Clinical Trials /

Cabozantinib in High Grade Neuroendocrine Neoplasms

NCT04412629

Description:

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.

Related Conditions:
  • Neuroendocrine Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in High Grade Neuroendocrine Neoplasms
  • Official Title: Cabozantinib in High Grade Neuroendocrine Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: 20-x195
  • NCT ID: NCT04412629

Conditions

  • High Grade Neuroendocrine Neoplasms

Interventions

DrugSynonymsArms
CabozantinibCabometyxCabozantinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
CabozantinibExperimental-Cabozantinib 60 mg by mouth daily on days 1-21
  • Cabozantinib

Eligibility Criteria

        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 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
             within 28 days before the first dose of study treatment).

          -  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).

        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 l ow-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.

               -  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. 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). 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 HIV 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Through the end of treatment (estimated to be 4 months)
Safety Issue:
Description:ORR is defined as number of patients with complete response or partial response Complete response - Disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response - At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:Through completion of follow-up (estimated to be 1 year)
Safety Issue:
Description:-OS is defined as days from date of treatment to date of death. Patients alive or lost to follow-up are censored at the follow-up date.
Measure:Progression-free survival (PFS)
Time Frame:Through completion of follow-up (estimated to be 1 year)
Safety Issue:
Description:PFS is defined as the days from the date of treatment and death or progression, which occurs first. Patients alive without progression or lost to follow-up are censored at the last follow-up date. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Measure:Safety of regimen as measured by incidence of adverse events
Time Frame:From start of treatment through 30 days after last dose of study treatment (estimated to be 5 months)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

May 28, 2020