Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study (CABATEN)

  • STATUS
    Recruiting
  • End date
    Mar 24, 2024
  • participants needed
    144
  • sponsor
    Grupo Espanol de Tumores Neuroendocrinos
Updated on 24 March 2022
insulin
platelet count
cancer
absolute neutrophil count
metastatic disease
measurable disease
carcinoma
somatostatin
lung cancer
gilbert's syndrome
serum bilirubin
adrenaline
metastasis
neutrophil count
cabozantinib
liver metastasis
chemotherapy regimen
liver metastases
paraganglioma
pheochromocytoma
biological therapy
vascular endothelial growth factor
growth factors
neuroendocrine carcinoma
basic fibroblast growth factor
atezolizumab
neuroendocrine tumor
radionuclide therapy
carcinoid
carcinoid tumor
insulin-like growth factor 1 (igf-1)
prrt
cabozantinib 40 mg
adrenal pheochromocytoma
hepatic pathology

Summary

CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system.

The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) evaluated following RECIST v1.1 criteria in advanced endocrine tumors.

Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal gland and paraganglia) are characterized by being remarkably vascular and expressing several growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF), and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the resistance to prior antiangiogenic drugs.

The trial will include patients with advanced and refractory tumors of endocrine system and patients would be allocated to six different cohorts according to the following tumor types.

Description

CABATEN is a multicohort phase II study of cabozantinib plus atezolizumab in advanced and progressive tumors from endocrine system.

Hypothesis

The main hypothesis is that the administration of cabozantinib plus atezolizumab will improve the probability of expected objective response rate in advanced and refractory tumors of the endocrine system.

Objectives

The primary objective is to assess the efficacy of cabozantinib plus atezolizumab combination by means of radiological objective response rate (ORR) evaluated following RECIST v1.1 criteria in advanced endocrine tumors. Secondary objectives include:

  • To evaluate the safety profile of cabozantinib and atezolizumab combination, according to NCI-CTCAE V5.0.
  • Duration of response (DoR) as per RECIST V1.1.
  • Progression-free survival (PFS): median PFS as per RECIST V1.1.
  • Overall Survival (OS): median OS as per RECIST V1.1.
  • Tumor biomarkers: translational sub-study (optional).
    Treatment

All the subjects will be treated with the combination until disease progression, unacceptable toxicity, or patient consent withdrawal (whichever occurs first):

  • Cabozantinib 40 mg or 20 mg tablets, oral administration once daily continuously.
  • Atezolizumab 1200 mg administered intravenously (IV) every three weeks (cycle).
    Rationale

Endocrine tumors from different origins (thyroid, lung, pancreas and digestive tract, adrenal gland and paraganglia) are characterized by being remarkably vascular and expressing several growth factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (BFGF), and transforming growth factor (TGF)-α and -β. The (over) expression of some of these factors has been linked to poor prognosis. Cabozaninib, a VEGF inhibitor, in combination with atezolizumab, an inhibitor of PD-L1, may be active in endocrine tumors by overcoming the resistance to prior antiangiogenic drugs.

Patients allocation:

The trial will include patients with advanced and refractory tumors of endocrine system and patients would be allocated to six different cohorts according to the following tumor types:

Cohort 1: Well-differentiated neuroendocrine tumors of the lung and thymus (grades 1 and 2) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or investigational drugs.

Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane.

Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor radionuclide therapy (PRRT) if indicated, prior chemotherapy and biological therapy, such as somatostatin analogs, are allowed.

Cohort 5: Well-differentiated neuroendocrine tumors of digestive system after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy.

Cohort 6: Grade 3 neuroendocrine neoplasm of any origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT.

