Clinical Trials /

Cabozantinib With Radiation Therapy for the Treatment of Sarcomas of the Extremities

NCT04220229

Description:

This phase I/II trial studies the side effects and best dose of cabozantinib when given with radiation therapy and how well it works in treating patients with sarcoma of the extremities. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cabozantinib with radiation therapy may make the tumors smaller and reduce the amount of normal tissue that needs to be removed.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib With Radiation Therapy for the Treatment of Sarcomas of the Extremities
  • Official Title: A Phase 1/2 Study of Neoadjuvant Cabozantinib in Combination With Radiation Therapy for Sarcomas of the Extremities

Clinical Trial IDs

  • ORG STUDY ID: RG1003562
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: NCI-2019-08661
  • SECONDARY ID: 10051
  • NCT ID: NCT04220229

Conditions

  • Sarcoma of the Extremity
  • Stage I Soft Tissue Sarcoma of the Trunk and Extremities
  • Stage IA Soft Tissue Sarcoma of the Trunk and Extremities
  • Stage IB Soft Tissue Sarcoma of the Trunk and Extremities
  • Stage II Soft Tissue Sarcoma of the Trunk and Extremities

Interventions

DrugSynonymsArms
Cabozantinib S-malate1140909-48-3, BMS-907351, Butanedioic acid, Cabometyx, CometriqTreatment (cabozantinib S-malate , radiation therapy)
Cabozantinib1-CyclopropanedicarboxamideTreatment (cabozantinib S-malate , radiation therapy)

Purpose

This phase I/II trial studies the side effects and best dose of cabozantinib when given with radiation therapy and how well it works in treating patients with sarcoma of the extremities. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cabozantinib with radiation therapy may make the tumors smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description

      OUTLINE: This is a phase I, dose-escalation study of cabozantinib followed by a phase II,
      dose-expansion study.

      PHASE I: Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-21.
      Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
      Beginning cycle 2, patients also undergo standard of care radiation therapy for 5-6 weeks.

      PHASE II: Patients receive cabozantinib S-malate PO QD on days 1-21. Cycles repeat every 21
      days in the absence of disease progression or unacceptable toxicity. Beginning cycle 1,
      patients also undergo standard of care radiation therapy for 5-6 weeks.

      After completion of study treatment, patients are followed up at 30 days and then every 12
      weeks for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib S-malate , radiation therapy)ExperimentalPHASE I: Patients receive cabozantinib S-malate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Beginning cycle 2, patients also undergo standard of care radiation therapy for 5-6 weeks. PHASE II: Patients receive cabozantinib S-malate PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Beginning cycle 1, patients also undergo standard of care radiation therapy for 5-6 weeks.
  • Cabozantinib S-malate
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria:

          -  Subject must have a histologically confirmed diagnosis of sarcomas of the extremities
             for which radiation therapy is a planned intervention.

               -  For Phase 1 dose escalation, this may include neoadjuvant, adjuvant, or
                  palliative treatment

               -  For Phase 2 dose expansion, this will only include neoadjuvant radiation prior to
                  a planned surgery. Subjects receiving radiation therapy for non-neoadjuvant
                  treatment are not included in phase 2

          -  Subjects must have one or more measurable target lesions by RECIST version (v) 1.1,
             assessed via computed tomography (CT) scan or magnetic resonance imaging (MRI)

          -  At the time of study enrollment, subjects must have a tumor burden that is judged to
             be potentially resectable (Phase 2 only. Phase 1 subjects may be neoadjuvant,
             adjuvant, or palliative)

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 (>= 1.5 GI/L) without granulocyte
             colony-stimulating factor support in the last 28 days

          -  White blood cell count >= 2500/mm^3 (>= 2.5 GI/L)

          -  Platelets >= 100,000/mm^3 (>=100 GI/L) without transfusion in the last 28 days

          -  Hemoglobin >= 9 g/dL (>= 90 g/L) without transfusion in the last 28 days

          -  Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 3 X upper limit of
             normal (ULN)

          -  Alkaline phosphatase (ALP) =< 3 X upper limit of normal (ULN)

             * ALP =< 5 X ULN is permitted in subjects with documented bone metastases (phase 1
             only)

          -  Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 X ULN)

          -  Serum albumin >= 2.8 g/dl

          -  Serum creatinine =< 2.0 x ULN or calculated creatinine clearance >= 30 mL/min (>= 0.5
             mL/sec) using the Cockcroft-Gault equation

          -  Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Male or non-pregnant and non-breast feeding female:

               -  Females of child-bearing potential must agree to use highly effective
                  contraception without interruption from initiation of therapy and while on study
                  medication and have a negative serum pregnancy test (B-hCG) result at screening
                  and agree to ongoing pregnancy testing during the study, and at the end of study
                  treatment. A highly effective method of contraception is defined as one that
                  results in a low failure rate (that is, < 1% per year), when used consistently
                  and correctly, such as implants, injectables, combined oral contraceptives, some
                  intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner

               -  Male subjects must practice abstinence or agree to use a condom during sexual
                  contact with a pregnant female or a female of childbearing potential while
                  participating in the study

          -  Life expectancy of > 3 months, as determined by the investigator

          -  Ability to understand and sign informed consent

          -  Willingness and ability to comply with scheduled visits, laboratory tests, and other
             study procedures

          -  Resolution to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
             (CTCAE) 5.0 for any toxicities related to any prior treatment (except alopecia)

        Exclusion Criteria:

          -  Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
             (including investigational) for the investigational diagnosis.

               -  For phase 1 dose escalation subjects, prior therapy is permitted. Phase 1
                  subjects will not be eligible for inclusion if they have received any of the
                  following:

                    -  Prior treatment with cabozantinib

                    -  Receipt of any type of small molecule kinase inhibitor (including
                       investigational kinase inhibitor) within 2 weeks before first dose of study
                       treatment

               -  For phase 2 dose expansion subjects, no prior systemic therapy is permitted

          -  Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before the first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible.

             * Phase 1 dose expansion subjects only. Phase 2 dose escalation subjects may not have
             any prior radiation therapy for the investigational diagnosis

          -  Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A
             subject with controlled and asymptomatic CNS metastases may participate in the phase 1
             component study. As such, the subject must have completed any prior treatment for CNS
             metastases >= 28 days (including radiotherapy and/or surgery) prior to start of
             treatment in this study and should not be receiving chronic corticosteroid therapy for
             the CNS metastases. Subjects with known CNS metastases are excluded from phase 2

          -  Concomitant anticoagulation with oral anticoagulants(e.g., warfarin, direct thrombin
             and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed
             anticoagulants are the following:

               -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is
                  permitted

               -  Low-dose low molecular weight heparins (LMWH) are permitted

               -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
                  known brain metastases who are on a stable dose of LMWH for at least 6 weeks
                  before first dose of study treatment, and who have had no clinically significant
                  hemorrhagic complications from the anticoagulation regimen or the tumor. Subjects
                  with hemoptysis, central nervous system hemorrhage or gastrointestinal hemorrhage
                  within the last 6 months prior to treatment are excluded

          -  The subject has 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) > 150 mm
                       Hg systolic or > 100 mm Hg diastolic despite optimal anti-hypertensive
                       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.

        Uncontrolled serious medical or psychiatric illness

          -  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 (e.g., 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. Subjects with clinically relevant ongoing complications
                       from prior surgery are not eligible

                    -  Corrected QT interval calculated by the Bazett's formula (corrected QT
                       [QTc]) > 480 ms per electrocardiogram (ECG) within 28 days before first dose
                       of study treatment

          -  Note: If a single ECG shows a QTc with an absolute value > 480 ms, two additional ECGs
             at intervals of approximately 3 min must be performed within 30 min after the initial
             ECG, and the average of these three consecutive results for QTc will be used to
             determine eligibility

               -  Pregnant or lactating females

               -  Inability to swallow tablets

               -  Previously identified allergy or hypersensitivity to components of the study
                  treatment formulations

               -  Diagnosis of another malignancy within 2 years before first dose of study
                  treatment, except for superficial skin cancers, or localized, low grade tumors
                  deemed cured and not treated with systemic therapy

               -  Concurrent use of medications (especially those interacting with CYP3A417) that
                  potentially interact unsafely with cabozantinib which cannot be discontinued or
                  substituted

               -  Subjects with a sarcoma which has other, defined treatments or biology distinctly
                  different from those of soft tissue sarcomas in general. Including, but not
                  limited to, Ewing's sarcoma, rhabdomyosarcoma, gastrointestinal stromal tumors,
                  Kaposi's sarcoma, Wilms' tumor

               -  Transfusion of blood product or granulocyte-colony stimulating factor (G-CSF)
                  support factor within the last 28 days

               -  Recent infection requiring systemic anti-infective treatment that was completed
                  =< 14 days prior to enrollment (except for uncomplicated urinary tract infection
                  or upper respiratory tract infection)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose of cabozantinib S-malate (cabozantinib) (Phase I)
Time Frame:Up to 21 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Rate of pathologic response
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Rate of surgical excision with negative margins
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Response rate (complete, partial, overall)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Measure:Pattern of and time to local versus (vs.) distant recurrences
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Relapse-free and overall survival
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 28 days after last dose of investigational product
Safety Issue:
Description:Adverse events will be graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Measure:Rate of treatment discontinuation prior to neoadjuvant radiation therapy
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Washington

Trial Keywords

  • Soft Tissue / Sarcoma

Last Updated

January 6, 2020