HGUS EORTC E62113-55115

A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in High Grade Undifferentiated Uterine Sarcoma (HGUS) after stabilization or response to doxorubicin +/- ifosfamide following surgery or in metastatic first line treatment.

Inclusie criteria

  1. Vrouwen ≥ 18 jaar, WHO performance 0-2.
  2. PA-bevestigde diagnose HGUS (centrale review). NB: laaggradig ESS, leiomyosarcoom, carcinosarcoom, adenosarcoom, rhabdomyosarcoom (alveolair of embryonaal) en PNET in de wekedelen van cervix of uterus komen NIET in aanmerking.
  3. Indicatie voor adjuvant of palliatief behandeling met doxorubicine +/- ifosfamide.
  4. Geen eerdere chemotherapie
  5. 1 paraffine  blokje van het tumorweefsel of ten minste 1 H/E (haematoxyline/eosine) en 15 ongekleurde preparaten beschikbaar voor centrale herbeoordeling van het weefsel.
  6. Geen progressie  (CR, PR, SD) aan het einde van de eerstelijns standaardchemotherapie (4 tot 6 cycli van doxorubicine, alleen toegediend of in combinatie met ifosfamide).
  7. Standaard acceptabele orgaanfuncties (inclusief cardiaal),  chemie/hematologie lab uitslagen.
  8. Geen verhoogd risico op bloeding, perforatie of fisteling.
  9. Informed consent

Exclusie criteria

NVT

Randomisatie
Niet-progressieve patiënten (CR, PR, SD) aan het einde van de eerstelijns behandeling zullen worden gerandomiseerd tussen monotherapie cabozantinib 60 mg 1 DD PO of placebo 1 DD PO. De studiebehandeling wordt voortgezet tot ze beëindigd is (2 jaar) of tot progressie, intolerantie of intrekken toestemming. De in de controlearm gerandomiseerde patiënten kunnen cabozantinib krijgen ten tijde van progressie, na het opheffen van de blindering.

Aanvullende onderzoeken bij randomisatie of tijdens de studie
Before Registration

♦ Registration must occur 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.

The following examinations will be performed within 4 weeks prior to registration.

♦ Informed consent according to ICH/GCP

♦ EORTC Quality of Life Questionnaires (QLQ-C30 + QLQ-EN24).

♦ Demographics: age

♦ Physical examination: height and body weight

♦ Tumor evaluation prior to 1st line treatment (by RECIST 1.1) [will be collected]

Prior to randomization

♦ Tumor tissue: 1 formalin fixed paraffin embedded (FFPE) block of tumor tissue (if not available, at least 1 H/E (haematoxylin/eosin) and 15 unstained slides) must be sent for histological central review and confirmation of diagnosis after registration of patients. Tumor tissue needs to be sent immediately after successful registration. Note: central pathology review results need to be available in order to complete randomization (refer to chapter 17.3).

The following examinations and tests will be performed within 8 weeks before start of protocol treatment and before randomization.

♦ Tumor evaluation (by RECIST 1.1)

♦Complete medical history: use of tamoxifen/oral contraception, concurrent illnesses, and history of past oncological or chronic diseases, extensive summary of first line doxorubicin based chemotherapy (cumulative dose, duration).

♦ Physical examination: including body weight, blood pressure, temperature and WHO/ECOG performance status

♦ Clinical laboratory tests (if the labs performed prior to randomization are also within 3 days of the first dose of study treatment, they do not need to be repeated)

♦ Urine Dipstick.

♦ LVEF (Echo or MUGA).

♦ 12 Lead ECG.

♦ Urine/serum pregnancy test (for women of child-bearing potential).

♦ AE assessment CTCAE 4.0 according to standard practice (per event reporting)

♦ EORTC Quality of Life Questionnaire (QLQ-C30 + QLQ-EN24).

♦ Blood sample for the correlated translational research (15 mL collected in EDTA tubes)

During protocol treatment (cabozantinib/placebo)

Note: The protocol treatment should start within 12 weeks after last administration first line treatment

The following examinations and tests will be performed within 3 days prior to each cycle, unless specified otherwise below.

♦ Physical examination: including body weight, blood pressure, temperature and WHO/ECOG performance status

♦ Clinical laboratory tests (Every 2 weeks for the first 2 cycles, then prior to each cycle (4 weeks).

♦ Urine Dipstick (every 2 week for the first 2 cycles, then prior to each cycle (4 weeks).

♦ 12 Lead ECG (to be done at the beginning of cycle 1 & 2, then every other cycle) and if clinically indicated.

♦ If clinically indicated LVEFs (Echo or MUGA) will be performed.

♦ Urine/serum pregnancy test (For women of child-bearing potential).

♦ The disease will be assessed every 8 weeks during the first year of the maintenance period, then every 12 weeks in the second year of therapy regardless of interruptions and delays in therapy.

♦ All sites that were found to be involved at the initial assessment will be re-investigated by the same method.

♦  AE assessment CTCAE 4.0 according to standard practice (per event reporting)

♦ EORTC Quality of Life Questionnaire (QLQ-C30 + QLQ-EN24) will be assessed every 8 weeks during the first year of the maintenance period, regardless of interruptions and delays in therapy.

♦ Blood sample for the correlated translational research at the end of 1st & 2nd cycles i.e. after 4 & 8 weeks of therapy (if no delays)

At the end of protocol treatment
The following examination should be performed within 30 days after last administration of study drug and before start of any further anti-cancer treatment:

♦ Physical examination: including body weight, blood pressure, temperature and WHO/ECOG performance status

♦ AE assessment CTCAE 4.0 according to standard practice (per event reporting) up to 30 days after last administration of study drug.

♦ The disease will be assessed if disease progression was not the cause of drug discontinuation as described in section 6.2.

♦ 12 Lead ECG

♦ If clinically indicated LVEFs (Echo or MUGA) will be performed.

♦ EORTC Quality of Life Questionnaire (QLQ-C30 + QLQ-EN24)

♦ Blood sample for the correlated translational research at time of permanent discontinuation of study treatment for any reason

Follow-up
As long as patients have not progressed (according to RECIST 1.1) within the official 2 years protocol treatment period, the disease assessment should be performed until documentation of progression every 8 weeks (+/- 1 week) during the first year after randomization and every 12 weeks (+/- 1 week) during the second year and subsequently every 16 weeks until disease progression is documented, follow-up for survival will be done every 6 months.

Flowchart

Samenvatting

Patiënteninformatie

Deelnemende ziekenhuizen:
AMC
Contact persoon: A.M. Westermann, medisch oncoloog AMC, Amsterdam e-mail: secr-onco@amc.nl
Maastricht UMC
Radboud UMC

Controle factsheet: februari 2017