Clinical Trials /

Pazopanib vs. Pazopanib Plus Gemcitabine

NCT02203760

Description:

This study is a prospective, randomized, open-label, multicenter phase II trial in order to determine progression-free survival of patients with refractory or relapsed metastatic uterine leiomyosarcomas or other metastatic uterine tumours.

Related Conditions:
  • Uterine Carcinosarcoma
  • Uterine Corpus Leiomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pazopanib vs. Pazopanib Plus Gemcitabine
  • Official Title: Pazopanib vs. Pazopanib Plus Gemcitabine in Patients With Relapsed or Metastatic Uterine Leiomyosarcomas or Uterine Carcinosarcomas: a Multi-center, Randomized Phase-II Clinical Trial of the NOGGO and AGO - PazoDoble -

Clinical Trial IDs

  • ORG STUDY ID: NOGGO U1
  • SECONDARY ID: 2012-003810-15
  • NCT ID: NCT02203760

Conditions

  • Leiomyosarcoma or Carcinosarcoma

Interventions

DrugSynonymsArms
Pazopanib plus GemcitabineVotrient and GemzarPazopanib plus Gemcitabine
PazopanibVotrientPazopanib

Purpose

This study is a prospective, randomized, open-label, multicenter phase II trial in order to determine progression-free survival of patients with refractory or relapsed metastatic uterine leiomyosarcomas or other metastatic uterine tumours.

Detailed Description

      Study design:

      This study is a prospective, randomized, open-label, multicenter phase II trial in order to
      determine progression-free survival of patients with refractory or relapsed metastatic
      uterine leiomyosarcomas or other metastatic uterine tumours.

      Indication:

      Relapsed or metastatic uterine leiomyosarcomas or carcinosarcomas

      Randomization:

      Patients with uterine leiomyosarcomas will be randomized in a 1:1-fashion to receive the
      following therapy

        -  Arm A: Pazopanib 800 mg orally once daily plus Gemcitabine 1000 mg/m2 i.v. over 30 min d
           1 and d 8 q3w or

        -  Arm B: Pazopanib 800 mg orally once daily Patients with uterine carcinosarcomas will be
           treated according to Arm A.

      Planned number of patients:

      87 patients with uterine leiomyosarcomas 20 patients with uterine carcinosarcomas

      Treatment schedules:

      Patients with uterine leiomyosarcomas will be randomized in a 1:1-fashion to receive the
      following therapy • Arm A (experimental arm / combination arm): Pazopanib 800 mg orally once
      daily plus Gemcitabine 1000 mg/m2 i.v. over 30 min d 1 and d 8 q3w or

      • Arm B (control arm / monotherapy arm): Pazopanib 800 mg orally once daily Patients with
      uterine carcinosarcomas will be treated according to Arm A.

      Planned treatment duration per subject:

      Patients continue on study treatment until disease progression, death, unacceptable toxicity
      or withdrawal of consent for any reason.
    

Trial Arms

NameTypeDescriptionInterventions
Pazopanib plus GemcitabineExperimentalArm A: Pazopanib 800 mg orally once daily plus Gemcitabine 1000 mg/m2 i.v. over 30 min d 1 and d 8 q3w or
  • Pazopanib plus Gemcitabine
PazopanibActive ComparatorPazopanib 800 mg orally once daily
  • Pazopanib

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects must provide informed consent prior to performance of study-specific
             procedures or assessments, and must be willing to comply with treatment and follow-up.
             Procedures conducted as part of the subject's routine clinical management (e.g., blood
             count, imaging study) and obtained prior to signing of informed consent may be
             utilized for screening or baseline purposes provided these procedures are conducted as
             specified in the protocol

          2. Histologically or cytological confirmed uterine leiomyosarcoma or uterine
             carcinosarcoma including any subtypes

          3. Patients with a contraindication for doxorubicin OR patients must have received prior
             chemotherapies

          4. For patients with prior anthracycline therapy normal cardiac function with LVEF at
             least 50% must be assessed by quantitative echocardiogram or MUGA scan

