Trial of Cabozantinib (XL184) in Non-Small Cell Lung Cancer With Brain Metastases

Stopped early · Phase 2

Conditions studied: Non Small Cell Lung Cancer (NSCLC), Metastases to the Brain

In brief

This is an open-label phase II clinical trial designed to allow a preliminary assessment of the efficacy and safety of cabozantinib in unselected Non-Small Cell Lung Cancer (NSCLC) patients with metastases to the brain and in the subset of patients with c-MET amplified Non-Small Cell Lung Cancer with metastases to the brain. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating investigator. Patients who have undergone treatment for their brain metastases with Whole-Brain Radiation Therapy (WBRT), stereotactic radiosurgery (SRS) or surgery must be clinically stable and recovered from all procedures at the time of study enrollment.

Key facts

Study ID

NCT02132598

Run by

Liza Villaruz, MD

People needed

5

Starts

2015-12-01

Expected to finish

2019-08-09

Last updated by the study team

2021-03-10

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. (Patients must have received at least one regimen for systemic disease which may be cytotoxic or oral tyrosine kinase inhibitor therapy.)
• Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating physician
• Patients who have undergone treatment for their brain metastases with whole brain radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable and recovered from all procedures at the time of study enrollment.
• Patients must have tumor tissue available for submission that is sufficient to complete c-MET Fluorescence in Situ Hybridization (FISH) studies as well as routine molecular profiling at the UPMC. Patients must agree to submission of these specimens as defined in Section 9.
• c-MET amplification will be determined by FISH ratio (c-MET/CEP7) > 2.0, based on testing of the primary tumor and/or site of metastatic disease
• Patients' tumors must undergo testing for Epidermal Growth Factor Receptor (EGFR) exon 19 deletion, EGFR exon 21 L858R substitution, and anaplastic lymphoma kinase (ALK) rearrangements. If positive, patients must have been treated with an appropriate tyrosine kinase inhibitors (TKI) prior to enrolling to the study.
• The subject has had an assessment of all extracranial disease sites (e.g., by computerized tomography (CT) scan, positron emission tomography-CT, and bone scan as appropriate) within 28 days before the first dose of cabozantinib.
• The subject must have a baseline brain MRI scan or CT scan of the head (in patients unable to obtain an MRI) within 14 days prior to first dose of cabozantinib.
• Patients receiving glucocorticoids must be on a stable dose of glucocorticoids during the 5 days prior to the baseline brain imaging.
• Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Subjects having undergone recent resection or biopsy of an intracranial tumor will be eligible as long as all of the following conditions apply:
• First dose of cabozantinib occurs at least 28 days after surgery, and the subject has recovered from the effects of surgery
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%)
• Patients must have normal organ and marrow function as defined below: (within 4 days of beginning treatment unless noted otherwise)
• Hemoglobin ≥9 g/dL
• Absolute Neutrophil Count (ANC) ≥1,500/mm3 (no CSF support)
• Platelets ≥100,000/mm3
• Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Bilirubin (Gilbert's Disease) < 3.0 mg/dL
• Aspartate Aminotransferase (AST) (SGOT) ≤3.0 × ULN
• Alanine Aminotransferase (ALT) (SGPT) ≤3.0 × ULN
• Serum creatinine ≤ 1.5 x ULN
• Creatinine clearance (CrCl) ≥40 mL/min
• For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

You may not qualify if…

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies; including investigational biologic agents) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.
• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.
• Prior treatment with cabozantinib or other c-MET directed therapy.
• The subject has received radiation therapy as follows:
• To the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has with ongoing complications or is without complete recovery and healing from prior radiation therapy
• To bone or brain metastasis within 14 days of the first dose of study treatment
• To any other site(s) within 28 days of the first dose of study treatment
• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment.
• The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
• The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment.
• The subject is receiving concomitant treatment with warfarin, warfarin-related agents, or low molecular weight heparin (LMWH) at the time of study entry at therapeutic doses. Low-dose warfarin (≤ 1 mg/day) or LMWH at prophylactic doses are permitted.
• The subject has received enzyme-inducing anti-epileptic agents within 2 weeks before the first dose of cabozantinib (e.g., carbamazepine, phenytoin, phenobarbital, primidone). Other enzyme inducing agents prohibited within 2 weeks before the first dose of cabozantinib include rifampin, rifabutin, rifapentin, and St. John's Wort.
• The subject has experienced any of the following:
• Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment b.Hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment
• Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The subject has radiographic evidence of cavitating pulmonary lesion(s)
• The subject has tumor abutting, invading or encasing any major blood vessels.
• The subject has evidence of tumor invading the Gastro Intestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening
• Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
• Any history of congenital long QT syndrome
• Any of the following within 6 months before the first dose of study treatment:
• unstable angina pectoris 2.clinically-significant cardiac arrhythmias 3.stroke (including Transient Ischemic Attack (TIA), or other ischemic event) 4.myocardial infarction (MI) 5.thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)

Where it is running

• University of Pittsburgh Cancer Institute- Hillman Cancer Center — Pittsburgh, Pennsylvania, United States

Full record on ClinicalTrials.gov

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