Clinical Trials /

Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma

NCT03370718

Description:

This phase II trial studies how well cabozantinib works in treating patients with adrenal cortex cancer that has spread to nearby tissue, lymph nodes, or other places in the body, and cannot be removed by surgery. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Adrenal Cortex Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in Treating Patients With Locally Advanced or Metastatic Unresectable Adrenocortical Carcinoma
  • Official Title: A Phase II Study to Evaluate the Effects of Cabozantinib in Patients With Unresectable/Metastatic Adrenocortical Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2016-0741
  • SECONDARY ID: NCI-2018-00973
  • SECONDARY ID: 2016-0741
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03370718

Conditions

  • Metastatic Carcinoma in the Adrenal Cortex
  • Stage III Adrenal Cortex Carcinoma AJCC v8
  • Stage IV Adrenal Cortex Carcinoma AJCC v8
  • Unresectable Adrenal Cortex Carcinoma

Interventions

DrugSynonymsArms
CabozantinibTreatment (cabozantinib)

Purpose

This phase II trial studies how well cabozantinib works in treating patients with adrenal cortex cancer that has spread to nearby tissue, lymph nodes, or other places in the body, and cannot be removed by surgery. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate progression free survival at 4 months.

      SECONDARY OBJECTIVES:

      I. Best overall response rate. II. Overall survival (OS). III. Toxicity assessment by the
      Common Terminology Criteria for Adverse Events (CTCAE) version (V)4.0.

      EXPLORATORY OBJECTIVES:

      I. Pharmacokinetics and cabozantinib serum levels to assess correlation with response to
      therapy.

      II. Steroid hormone biomarkers as markers of disease response. III. Study the effect of
      cabozantinib on immune markers by obtaining optional biopsy and blood samples collections at
      baseline, during therapy and at time of progression.

      IV. Pharmacogenomics of drug disposition gene variants that potentially influence
      cabozantinib pharmacokinetics (PK).

      OUTLINE:

      Patients receive cabozantinib orally (PO) once daily (QD) in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30-37 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib)ExperimentalPatients receive cabozantinib PO QD in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of adrenocortical carcinoma (ACC) based on either: i). Weiss
             Score of >= 3 in patients who had earlier surgical resection OR ii). biopsy results
             compatible with ACC in the context of clinical setting highly suggestive of ACC
             (adrenal mass > 4 cm invading surrounding organs or associated with distant
             metastases).

          -  Locally advanced or metastatic disease not amenable to surgery with curative intent
             with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
             as determined by the investigator based on an assessment of all known disease sites by
             computerized tomography (CT) scan or magnetic resonance imaging (MRI) of
             chest/abdomen/pelvis within 28 days before the first dose of cabozantinib. In patients
             with intravenous (IV) contrast allergy or borderline renal function, CT without IV
             contrast or 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) CT may
             be used as clinically indicated.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  Recovery to baseline or =< grade 1 CTCAE v.4.0 from toxicities related to any prior
             treatments, unless adverse events (AEs) are clinically nonsignificant and/or stable on
             supportive therapy.

          -  Life expectancy of at least 3 months.

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support
             (obtained within 28 days prior to the first dose of cabozantinib).

          -  Platelets >= 100,000/mm^3 (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Hemoglobin >= 9 g/dL (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Bilirubin =< 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert's
             disease, bilirubin =< 3.0 mg/dL (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Serum albumin >= 2.8 g/dl (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min. For
             creatinine clearance estimation, the Cockcroft and Gault equation should be used
             (obtained within 28 days prior to the first dose of cabozantinib).

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
             (obtained within 28 days prior to the first dose of cabozantinib).

          -  Lipase =< 2.0 x the upper limit of normal and no radiologic or clinical evidence of
             pancreatitis (obtained within 28 days prior to the first dose of cabozantinib).

          -  Urine protein/creatinine ratio (UPCR) =< 1 (obtained within 28 days prior to the first
             dose of cabozantinib).

          -  Serum phosphorus >= 2.5 mg/dl (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Calcium >= 8 mg/dL (obtained within 28 days prior to the first dose of cabozantinib).

          -  Magnesium >= 1.2 mg/dL (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Potassium >= 3.0 meq/L (obtained within 28 days prior to the first dose of
             cabozantinib).

          -  Capable of understanding and complying with the protocol requirements and has signed
             the informed consent document.

          -  Sexually active patients (men and women) must agree to use medically accepted barrier
             methods of contraception (e.g. male or female condom) during the course of the study
             and for 4 months after the last dose of study drug(s), even if oral contraceptives are
             also used. All sexually active subjects of reproductive potential must agree to use
             both a barrier method and a second method of birth control during the course of the
             study and for 4 months after the last dose of study drug(s).

          -  Women of childbearing potential must have a negative pregnancy test at screening.
             Women of childbearing potential include women who have experienced menarche and who
             have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is
             defined as amenorrhea >= 12 consecutive months. Note: 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, anti-estrogens, ovarian suppression
             or any other reversible reason.

        Exclusion Criteria:

          -  Received cytotoxic chemotherapy, radiation therapy, or targeted therapy (including
             investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or
             antibodies) within 28 days of study enrollment.

          -  For patients who received mitotane within 6 months of consenting, mitotane should have
             been stopped at least 28 days prior to study enrollment AND to have mitotane serum
             level of < 2 mg/L.

          -  Prior treatment with cabozantinib or other cMET inhibitors.

          -  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 the first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of the start of study
             treatment.

          -  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.

          -  Prothrombin time (PT)/ international normalized ratio (INR) or partial thromboplastin
             time (PTT) test >= 1.3 x the laboratory ULN within 28 days before the first dose of
             study treatment.

          -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
             and Factor Xa inhibitors), platelet inhibitors (e.g., clopidogrel) or therapeutic
             doses of low molecular weight heparins (LMWH). Low dose aspirin for cardioprotection
             (per local applicable guidelines) and low-dose LMWH are permitted. Anticoagulation
             with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH
             for at least 6 weeks before the first dose of study treatment, and who have had no
             clinically significant hemorrhagic complications from the anticoagulation regimen or
             the tumor.

          -  Severe and uncontrolled Cushing syndrome despite medical management (e.g., systolic
             blood pressure > 160 mmHg or hyperglycemia with fasting glucose above 300 mg/dL).

          -  The use of strong CYP3A4 inhibitor (with the exception of ketoconazole).

          -  The subject has experienced any of the following: a. clinically-significant
             gastrointestinal bleeding within 6 months before the first dose of study treatment; b.
             hemoptysis >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose
             of study treatment; c. any other signs indicative of pulmonary hemorrhage within 3
             months before the first dose of study treatment. Tumor invading any major blood vessel
             at the time of study enrollment.

          -  Evidence of tumor invading the gastrointestinal (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, or the subject with
             radiographic evidence of cavitating pulmonary lesion(s); or subjects with tumor
             invading or encasing any major blood vessels.

          -  Uncontrolled, significant concurrent or recent illness including, but not limited to,
             the following conditions: a. Cardiovascular disorders including i. congestive heart
             failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV
             (severe) at the time of screening ii. concurrent uncontrolled hypertension defined as
             sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite
             optimal antihypertensive treatment within 7 days of the first dose of study treatment
             iii. any history of congenital long QT syndrome or iv. any of the following within 6
             months before the first dose of study treatment: unstable angina pectoris,
             clinically-significant cardiac arrhythmias, stroke (including transient ischemic
             attack [TIA], or other ischemic event) within 90 days of the first dose of study
             treatment, myocardial infarction, clinically significant thromboembolic event within
             42 days of randomization requiring therapeutic anticoagulation.

          -  (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this
             study) b. gastrointestinal disorders particularly those associated with a high risk of
             perforation or fistula formation including: i. any of the following within 28 days
             before the first dose of study treatment: intra-abdominal tumor/metastases invading GI
             mucosa, active peptic ulcer disease; patients must be completely recovered,
             inflammatory bowel disease (including ulcerative colitis and Crohn's disease), acute
             pancreatitis, pancreatic duct or common bile duct obstruction, acute diverticulitis,
             acute cholecystitis, symptomatic cholangitis or recent appendicitis within 1 month of
             first dose of cabozantinib; patients must be completely recovered from these
             conditions, clinically significant malabsorption syndrome, c. endocrine disorders,
             uncontrolled Cushing syndrome despite of adequate medical therapy.

          -  Any of the following within 6 months before the first dose of study treatment:
             abdominal fistula, gastrointestinal perforation, bowel obstruction or gastric outlet
             obstruction, intra-abdominal abscess. Note: complete resolution of an intra-abdominal
             abscess must be confirmed prior to initiating treatment with cabozantinib even if the
             abscess occurred more than 6 months before the first dose of study treatment. Other
             disorders associated with a high risk of fistula formation including percutaneous
             endoscopic gastrostomy (PEG) tube placement within 90 days before the first dose of
             study therapy.

          -  Other clinically significant disorders such as: i. active infection requiring systemic
             antibiotic treatment within 14 days before the first dose of study treatment ii.
             serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of
             study treatment iii. history of organ transplant iv. concurrent uncompensated
             hypothyroidism or thyroid dysfunction (thyroid-stimulating hormone [TSH] above 10)
             within 28 days before the first dose of study treatment v. major surgery within 12
             weeks before the first dose of study treatment. Complete wound healing from major
             surgery must have occurred 1 month before the first dose of study treatment. Minor
             surgery within 28 days before the first dose of study treatment with complete wound
             healing at least 10 days before the first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior surgery are not eligible.

          -  Unable to swallow tablets.

          -  A corrected QT interval calculated by the Fridericia formula (QTcF) > 500 milliseconds
             within 28 days before first dose of study treatment. Three electrocardiograms (ECGs)
             must be performed for eligibility determination. If the average of these three
             consecutive results for QTcF is =< 500 milliseconds, the subject will be eligible.

          -  Pregnant or breastfeeding.

          -  A previously identified allergy or hypersensitivity to components of the study
             treatment formulation.

          -  Unable or unwilling to abide by the study protocol or cooperate fully with the
             investigator or designee.

          -  Evidence within 2 years of the start of study treatment of another malignancy which
             required systemic treatment except for breast ductal carcinoma-in situ, cured
             non-melanoma skin cancer, or cured in situ cervical carcinoma.

          -  Any other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality which, in the judgment of the investigator, would have made the patient
             inappropriate for entry into this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Time Frame:At 4 months
Safety Issue:
Description:PFS rates will be monitored simultaneously using the Bayesian approach of Thall, Simon, Esty as extended by Thall and Sung. PFS is defined as no disease progression or death within the first 4 months of the proposed treatment.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE)
Time Frame:Up to 30-37 days post-treatment
Safety Issue:
Description:Toxicity defined as any grade >= 3 toxicity that is attributed to cabozantinib. Toxicity rates will be monitored simultaneously using the Bayesian approach of Thall, Simon, Esty as extended by Thall and Sung.
Measure:Overall survival (OS) as defined by RECIST 1.1 criteria
Time Frame:Up to 30-37 days post-treatment
Safety Issue:
Description:Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Measure:Overall response rate (ORR) as defined by RECIST 1.1 criteria
Time Frame:Up to 30-37 days post-treatment
Safety Issue:
Description:Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize categorical variables. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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