) ≥ 30 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:
- Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72). Female:
- Multiply above result by 0.85
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). In case of liver metastases ALT and AST ≤ 5.0 x ULN are acceptable. ALP ≤ 5 x ULN with documented bone metastases.
- Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg), or 24-h urine protein ≤ 1 g
- Capable of understanding and complying with the protocol requirements.
- Women of childbearing potential* must have a negative pregnancy test at screening.
- Additional pregnancy testing will be performed in WOCBP at monthly intervals. Patients of reproductive potential (men and women) must agree to use highly effective methods of contraception during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. - Able to give written informed consent
Who cannot join
- 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.
- Treatment with mitotane <28 days prior study inclusion OR mitotane serum/plasma concentration documented of ≥2 mg/L at screening. Up to 5 mg/L are acceptable with Sponsor approval.
- 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).
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- 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:
- 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.
- Lesions invading or encasing any major blood vessels. In subjects with liver metastases and lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible
- Other clinically significant disorders that would preclude safe study participation.
- Serious non-healing wound/ulcer/bone fracture.
- Uncompensated/symptomatic hypothyroidism.
- Severe and uncontrolled Cushing's syndrome despite medical management (e.g. systolic blood pressure >160 mmHg, hyperglycemia with fasting glucose >300 mg/dL)
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) or dental surgery/invasive dental procedures within 28 days before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment [add reference for Fridericia formula].
- Pregnant or lactating females
- Inability to swallow tablets.
- Previously identified allergy or hypersensitivity to components of the study treatment formulations.
- Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 2 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality which, in the judgment of the investigator, would have made the patient inappropriate for entry into this study
- Any other severe acute or chronic medical or psychiatric condition or laboratory ab normality which, in the judgment of the investigator, would have made the patient inappropriate for entry into this study.
Trial locations and contacts
2 sites in 1 country.
Germany2 sites
University Hospital Munich, Department of Internal Medicine IV
München, 80336
University Hospital Würzburg
Würzburg, 97080
About this study
Official title: A Multicenter, Open-label, Phase II Study to Evaluate the Efficacy and Safety of Cabozantinib in Advanced (Unresectable or Metastatic) Adrenocortical Carcinoma
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
- Being tested
- Cabozantinib-s-malate
- Keywords
- adrenal cancer, adrenal cortex neoplasm, adrenal cortical carcinoma, cabozantinib, c-MET
- Medical subject headings
- Adrenocortical Carcinoma, Adrenal Gland Neoplasms, Adrenal Cortex Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cabozantinib-s-malateDrug
oral cabozantinib-S-malate 60 mg as a daily single oral dose continuously
| Study group | Role | What they receive |
|---|---|---|
| Cabozantinib | Experimental | oral cabozantinib as tablets continuously (60 mg single dose, tablets) Receives: Drug: Cabozantinib-s-malate |
What is being measured
The primary outcome is the main question the study is designed to answer.
progression free survival at 4 months
Measured: 4 months
Secondary outcomes (7)
Objective Response Rates (ORR)
Measured: 12 months
Duration of response (DR)
Measured: 12 months
progression-free survival
Measured: 12 months
overall survival
Measured: 12 months
best percentage change in size of target lesions
Measured: 12 months
treatment emergent adverse events (CTC-AE 4.03)
Measured: 12 months
quality of life by EORTC QLQ-C30
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2018
- Study start4 Jun 2019
- Primary completion31 Dec 2024 (estimated)
- Study completion30 Apr 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Adrenocortical CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 37 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Wuerzburg University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Matthias Kroiss, MD, PhD, Study director, Wuerzburg University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03612232
- Sponsor's protocol ID
- CaboACC
- Acronym
- CaboACC
- Status last verified
- Dec 2023
- First submitted
- 12 Jul 2018
- Last updated
- 19 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 26282167Kroiss 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.
PubMed 31900481
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Open-label, Phase II Study to Evaluate the Efficacy and Safety of Cabozantinib in Advanced (Unresectable or Metastatic) Adrenocortical Carcinoma
- ClinicalTrials.gov ID
- NCT03612232
- Acronym / sponsor ID
- CaboACC / CaboACC
- Conditions
- Adrenocortical Carcinoma
- Keywords
- adrenal cancer, adrenal cortex neoplasm, adrenal cortical carcinoma, cabozantinib, c-MET
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 37 participants (estimated)
- Lead sponsor
- Wuerzburg University HospitalUniversity, hospital or other
- Study start
- 4 Jun 2019 (actual)
- Primary completion
- 31 Dec 2024 (estimated)
- Study completion
- 30 Apr 2025 (estimated)
- First posted
- 2 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cabozantinib | Experimental | Drug: Cabozantinib-s-malateoral cabozantinib as tablets continuously (60 mg single dose, tablets) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Histological confirmation of ACC based on either:
- 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
Key exclusion criteria (29 listed)
- 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.
- Treatment with mitotane <28 days prior study inclusion OR mitotane serum/plasma concentration documented of ≥2 mg/L at screening. Up to 5 mg/L are acceptable with Sponsor approval.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cabozantinib-s-malateoral cabozantinib-S-malate 60 mg as a daily single oral dose continuously | Drug | Cabozantinib |
Primary outcome
progression free survival at 4 months
Time frame: 4 months
7 secondary outcomes
Objective Response Rates (ORR)
Time frame: 12 months
Duration of response (DR)
Time frame: 12 months
progression-free survival
Time frame: 12 months
overall survival
Time frame: 12 months
best percentage change in size of target lesions
Time frame: 12 months
treatment emergent adverse events (CTC-AE 4.03)
Time frame: 12 months
quality of life by EORTC QLQ-C30
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2024.
- Background: PubMed 26282167Phan 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.
- Background: PubMed 31900481Kroiss 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.
- Wuerzburg University HospitalLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Matthias Kroiss, MD, PhD study director
Wuerzburg University Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cabozantinib-s-malate in people with Adrenocortical Carcinoma, run by Wuerzburg University Hospital at 2 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
progression free survival at 4 months (time frame: 4 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03612232, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2024.