          5. Prior Gemcitabine containing chemotherapy is permitted provided that at least 8 weeks
             have elapsed since the last dose of therapy

          6. ECOG performance status 0-1

          7. At least 18 years old

          8. Measurable disease according to RECIST v 1.1 criteria (in case of tumour debulking -
             staging CT-scan after surgery)

          9. Able to swallow and retain oral medication

         10. Adequate organ system function as defined in Table 1

        Table 1: Definitions for Adequate Organ Function System Laboratory Values Hematologic
        Absolute neutrophil count (ANC) > = 1.5 X 109/L Hemoglobin1 > = 9 g/dL (5.6 mmol/L)
        Platelets > = 100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)4 <=
        1.2 X upper limit of normal (ULN) Partial thromboplastin time (PTT) <=1.2 X ULN Hepatic2
        Total bilirubin <= 1.5 X ULN AST and ALT <= 2.5 X ULN Renal Serum creatinine <= 1.5 mg/dL
        (133 µmol/L)

        Or, if greater than 1.5 mg/dL:

        Calculated creatinine clearance > = 50 mL/min

        Urine Protein to Creatinine Ratio (UPC)3 < 1

          1. Subjects may not have had a transfusion within 7 days prior to screening assessment.

          2. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted

          3. If UPC > = 1, then a 24-hour urine protein must be assessed. Subjects must have a
             24-hour urine protein value <1g to be eligible.

          4. Subjects receiving anticoagulant therapy are eligible if their INR is stable and
             within the recommended range for the desired level of anticoagulation

        11. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
        including any female who has had:

          -  A hysterectomy

          -  A bilateral oophorectomy (ovariectomy)

          -  A bilateral tubal ligation

          -  Is post-menopausal Subjects not using hormone replacement therapy (HRT) must have
             experienced total cessation of menses for ≥ 1 year and be greater than 45 years in
             age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40
             mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).

        Subjects using HRT must have experienced total cessation of menses for >= 1 year and be
        greater than 45 years of age OR have had documented evidence of menopause based on FSH and
        estradiol concentrations prior to initiation of HRT

        OR

        Negative serum pregnancy test of women of childbearing potential performed within 1 week
        prior to the first dose of study treatment, preferably as close to the first dose as
        possible, and agrees to use adequate contraception. Acceptable contraceptive methods, when
        used consistently and in accordance with the product label and the instructions of the
        physicians are as followed for 14 days before exposure to investigational product, through
        the dosing period and for at least 21 days after the last dose of investigational product:

          -  Complete abstinence from sexual intercourse

          -  Oral contraceptive, either combined or progestogen alone

          -  Injectable progestogen

          -  Implants of levonorgestrel

          -  Estrogenic vaginal ring

          -  Percutaneous contraceptive patches

          -  Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate
             of less than 1% per year

          -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to the
             female subject's entry into the study, and this male is the sole partner for that
             subject

          -  Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps)
             with a vaginal spermicidal agent (foam/gel/film/cream/suppository) Female subjects who
             are lactating should discontinue nursing prior to the first dose of study drug and
             should refrain from nursing throughout the treatment period and for 14 days following
             the last dose of study drug.

        Exclusion Criteria:

          1. Prior malignancy

             • Note: Subjects who have had another malignancy and have been disease-free for 5
             years, or subjects with a history of completely resected non-melanomatous skin
             carcinoma or successfully treated in situ carcinoma are eligible.

          2. Patient has received prior treatment with any anti-angiogenic agent including
             bevacizumab and tyrosine kinase inhibitors

          3. Active malignancy or any malignancy in the last 5 years prior to first dose of study
             drug other than LMS and CS

          4. History or clinical evidence of central nervous system (CNS) or leptomeningeal
             metastases, except for individuals who have previously-treated CNS metastases, are
             asymptomatic, and have had no requirement for steroids or anti-seizure medication for
             6 months prior to first dose of study drug. Screening with CNS imaging studies
             (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if
             clinically indicated or if the subject has a history of CNS metastases

          5. Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including, but not limited to:

