Clinical Trials /

Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma

NCT04200443

Description:

This phase II trial studies how well cabozantinib and temozolomide work in treating patients with leiomyosarcoma or other soft tissue sarcoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib and temozolomide may work better than either one alone in treating patients with leiomyosarcoma or other soft tissue sarcoma. Cabozantinib is an investigational drug, which means that it has not been approved by the United States (US) Food and Drug Administration (FDA) or any other regulatory agencies for sale or use by the public for the indication under investigation in this study.

Related Conditions:
  • Leiomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma
  • Official Title: A Phase II Study of Cabozantinib and Temozolomide in Patients With Unresectable or Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas

Clinical Trial IDs

  • ORG STUDY ID: NU 19S01
  • SECONDARY ID: STU00210699
  • SECONDARY ID: NU 19S01
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2019-08090
  • NCT ID: NCT04200443

Conditions

  • Metastatic Leiomyosarcoma
  • Metastatic Soft Tissue Sarcoma
  • Stage III Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIA Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIB Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IIIC Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IV Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IVA Uterine Corpus Leiomyosarcoma AJCC v8
  • Stage IVB Uterine Corpus Leiomyosarcoma AJCC v8
  • Unresectable Leiomyosarcoma
  • Unresectable Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
CabozantinibTreatment (cabozantinib, temozolomide)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZTreatment (cabozantinib, temozolomide)

Purpose

This phase II trial studies how well cabozantinib and temozolomide work in treating patients with leiomyosarcoma or other soft tissue sarcoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib and temozolomide may work better than either one alone in treating patients with leiomyosarcoma or other soft tissue sarcoma. Cabozantinib is an investigational drug, which means that it has not been approved by the United States (US) Food and Drug Administration (FDA) or any other regulatory agencies for sale or use by the public for the indication under investigation in this study.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the progression-free survival (defined as complete response [CR]+partial
      response [PR]+stable disease [SD]) assessed at 12 weeks for subjects in Cohort 1
      (Leiomyosarcoma Arm) treated with cabozantinib and temozolomide as defined by Response
      Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate (defined as CR+PR) for subjects in Cohort 1 treated
      with a combination of cabozantinib and temozolomide.

      II. To determine the clinical benefit rate (CR+PR+SD) for subjects in Cohort 1 treated with a
      combination of cabozantinib and temozolomide.

      III. To evaluate the median progression free rate for subjects with combination of
      cabozantinib and temozolomide.

      IV. To evaluate overall survival for subjects in Cohort 1 treated with a combination of
      cabozantinib and temozolomide.

      V. To assess safety and tolerability for subjects treated with a combination of cabozantinib
      and temozolomide.

      VI. To determine the overall response rate (defined as CR+PR) in Cohort 2 (other soft tissue
      sarcomas).

      VII. To assess Quality of Life (QoL) and subject-reported outcomes as measured by the
      European Organization for Research and Treatment of Cancer (EORTC) Quality of Life
      Questionnaire (QLQ-C30) and the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

      EXPLORATORY OBJECTIVE:

      I. To estimate the correlation of progression free rate (PFR) and overall survival (OS) to
      levels of sVEGFR2, PIGF, VEGF, HGF, sMET, VEGF-C, VEGF-D, and soluble AXL.

      OUTLINE:

      Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and temozolomide PO QD
      on days 1-5. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients with progressive disease (PD) are followed up
      every 6 months for up to 2 years and patients without PD are followed up every 6 months for
      up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib, temozolomide)ExperimentalPatients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have a histologically confirmed diagnosis of unresectable or metastatic:

               -  Uterine and non-uterine leiomyosarcoma

               -  Other soft tissue sarcoma (non-leiomyosarcoma)

               -  Note: Subjects with any one of the following soft tissue sarcoma histological
                  subtypes will not be eligible for participation: alveolar soft-part sarcoma,
                  dermatofibrosarcoma, gastrointestinal stromal tumor (GIST), Kaposi sarcoma, mixed
                  mesodermal tumor/carcinosarcoma, rhabdomyosarcoma (embryonal and alveolar), and
                  low grade (grade 1) sarcomas

          -  Subjects must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
             of 0-1

          -  Subjects with 0 - 5 prior chemotherapy regimens for recurrent/metastatic disease are
             eligible. It will be up to the investigator to determine what constitutes a regimen in
             each case

          -  Subjects with prior next generation sequencing (NGS) reports completed on their tumor
             specimen will have this data collected

          -  Subjects must have measurable disease by RECIST 1.1

          -  Subjects must have adequate organ and bone marrow function, based upon meeting all of
             the following laboratory:

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

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3 (>= 1.5 GI/L) without granulocyte colony
             stimulating factor support

          -  Hemoglobin >= 9 g/dL (>= 90 g/L)

          -  Platelets >= 100,000/mm^3 (>= 100 GI/L) without transfusion

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with Gilbert's
             disease =< 3 x ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT])
             =< 3 X upper limit of normal (ULN)

