Cabozantinib in High Grade Neuroendocrine Neoplasms
Cabozantinib in High Grade Neuroendocrine Neoplasms
High grade neuroendocrine neoplasm patients are treated with platinum doublets such as
 carboplatin and etoposide mimicking the current guidelines for small cell lung cancer (SCLC).
 Unfortunately, recurrences are common and most patients with metastatic disease succumb to it
 within a year. There is no extensive literature or consensus on second- or third-line options
 (which include FOLFOX, FOLFIRI, capecitabine and temozolomide, taxanes or immunotherapy) and
 there is urgent need for better regimens.
Inclusion Criteria:

 -Histologically or cytologically confirmed high-grade neuroendocrine tumor that has
 progressed on first line 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.

 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

 -  Hemoglobin ≥ 9.0 g/dL

 -  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.

 -  The effects of cabozantinib on the developing human fetus are unknown. For this
 reason, women of childbearing potential and men must agree to use adequate
 contraception (e.g. barrier methods, including male condom, female condom, or
 diaphragm with spermicidal gel) prior to study entry, for the duration of study
 participation, and for 4 months after the last dose of study treatment. Should a woman
 become pregnant or suspect she is pregnant while participating in this study, she must
 inform her treating physician immediately. Men treated or enrolled on this protocol
 must also agree to use adequate contraception prior to the study, for the duration of
 the study, and for at least 4 months after the last dose of study treatment.

 -  Ability to understand and willingness to sign an IRB approved written informed consent
 document (or that of legally authorized representative, if applicable).

 -  Patient 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.

 -  Patients with treated brain metastases are eligible if there is no evidence of
 progression for at least 4 weeks after CNS-directed treatment, as ascertained by
 clinical examination and brain imaging (MRI or CT scan) during the screening period.
 Eligible subjects must be neurologically asymptomatic and without corticosteroid
 treatment at the time of 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. GI surgery removal or biopsy of brain metastasis) within
 8 weeks before first dose of study treatment. Complete wound healing from
 major surgery must have occurred 1 month before first dose and from minor
 surgery (e.g., simple excision, tooth extraction) at least 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). Patients with
 clinically relevant ongoing complications from prior surgery are not
 eligible.

 -  Pregnant and/or breastfeeding. Women of childbearing potential must have a
 negative pregnancy test within 15 days of study entry. Women of childbearing
 potential are defined as premenopausal females capable of becoming pregnant
 (i.e., females who have had any evidence of menses in the past 12 months,
 with the exception of those who had prior hysterectomy or bilateral
 oophorectomy). However, women who have been amenorrheic for 12 or more
 months are still considered to be of childbearing potential if the
 amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body
 weight, ovarian suppression, or other reasons.

 -  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. Recommend exclusion of specific ART agents based
 on predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates,
 concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers
 (efavirenz) should be contraindicated).