Details
Condition Neuroendocrine Tumor, Anaplastic Thyroid Cancer, Adenocarcinoma, Pheochromocytoma, Paraganglioma
Treatment Cabozantinib 40 MG
Clinical Study IdentifierNCT04400474
SponsorGrupo Espanol de Tumores Neuroendocrinos
Last Modified on24 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Male or female subjects ≥ 18 years old
Willingness to participate in the study by signing informed consent form (ICF) approved by the trial Central Ethic Committee (CEIm)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Measurable disease per RECIST 1.1 as determined by the investigator
Patients with an histopathologically confirmed disease (as per local pathology report), meeting one of the following (according to WHO 2010 classification)
Cohort 1: Well-differentiated neuroendocrine tumours of the lung and thymus (WHO grade 1 and 2, typical and atypical carcinoids) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy
Cohort 2: Anaplastic thyroid cancer in first-line or after progression to chemotherapy or investigational drugs. Primary tumour can be resected or not but risk of aerodigestive compression or bleeding should be ruled out
Cohort 3: Adrenocortical carcinoma after progression to chemotherapy and/or mitotane
Cohort 4: Pheochromocytoma and paraganglioma after progression to peptide receptor radionuclide therapy (PRRT) if indicated. Prior chemotherapy and biological therapy, such as somatostatin analogs, are allowed
Cohort 5: Well-differentiated neuroendocrine tumours of digestive system (WHO grade 1 and 2) after progression to somatostatin analogs, targeted agents, PRRT, and/or chemotherapy
Cohort 6: Grade 3 neuroendocrine neoplasm (WHO grade 3, including neuroendocrine (NET) and neuroendocrine carcinomas (NEC) G3) of any origin, excluding small cell lung cancer, after progression to chemotherapy or targeted agents/PRRT
Recovery from toxicity related to any prior treatments to ≤ Grade 1, unless the
Ability to swallow tablets
adverse events (AEs) are clinically non-significant and/or stable on
Adequate normal organ and marrow function as defined below
supportive therapy
Absolute neutrophil count (ANC) > 1500 per mm
Haemoglobin ≥ 9.0 g/dL
Platelet count ≥ 100,000 per mm
Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance
Serum bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician
Aspartate Transaminase (AST) (SGOT)/Alanine aminotransferase (ALT) (SGPT) ≤ 2.5x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3x ULN
Males should agree to abstain from sexual intercourse with a female partner or agree to use a double barrier method of contraception (i.e.condom with spermicide, in addition to having their female partner use some contraceptive measures such as, intrauterine device (IUD) or cervical caps), for the duration of the study and for 4 months after participation in the study
Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up
Female subjects of childbearing potential (not surgically sterile or at least 2 years
postmenopausal) must provide a negative urine pregnancy test at Screening, and
use a medically accepted double barrier method of contraception (i.e condom
with spermicide \+ IUD or cervical caps). In addition, they must agree to
continue the use of this double barrier method for the duration of the study
and for 4 months after participation in the study

Exclusion Criteria

Prior treatment with cabozantinib or any immune checkpoint inhibitor therapy (e.g, CTLA4, PD-1, or PD-L1 targeting agent)
Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer. Patients should have been out of mitotane for at least 4 weeks
Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 2 weeks before starting treatment
Current or prior use of immunosuppressive medication within 2 weeks before the first dose of cabozantinib and atezolizumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
Active or prior documented autoimmune disease within the past 2 years. Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis)
History of allogeneic organ transplant
Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment
Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before inclusion. Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not eligible (e.g, radiation esophagitis or other inflammation of the viscera)
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before inclusion. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of study treatment
Concomitant anticoagulation with oral anticoagulants (e.g, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (e.g, clopidogrel), except for the following allowed anticoagulants
Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases and who are on a stable dose of LMWH for at least 6 weeks before inclusion and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumour
Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by the New York Heart Association, unstable angina pectoris, and serious cardiac arrhythmias
The subject has uncontrolled, significant intercurrent or recent illness including
but not limited to, the following conditions
b. Gastrointestinal disorders (e.g, malabsorption syndrome or gastric outlet
ii. Uncontrolled hypertension defined as sustained blood press > 150 mm hg systolic or
> 100 mm hg diastolic despite optimal antihypertensive treatment
iii. Stroke, including transient ischemic attack (TIA), myocardial infarction, other
ischemic event, or thromboembolic event, e.g, deep venous thrombosis (DVT) and
pulmonary embolism) within 6 months before inclusion. Subjects with a more recent
diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at
least 6 weeks before study treatment
obstruction) including those associated with a high risk of perforation or fistula
formulation: i. Tumours invading the GI tract, active peptic ulcer disease
inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis
symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of
the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula
GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before
inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed
prior to start of the treatment
c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) of
red blood or history of other significant bleeding within 3 months before treatment
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. e
Lesions invading major pulmonary blood vessels. f. Other clinically significant
disorders such as: i. Active infection requiring systemic treatment, infection with
human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or
chronic hepatitis B or C infection
ii. Serious non-healing wound/ulcer/bone fracture. iii. Moderate to severe hepatic
impairment (child-pugh B or C). iv. Requirement for hemodialysis or peritoneal
dialysis. v. Uncontrolled diabetes mellitus. vi. History of solid organ
transplantation
Major surgery (e.g, GI surgery and removal or biopsy of brain metastasis) within 8
weeks before inclusion. Complete wound healing from major surgery must have occurred 4
weeks before study treatment and from minor surgery (e.g, simple excision, tooth
extraction) at least 10 days before 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 within 28
days before study treatment
Note: if a single ECG shows a QTCf with an absolute value > 500 ms, two additional
ECGs at intervals of approximately 3 min must be performed within 30 min after the
initial ECG, and the average of these 3 consecutive results for qtcf will be used to
determine eligibility
Pregnant or lactating females
Inability to swallow tablets
Previously identified allergy or hypersensitivity to components of the study treatment
formulations
Diagnosis of another malignancy within 3 years before study treatment, except for
superficial skin cancers, or localized, low grade tumors deemed cured and not treated
with systemic therapy
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