          -  Alkaline phosphatase (ALP) =< 3 X ULN. ALP =< 5 x ULN with documented bone metastases

          -  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 (=< 113.2 mg/mmol)

          -  Prothrombin time (PT/institutional normalized ratio [INR]) or partial thromboplastin
             time (PTT) test =< 1.3 x the laboratory ULN

          -  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. Females
             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

          -  Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
             (CTCAE) version (v.)5.0 from toxicities related to any prior treatments, unless AE(s)
             are clinically nonsignificant and/or stable on supportive therapy

          -  Subjects with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression

          -  Subjects must be capable of understanding and complying with the protocol requirements
             and must have signed the informed consent document

        Exclusion Criteria:

          -  Inability to swallow tablets

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

          -  Subjects with a prior or concurrent malignancy whose natural history or treatment does
             have the potential to interfere with the safety or efficacy assessment of the
             investigational regiment are ineligible for this trial

          -  Pregnant or lactating females. Pregnant women are excluded from this study because
             cabozantinib and temozolomide are antineoplastic agents with potential for teratogenic
             or abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with cabozantinib and
             temozolomide, breastfeeding should be discontinued if the mother is treated with
             cabozantinib and temozolomide

          -  Prior treatment with cabozantinib or temozolomide

          -  Receipt of any of the following:

               -  Any type of small molecule kinase inhibitor (including investigational kinase
                  inhibitor) within 14 days before first dose of study treatment

               -  Any type of cytotoxic, biologic or other systemic anticancer therapy (including
                  investigational) within 28 days before first dose of study treatment

               -  Radiation therapy for bone metastasis within 14 days before first dose of study
                  treatment

               -  Any other radiation therapy within 28 days before first dose of study treatment

               -  Systemic treatment with radionuclides within 42 days before the first dose of
                  study treatment

                    -  Note: Subjects with clinically relevant ongoing complications from prior
                       radiation therapy are not eligible

               -  Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 56
                  days before the first dose of study treatment

                    -  Note: Complete wound healing from major surgery must have occurred 28 days
                       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 Bazetts formula (QTcF) > 500 ms per
             electrocardiogram (ECG) within 28 days before first dose of study treatment

               -  Note: If a single electrocardiography (ECG) shows a QTcF with an absolute value >
                  500 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 QTcF will be used to determine eligibility

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Subjects with known history or current symptoms of cardiac disease, or
                       history of treatment with cardiotoxic agents, should have a clinical risk
                       assessment of cardiac function using the New York Heart Association
                       Functional Classification. To be eligible for this trial, subjects should be
                       class 2B or better

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) ˃ 150 mm
                       Hg systolic or ˃ 100 mm Hg diastolic despite optimal antihypertensive
                       treatment

                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
                       (MI), or other ischemic event within 6 months before the first dose

               -  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 the first dose

                         -  Note: Complete healing of an intra-abdominal abscess must be confirmed
                            before the 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 84 days before the 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)

          -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
             and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Washout period
             is considered to be 5 half-lives of the drug. Allowed anticoagulants are the
             following:

               -  Low-dose aspirin for cardio protection (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 42 days
                  before first dose of study treatment, and who have had no clinically significant
                  hemorrhagic complications from the anticoagulation regimen or the tumor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:After the first 12 weeks of therapy
Safety Issue:
Description:PFS will be the time from the start of treatment to the time of progression, with progression defined as changes in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Secondary Outcome Measures

Measure:Presence of response (Cohort 1)
Time Frame:At weeks 6 and 12, then every 2 cycles up to 5 years
Safety Issue:
Description:Will be defined as complete response (CR) + partial response (PR).
Measure:Clinical benefit rate (Cohort 1)
Time Frame:At weeks 6 and 12, then every 2 cycles up to 5 years
Safety Issue:
Description:Will be defined as CR + PR + stable disease (SD).
Measure:Median progression free rate
Time Frame:Up to 5 years
Safety Issue:
Description:Will assess the time from the first dose of study treatment until progression based upon changes in RECIST 1.1, unequivocal clinical deterioration, or death from any cause.
Measure:Overall survival (OS) (Cohort 1)
Time Frame:Up to 2 years
Safety Issue:
Description:Will assess the time from the first dose of the study treatment until death from any cause, up to a maximum follow-up of two years.
Measure:Incidence of adverse events
Time Frame:From time of first treatment up to 5 years
Safety Issue:
Description:Will assess the presence of all toxicities outlined in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Overall response rate (Cohort 2)
Time Frame:At weeks 6 and 12, then every 2 cycles up to 5 years
Safety Issue:
Description:
Measure:Quality of life
Time Frame:5 years
Safety Issue:
Description:Will be measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).
Measure:Subject-reported outcomes
Time Frame:5 years
Safety Issue:
Description:Will be assessed by the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Northwestern University

Last Updated

December 13, 2019