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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04200443
Recruitment Status : Not yet recruiting
First Posted : December 16, 2019
Last Update Posted : December 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Northwestern University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Cabozantinib Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Temozolomide Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Cabozantinib and Temozolomide in Patients With Unresectable or Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas
Estimated Study Start Date : January 9, 2020
Estimated Primary Completion Date : November 1, 2021
Estimated Study Completion Date : November 1, 2022


Arm Intervention/treatment
Experimental: Treatment (cabozantinib, temozolomide)
Patients 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.
Drug: Cabozantinib
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Temozolomide
Given PO
Other Names:
  • CCRG-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
  • TMZ




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: After the first 12 weeks of therapy ]
    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 :
  1. Presence of response (Cohort 1) [ Time Frame: At weeks 6 and 12, then every 2 cycles up to 5 years ]
    Will be defined as complete response (CR) + partial response (PR).

  2. Clinical benefit rate (Cohort 1) [ Time Frame: At weeks 6 and 12, then every 2 cycles up to 5 years ]
    Will be defined as CR + PR + stable disease (SD).

  3. Median progression free rate [ Time Frame: Up to 5 years ]
    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.

  4. Overall survival (OS) (Cohort 1) [ Time Frame: Up to 2 years ]
    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.

  5. Incidence of adverse events [ Time Frame: From time of first treatment up to 5 years ]
    Will assess the presence of all toxicities outlined in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  6. Overall response rate (Cohort 2) [ Time Frame: At weeks 6 and 12, then every 2 cycles up to 5 years ]
  7. Quality of life [ Time Frame: 5 years ]
    Will be measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).

  8. Subject-reported outcomes [ Time Frame: 5 years ]
    Will be assessed by the EuroQoL-Group Health Questionnaire (EQ-5D-5L).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04200443


Contacts
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Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
Contact: Mahesh Seetharam    480-342-4800    Seetharam.mahesh@mayo.edu   
Principal Investigator: Mahesh Seetharam         
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
Contact: Steven Attia    904-953-2558    attia.steven@mayo.edu   
Principal Investigator: Steven Attia         
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Contact: Mark Agulnik    312-695-1222    m-agulnik@northwestern.edu   
Principal Investigator: Mark Agulnik         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States, 52242
Contact: Varun Monga    319-384-9497    varun-monga@uiowa.edu   
Principal Investigator: Varun Monga         
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Contact: Scott H. Okuno    507-284-4849    Okuno.scott@mayo.edu   
Principal Investigator: Scott H. Okuno         
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Contact: Brian A. Van Tine    314-747-8475    bvantine@dom.wustl.edu   
Principal Investigator: Brian A. Van Tine         
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Contact: John A. Charlson    414-805-4600    jcharlso@mcw.edu   
Principal Investigator: John A. Charlson         
Sponsors and Collaborators
Northwestern University
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark Agulnik, MD Northwestern University
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Responsible Party: Northwestern University
ClinicalTrials.gov Identifier: NCT04200443    
Other Study ID Numbers: NU 19S01
STU00210699 ( CTRP (Clinical Trial Reporting Program) )
NU 19S01 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
NCI-2019-08090 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: December 16, 2019    Key Record Dates
Last Update Posted: December 16, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Sarcoma
Leiomyosarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Muscle Tissue
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents