E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High Grade Undifferentiated Uterine Sarcoma (HGUS) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046821 |
E.1.2 | Term | Uterine sarcoma NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the trial is to assess, in High Grade Undifferentiated Uterine Sarcoma (HUGS), the activity (PFS at 4 months) of maintenance treatment with cabozantinib when compared with placebo after clinical benefit from standard chemotherapy (doxorubicin +/- ifosfamide) (given as an adjuvant treatment after curative surgery, or for locally advanced or metastatic disease). |
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E.2.2 | Secondary objectives of the trial |
♦ To assess the efficacy of maintenance treatment with cabozantinib when compared with placebo, using progression-free survival, overall survival, response rate, and duration of response among patients with measurable disease.
♦ To describe the safety profile of cabozantinib in patients with HGUS
♦ To explore the response rate to chemotherapy in first line treatment for patients with measurable disease |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) At registration
- Patients can be registered no earlier than 4 weeks prior to start of the 1st line treatment and no later than 4 weeks after last administration of 1st line treatment. Patients who are suitable for treatment with doxorubicin +/- ifosfamide and fall within one of the following patient populations:
. Locally advanced: newly diagnosed high grade undifferentiated uterine sarcoma with advanced disease (stage III or stage IV) or residual disease after primary surgery
. Metastatic: diagnosed high grade undifferentiated uterine sarcoma with disease relapse after local treatment for primary tumor
- 1 formalin fixed paraffin embedded block of tumor tissue (if not available, at least 1 haematoxylin/eosin and 15 unstained slides) is sent after registration of a patient. Histological central review is mandatory to confirm histology and grade.
- Patients must be at least 18 years old
- Before patient registration, written informed consent for central collection of tissue block or slides and any other trial-specific procedures must be obtained
2) At Randomization
Patients can be randomized within 12 weeks after last administration of 1st line treatment, before the start of protocol treatment
- Central pathological confirmation: Histological evidence of high grade undifferentiated uterine sarcoma
- Non-progressive patients (CR, PR, SD) after first line treatment (standard chemotherapy consisting of 4 to 6 cycles of doxorubicin alone or in combination with ifosfamide) and at time of randomization.
- Patients able to swallow and retain oral tablets.
- WHO/ECOG performance status 0-2
- The subject has organ and marrow function and laboratory values as follows before randomization
. Absolute neutrophil count (ANC) ≥ 1500/mm3 without colony stimulating factor support for 7 days
. Platelets ≥ 100,000/mm3
. Hemoglobin ≥ 9 g/dL
. Bilirubin ≤ 1.5 × the upper limit of normal. For subjects with known Gilbert’s disease, bilirubin ≤ 3.0 mg/dL
. Serum albumin ≥ 2.8 g/dl
. Serum creatinine ≤ 1.5 × the upper limit of normal or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) × 0.85
. Alanine aminotransferase and aspartate aminotransferase ≤ 3.0 × the upper limit of normal
. Lipase < 2.0 × the upper limit of normal and no radiologic or clinical evidence of pancreatitis
. Urine Dipstick: If Urine Dipstick ≥ 2+, determine Urine Protein to Creatinine Ratio (UPCR) by quantitative analysis; if UPCR ≥ 1, then a 24-hour urine protein must be assessed. Any patient with protein > 150 mg over 24 hours would not be eligible.
. Serum phosphorus, calcium, magnesium and potassium ≥ lower limit of normal
. Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 × the upper limit of normal
- Clinically normal cardiac function based on the institutional lower limit of normal (LVEF assessed by MUGA or ECHO), normal 12 lead ECG (no prolongation of corrected QT interval (QTc) > 480 msecs) and no 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
- Women of child bearing potential must have a negative serum/urine pregnancy test within 3 days prior to the first dose of study treatment.
- Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last study treatment.
- Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 8 weeks after the last study treatment.
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
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E.4 | Principal exclusion criteria |
At randomization
- The following tumor types are NOT eligible: low-grade ESS, leiomyosarcoma (low, intermediate or high grade), carcinosarcoma, adenosarcoma, rhabdomyosarcoma (alveolar or embryonal) and soft tissue PNET of uterus/cervix.
- concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
- patient with poorly controlled hypertension defined at baseline as blood pressure (BP) >150/90
- patients who have suffered a cerebrovascular accident at any time in the past, patients who have suffered a transient ischemic attack in the past 6 months, patients who have suffered a deep venous thrombosis (DVT) or a pulmonary embolism in the past 6 months
note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents and remained stable for at least 6 weeks are eligible.
- Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
♦ Any of the following within 28 days before the first dose of study treatment
- "known" intra-abdominal tumor/metastases invading GI mucosa
- active peptic ulcer disease,
- inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
- malabsorption syndrome
♦ Any of the following within 6 months before the first dose of study treatment:
- abdominal or vaginal 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 study treatment (Cabozantinib/placebo) even
- patients with radiographic evidence of cavitating pulmonary lesion(s).
- patients with tumor in contact with, invading or encasing any major blood vessels.
- patients evidence of tumor invading the 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 study treatment (Cabozantinib/placebo).
- evidence of active bleeding or bleeding diathesis.
- hemoptysis ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment. Note: Any patient with a prior history of hemoptysis associated with metastatic disease must have a bronchoscopy to rule out endobronchial lesions. A patient with an endobronchial lesion would be excluded from study.
- signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
- clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
- prior major surgery or trauma within 6 weeks prior to first dose of study drug and any wound, fracture, or ulcer should be completely healed.
- concurrent or planned treatment with strong inhibitors or inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)
- contraindications to cabozantinib (e.g. no known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to cabozantinib)
- planned use of chemotherapy, radiation therapy, radionuclide treatment, small molecule TKI or hormonal therapy, and any other investigational agent (Cabozantinib/placebo) during the treatment period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival rate |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 4 months after randomization to cabozantinib or placebo |
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E.5.2 | Secondary end point(s) |
1. Progression free survival rate
2. Overall survival
3. response rate and duration of response to cabozantinib
4. Response rate to doxorubicin-based chemotherapy after registration on trial for the patients with measurable disease
5. Quality of life (QoL)
6. Safety of cabozantinib in HGUS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1+2+3+4: prior to registration; prior to randomization; every 8 weeks during the first year of the maintenance period, then every 12 weeks; within 30 days after last dose (if no progression since randomization)
5. prior to registration; prior to randomization; within 3 days prior to each cycle, every 8 weeks during the first year of the maintenance period, then every 12 weeks; within 30 days after last dose
6. as of randomization, continuously per event up to 30 days after last dose; for patient who cross-over to cabozantinib after progression: every 4 weeks until further progression |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study occurs when all of the following criteria have been satisfied:
-Thirty days after all patients have stopped protocol treatment.
-The trial is mature for the analysis of the primary endpoint as defined in the protocol, ie. all randomized patients have adequate follow-up to determine their PFS status at 4 months.
-The database has been fully cleaned and frozen for this analysis. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |