Cabozantinib in Advanced Adrenocortical Carcinoma

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT03612232

Studienbeginn:
Juni 2019

Letztes Update:
15.07.2022

Wirkstoff:
Cabozantinib-s-malate

Indikation (Clinical Trials):
Carcinoma, Adrenocortical Carcinoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Wuerzburg University Hospital

Collaborator:
-

Studienleiter

Matthias Kroiss, MD, PhD
Principal Investigator
Wuerzburg University Hospital

Kontakt

Matthias Kroiss, MD, PhD
Kontakt:
Phone: +4993120139740
E-Mail: Kroiss_M@ukw.de» Kontaktdaten anzeigen

Martin Fassnacht, MD
Kontakt:
Phone: +49931201-39200
E-Mail: Fassnacht_M@ukw.de» Kontaktdaten anzeigen

Studienlocations
(2 von 2)

University Hospital Munich, Department of Internal Medicine IV
80336 München
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Matthias Kroiss, MD, PhD
Phone: +4989440052221
E-Mail: matthias.kroiss@med.lmu.de

Jacqueline Putz
Phone: +4989440052414
E-Mail: jacqueline.putz@med.lmu.de» Ansprechpartner anzeigen

University Hospital Würzburg
97080 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Martin Fassnacht, MD
Phone: +4993120139200
E-Mail: Fassnacht_M@ukw.de

Miriam Reuter, MD
Phone: +4993120140763
E-Mail: Reuter_M1@ukw.de» Ansprechpartner anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

Inclusion criteria:

- 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:

1. Absolute neutrophil count (ANC) ≥ 1500/μL without colony stimulating factor

support, white blood cell count ≥ 2500/μL.

2. Platelets ≥ 100,000/μL without transfusion

3. Hemoglobin ≥ 9 g/dL

4. Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known

Gilbert's disease, bilirubin ≤ 3.0 mg/dL

5. Serum albumin ≥ 2.8 g/dl

6. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN

7. 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

8. 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.

9. 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

Exclusion criteria:

- 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).

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:

1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable

guidelines) and low-dose low molecular weight heparins (LMWH).

2. 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.

- 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.

1. Serious non-healing wound/ulcer/bone fracture.

2. Uncompensated/symptomatic hypothyroidism.

3. Severe and uncontrolled Cushing's syndrome despite medical management (e.g.

systolic blood pressure >160 mmHg, hyperglycemia with fasting glucose >300 mg/dL)

4. 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.

Studien-Rationale

Primary outcome:

1. progression free survival at 4 months (Time Frame - 4 months)

Secondary outcome:

1. Objective Response Rates (ORR) (Time Frame - 12 months)

2. Duration of response (DR) (Time Frame - 12 months)

3. progression-free survival (Time Frame - 12 months)

4. overall survival (Time Frame - 12 months)

5. best percentage change in size of target lesions (Time Frame - 12 months)

6. treatment emergent adverse events (CTC-AE 4.03) (Time Frame - 12 months)

7. quality of life by EORTC QLQ-C30 (Time Frame - 12 months)

Geprüfte Regime

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

Quelle: ClinicalTrials.gov

Sie können folgenden Inhalt einem Kollegen empfehlen:

"Cabozantinib in Advanced Adrenocortical Carcinoma"

Bitte tragen Sie auch die Absenderdaten vollständig ein, damit Sie der Empfänger erkennen kann.

Die mit (*) gekennzeichneten Angaben müssen eingetragen werden!