Inclusion Criteria:
-Histologically or cytologically confirmed high-grade neuroendocrine tumor that has
progressed after at least one line of therapy, excluding small cell lung cancer (SCLC).
High grade includes any neuroendocrine neoplasm with a Ki-67 of >=20% or with mitotic count
of more than 20 mitoses per high power field or any poorly differentiated neoplasm or any
neoplasm lacking these that is deemed high grade by pathology consensus, based on other
markers (necrosis or IHC demonstrating p53 or RB mutation). This includes:
- - High grade well differentiated neuroendocrine neoplasms.
- - Transformed NENs from a lower to a higher grade (patient may have some low grade and
some high grade NENs)
- High grade neoplasms with significant expression of neuroendocrine markers such as
synaptophysin, chromogranin or INSM-1 or unknown origin neoplasms with gene expression
signatures consistent with neuroendocrine lineage (as per validated tissue of origin
testing, such as CancerType ID, after pathology consensus).
- - Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNEN), including MiNEN per WHO
and mixed neoplasms not fulfilling criteria of MiNEN.
The neuroendocrine component
would need to be a high-grade neuroendocrine tumor as documented by pathology review.
Note: Up to two prostate NEC patients (primary diagnosis, not transformed adenocarcinoma)
will be enrolled in the first phase. For the second phase, non gastroenteropancreatic or
lung histologies will be approved by PI.
Note: For ambiguous cases, will consult with a designated expert pathologist.
- - Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by
chest x-ray, or ≥ 10 mm with calipers by clinical exam.
- - Concurrent or prior somatostatin analogue therapy is allowed (for well differentiated
high grade neoplasms).
Prior use of investigational agents is allowed.
- - At least 18 years of age.
- - ECOG performance status ≤ 1 (Karnofsky ≥ 80%)
- Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating
factor support.
- - White blood cell count ≥ 2,500/mm3.
- - Platelets ≥ 100,000/mm3 without transfusion.
- - AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x
IULN with documented bone metastases.
- - Total bilirubin ≤ 1.5 x IULN (for subjects with gilbert's disease ≤ 3.0 x IULN)
- Serum albumin ≥ 2.8 g/dL.
- - Serum creatinine ≤ 2.0 x IULN or calculated creatinine clearance ≥ 30 mL/min by
Cockcroft-Gault.
- - Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
- PT/INR or PTT < 1.3 x IULN (within 7 days before the first dose of study
treatment)
- Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG)
- Recovery to baseline or ≤ grade 1 from toxicities related to any prior treatments,
unless adverse events are clinically nonsignificant and/or stable on supportive
therapy as per discussion with PI.
- - Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of study treatment.
- - Female subjects of childbearing potential must not be pregnant at screening.
Female
subjects are considered to be of childbearing potential unless one of the following
criteria are met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined
as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other
biological or physiological causes. In addition, females < 55 years-of-age must have a
serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause).
- - Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).
- - Willing to undergo 3 mandatory biopsies: in screening, on treatment prior to C2, and
at EOT, if safe and feasible.
Exclusion Criteria:
- - A history of other malignancy with the exception of malignancies for which all
treatment was completed at least 2 years before registration and the patient has no
evidence of disease.
Allowed are superficial skin cancers, or localized, low grade
tumors deemed cured and not treated with systemic therapy at any point in the prior
year.
- - Currently receiving any other investigational agents.
Prior use of investigational
agents is allowed.
- - Prior treatment with cabozantinib.
- - Receipt of any small molecule kinase inhibitor (including investigational kinase
inhibitor) within 2 weeks before the first dose of study treatment.
- - Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment.
- - Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
within 4 weeks before the first dose of study treatment.
Systemic treatment with
radionuclides within 6 weeks before the first dose of study treatment. Patients with
clinically relevant ongoing complications from prior radiation therapy are not
eligible.
- - 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.
- - Inability to swallow tablets.
- - A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cabozantinib or other agents used in the study.
- - 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.
- - Uncontrolled, significant intercurrent or recent illness including, but not limited
to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- - Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment.
- - 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.
- - Subjects with a diagnosis of incidental, subsegmental PE or DVT within
6 months are allowed if stable, asymptomatic, and treated with
anticoagulation for at least 1 week before first dose of study
treatment.
Prior liver-directed therapy within 6 months is also allowed
unless patient experienced significant complications, at PI discretion.
- - Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- 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.
- - Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose.
Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose.
- - Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage)
within 12 weeks before first dose.
- - Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
- - Lesions invading or encasing any major blood vessels.
- - Other clinically significant disorders that would preclude safe study participation.
- - Serious non-healing wound/ulcer/bone fracture.
- - Uncompensated/symptomatic hypothyroidism.
- - Moderate to severe hepatic impairment (Child-Pugh B or C).
- - Major surgery (e.g. laparascopic nephrectomy, GI surgery removal or biopsy
of brain metastasis) within 2 weeks before first dose of study treatment.
Minor surgeries 10 days before first dose (with the exception of the
baseline biopsy, which must have occurred no less than 6 days prior to the
first dose). Subjects must have complete wound healing from major or minor
surgery before first dose of study treatment. Patients with clinically
relevant ongoing complications from prior surgery are not eligible.
- - Pregnant and/or breastfeeding.
- - Patients with known HIV infection are eligible unless their CD4+ T-cell
counts are < 350 cells/mcL or they have a history of AIDS-defining
opportunistic infection within the 12 months prior to registration.
Concurrent treatment with effective ART according to DHHS treatment
guidelines is recommended.