               -  Active peptic ulcer disease

               -  Known intraluminal metastatic lesion/s with risk of bleeding

               -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
                  gastrointestinal conditions with increased risk of perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
                  abscess within 28 days prior to beginning study treatment

               -  Grade 3/4 diarrhea

          6. Corrected QT interval (QTc) > 450 Milliseconds using Barzett's formula

          7. History of any one or more of the following cardiovascular conditions within the past
             6 months:

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Coronary artery bypass graft surgery

               -  Symptomatic peripheral vascular disease

               -  Class III or IV congestive heart failure, as defined by the New York Heart
                  Association (NYHA)

               -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140
                  mmHg or diastolic blood pressure (DBP) of ≥ 90 mmHg].

             Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
             study entry. BP must be re-assessed on two occasions that are separated by a minimum
             of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from
             each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the
             study (refer to study protocol for details on BP control and re-assessment prior to
             study enrollment)

          8. History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

             • Note: Subjects with recent DVT who have been treated with therapeutic
             anti-coagulating agents for at least 6 weeks are eligible

          9. Major surgery or trauma within 28 days prior to study enrolment or any non- healing
             wound, fracture or ulcer (procedures such as catheter placement not considered to be
             major)

         10. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to Pazopanib or Gemcitabine

         11. Evidence of active bleeding or bleeding diathesis

         12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels

         13. Hemoptysis in excess of 2.5 mL(or one half teaspoon) within 8 weeks prior to the first
             dose of study drug

         14. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with subject's safety, provision of informed consent, or compliance to
             study procedures

         15. Unable or unwilling to discontinue use of prohibited medications listed in the study
             protocol for at least 14 days or five half-lives of a drug (whichever is longer) prior
             to the first dose of study drug and for the duration of the study

         16. Treatment with any of the following anti-cancer therapies

               -  Radiation therapy, surgery or tumour embolization within 14 days prior to the
                  first dose of study drug

               -  Chemotherapy, immunotherapy, biologic therapy, investigational therapy or
                  hormonal therapy within 14 days or five half-lives of a drug (whichever is
                  longer) prior to the first dose of study drug

         17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity, except alopecia

         18. Pregnancy (for women of childbearing potential to be confirmed by negative serum
             pregnancy test) or lactation period

             Women of childbearing potential:

             missing contraception (Pearl-Index <1, e.g. hormonal contraception including the
             combined oral contraceptive pill, the transdermal patch, and the contraceptive vaginal
             ring, intrauterine devices or sterilization) for 14 days before exposure to
             investigational product, during study treatment and for at least 21 days after the
             last dose of investigational product.

         19. Medical or psychological conditions that would not permit the subject to complete the
             study or sign informed consent

         20. Legal incapacity or limited legal capacity

         21. Participation in another clinical study with experimental therapy within 30 days prior
             to study enrolment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival assessed as rate of patients without progression Second malignancy or clinical progression - patients with unknown or missing PFS will be treated as non-responder
Time Frame:6 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective response rate (RECIST v1.1 criteria)
Time Frame:One year
Safety Issue:
Description:Time to progression (TTP) of a patient being defined as the time in months from start of the first therapy cycle until PD is observed
Measure:Objective response rate (RECIST v1.1 criteria)
Time Frame:One year
Safety Issue:
Description:Overall survival (OS) calculated from the day of study enrolment until the day of death
Measure:Objective response rate (RECIST v1.1 criteria)
Time Frame:one year
Safety Issue:
Description:Progression-free survival (PFS) calculated from the day of study enrolment until the day of progression/death
Measure:Safety
Time Frame:One year
Safety Issue:
Description:Toxicity and tolerability
Measure:Quality of life (EORTC QLQ-C30)
Time Frame:One year
Safety Issue:
Description:Quality of life (EORTC QLQ-C30)
Measure:Translational research program
Time Frame:One year
Safety Issue:
Description:Translational research within a tumour bank

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:North Eastern German Society of Gynaecological Oncology

Trial Keywords

  • Relapsed/metastatic uterine leiomyosarcomas/carcinosarcomas

Last Updated

December 13, 2019