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European Trial on Enhanced DNA Repair Inhibition in Ovarian Cancer (EUDARIO)

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ClinicalTrials.gov Identifier: NCT03783949
Recruitment Status : Recruiting
First Posted : December 21, 2018
Last Update Posted : December 21, 2018
Sponsor:
Collaborator:
European Commission
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Brief Summary:

This study will be performed in women with platinum-sensitive, high-grade serous, high-grade endometrioid, undifferentiated epithelial ovarian cancer, carcinosarcoma, fallopian tube or primary peritoneal cancer (proven by central histo-pathological review).

A total of 120 subjects will be randomized (1:1:1) to three different treatment arms: (A) Standard arm (arm A): Carboplatin (AUC5 d1, q3w i.v.) in combination with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, q4w) // (B) First experimental arm (arm B): Ganetespib (150 mg/m2, d1, q3w) in combination with Carboplatin (AUC5 d1, q3w i.v.) followed by maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w) // (C) Second experimental arm (arm C): Ganetespib (150 mg/m² d1, q3w i.v.) plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w).

Chemotherapy treatment will be given for 6 cycles, maintenance treatment with Ganetespib will be given for a maximum of 9 months or until disease progression, maintenance treatment with Niraparib can continue until disease progression.


Condition or disease Intervention/treatment Phase
Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Carcinoma Drug: Ganetespib Drug: Niraparib Drug: Carboplatin Drug: Paclitaxel Drug: Gemcitabine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Standard arm (arm A): Carboplatin (AUC5 d1, q3w i.v.) in combination with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, q4w) First experimental arm (arm B): Ganetespib (150 mg/m2, d1, q3w) in combination with Carboplatin (AUC5 d1, q3w i.v.) followed by maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w) Second experimental arm (arm C): Ganetespib (150 mg/m² d1, q3w i.v.) plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentre, Open-label, Three-arm Randomised Phase II Trial Assessing the Safety and Efficacy of the HSP90 Inhibitor Ganetespib in Combination With Carboplatin Followed by Maintenance Treatment With Niraparib Versus Ganetespib Plus Carboplatin Followed by Ganetespib and Niraparib Versus Carboplatin in Combination With Standard Chemotherapy Followed by Niraparib Maintenance Treatment in Platinum-sensitive Ovarian Cancer Patients
Actual Study Start Date : November 30, 2018
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : June 30, 2022


Arm Intervention/treatment
Active Comparator: Standard arm (arm A)
Carboplatin (AUC5 d1, q3w i.v.) in combination with Paclitaxel (175 mg/m² d1, q3w i.v.) or Carboplatin (AUC4 d1, q3w i.v.) in combination with Gemcitabine (1000 mg/m² d1, d8, q3w i.v.) followed by maintenance therapy with Niraparib (200/ 300 mg oral daily, q4w)
Drug: Niraparib
Niraparib starting dose during maintenance treatment will be 200mg or 300mg depending on subject's body weight and subject neutrophil count (QD)

Drug: Carboplatin
In combination with Gemcitabine: Carboplatin dose will be AUC4 (q3w) In combination with Paclitaxel: Carboplatin dose will be AUC5 (q3w)

Drug: Paclitaxel
Paclitaxel dose will be 175mg/m² (q3w)

Drug: Gemcitabine
Gemcitabine dose will be 1000mg/m² (q3w, d1 & d8)

Experimental: First experimental arm (arm B)
Ganetespib (150 mg/m2, d1, q3w) in combination with Carboplatin (AUC5 d1, q3w i.v.) followed by maintenance treatment with Niraparib (200/ 300 mg oral daily, q4w)
Drug: Ganetespib
Ganetespib dose during chemotherapy will be 150mg/m² (q3w) Ganetespib dose during maintenance treatment will be 100mg/m² (q1w)

Drug: Niraparib
Niraparib starting dose during maintenance treatment will be 200mg or 300mg depending on subject's body weight and subject neutrophil count (QD)

Drug: Carboplatin
In combination with Gemcitabine: Carboplatin dose will be AUC4 (q3w) In combination with Paclitaxel: Carboplatin dose will be AUC5 (q3w)

Experimental: Second experimental arm (arm C)
Ganetespib (150 mg/m² d1, q3w i.v.) plus Carboplatin (AUC5 d1, q3w i.v.) followed by Ganetespib (100 mg/m² d1, d8, d15, d22, q4w i.v.) and Niraparib (200 mg oral daily, q4w)
Drug: Ganetespib
Ganetespib dose during chemotherapy will be 150mg/m² (q3w) Ganetespib dose during maintenance treatment will be 100mg/m² (q1w)

Drug: Niraparib
Niraparib starting dose during maintenance treatment will be 200mg or 300mg depending on subject's body weight and subject neutrophil count (QD)

Drug: Carboplatin
In combination with Gemcitabine: Carboplatin dose will be AUC4 (q3w) In combination with Paclitaxel: Carboplatin dose will be AUC5 (q3w)




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 3 years 10 months ]
    Progression-free survival (PFS) by RECIST 1.1


Secondary Outcome Measures :
  1. Progression-free survival subgroup analysis [ Time Frame: 3 years 10 months ]
    Progression-free survival subgroup analysis

  2. Post-progression PFS (PFS2) [ Time Frame: 3 years 10 months ]
    Post-progression PFS (PFS2)

  3. Time to First Subsequent Therapy (TFST) [ Time Frame: 3 years 10 months ]
    Time to First Subsequent Therapy (TFST)

  4. Time to Second Subsequent Therapy (TSST) [ Time Frame: 3 years 10 months ]
    Time to Second Subsequent Therapy (TSST)

  5. Safety: Adverse events (AEs) [ Time Frame: 3 years 10 months ]
    Safety: Adverse events (AEs), measure according to NCI CTCAE, version 4.03

  6. Objective response rate (ORR) [ Time Frame: 3 years 10 months ]
    Objective response rate (ORR)

  7. Patients general health, functionality and well-being assessment using QLQ-C30 questionnaire [ Time Frame: 3 years 10 months ]
    Patient-reported outcome (PRO) questionnaire (QLQ-C30) will be used to assess patient's general health, functionality and well-being

  8. Overall survival (OS) [ Time Frame: 3 years 10 months ]
    Overall survival (OS)

  9. Patients general health, functionality and well-being assessment using QLQ-ov28 questionnaire [ Time Frame: 3 years 10 months ]
    Patient-reported outcome (PRO) questionnaire (QLQ-ov28) will be used to assess patient's general health, functionality and well-being

  10. Patients gastro-intestinal symptoms using Gastro-intestinal symptoms questionnaire [ Time Frame: 3 years 10 months ]
    Patient-reported outcome (PRO) questionnaire (gastro-intestinal symptoms) will be used to assess patient's gastro-intestinal symptoms


Other Outcome Measures:
  1. Biomarker analysis [ Time Frame: 3 years 10 months ]
    Biomarker analysis on DNA level (e.g. free circulating tumour DNA)

  2. Biomarker analysis [ Time Frame: 3 years 10 months ]
    Biomarker analysis on RNA level

  3. Biomarker analysis [ Time Frame: 3 years 10 months ]
    Biomarker analysis on protein level (e.g. circulating tumour cells)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must meet the following criteria to be eligible for study entry:

    • Ability to understand and willingness to sign and date a written informed consent document
    • Female patients ≥18 years of age
    • High-grade serous, high-grade endometrioid, undifferentiated epithelial ovarian cancer, carcinosarcoma, fallopian tube or primary peritoneal cancer
    • Platinum-sensitive relapse >6months after previous platinum-based treatment (calculated from the first day of the last cycle of the last platinum-based chemotherapy until the date of progression confirmed according to RECIST 1.1 on imaging)
    • No limits in number of prior lines
    • Measurable or evaluable disease according to RECIST 1.1
    • ECOG performance status 0-1
    • Adequate functions of the bone marrow
  • Platelets ≥ 100 x 109/L
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

    • Adequate function of the organs

  • Creatinine < 2 mg/dl (<177 μmol/L)
  • Total bilirubin ≤ 1.5 x upper limit of normal (≤ 2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN
  • SGOT/SGPT (AST/ALT) ≤ 2.5 x upper limit of normal unless liver metastases are present, in which case they must be ≤ 5 x ULN
  • Urinanalysis or urine dipstick for proteinuria less than 2+. Patients with ≥ 2+ on dipstick should undergo 24-hour urine collection and must demonstrate < 1 g of protein/24 hours; except the proteinuria is clearly related to a catheter in the urinary system.

    • Adequate coagulation parameter: aPTT ≤ 1.5 x ULN (patients on heparin treatment must have an aPTT between 1.5-2.5 x ULN), or INR ≤ 1.5. (In patients receiving anticoagulants (such as warfarin) INR must be between 2.0 and 3.0 in two consecutive measurements 1-4 days apart).
    • Participant receiving corticosteroids (dose < 10 mg/day methylprednisolone equivalent), including inhaled steroids, may continue as long as their dose is stable for at least 4 weeks prior to initiating protocol therapy.
    • Participants must agree to not donate blood during the study or for 90 days after the last dose of study treatment
    • Female participant has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-childbearing potential is defined as follows (by other than medical reasons):
  • ≥ 45 years of age and has not had menses for >1 year
  • Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
  • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by imaging. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See below for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
  • Birth Control: Participants of childbearing potential who are sexually active and their partners must agree to the use of a highly effective form of contraception throughout their participation beginning with time of consent, during the study treatment and for 180 days after last dose of study treatment(s):

    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

      • Oral route
      • Intravaginal route
      • Transdermal route
    • Progestogen-only hormonal contraception associated with inhibition of ovulation

      • Oral
      • Injectable
      • Implantable
    • Intrauterine device
    • Intrauterine hormone-releasing system
    • Bilateral tubal occlusion
    • Vasectomized partner
    • Sexual abstinence, if the preferred and usual lifestyle of the subject

      • Participant must agree to not breastfeed (or store breast milk for use) during the study or for 180 days afer the last dose of study treatment.
      • Haemoglobin ≥8.5 g/dl (patients may not receive a transfusion within 4 weeks prior to initiating study treatment)
      • Able to take oral medications
      • Availability of archival ovarian cancer tissue from primary diagnosis (delivery of FFPE block or slides is prerequisite for randomisation)

Exclusion Criteria:

  • Patients who meet any of the following criteria will be excluded from study entry:

    • Ovarian tumours with low malignant potential (i.e. borderline tumours)
    • Any prior radiotherapy to the pelvis or abdomen, or any radiotherapy encompassing > 20 % of the bone marrow within 2 weeks, or any radiotherapy within 1 week prior to Day 1 of protocol therapy
    • Surgery (including open biopsy and traumatic injury) within 4 weeks prior to first dose of Ganetespib, or anticipation of the need for major surgery during study treatment
    • Minor surgical procedures, within 24 hours prior to the first study treatment
    • Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Any serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.

  • Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin (>325 mg/day).
  • Patients with a history of diagnosis, detection or treatment of any prior malignancies ≤ 2 years prior to initiating protocol therapy, except: basal or squamous cell carcinoma of the skin and cervical cancer that has been definitively treated.
  • Clinically significant gastro-intestinal (GI) tract abnormalities that may increase the risk for GI bleeding and / or perforation 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), history of bowel obstruction within 1 year prior to first study treatment (excluding postoperative, i.e. within 4 weeks post surgery), other GI condition with increased risk of perforation such as recurrence deeply infiltrating into the muscularis or mucosa of the rectosigmoid or the mucosa of the bladder, or history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
  • Non-healing wound or non-healing bone fracture
  • Patients with symptomatic brain or leptomeningeal metastases (patients who are asymptomatic since treatment of brain or leptomeningeal metastases, eg. after irradiation, are eligible)
  • Left ventricular ejection fraction (LVEF) defined by ECHO below the institutional lower limit of normal
  • Cerebrovascular accident (CVA)/ stroke or transient ischemic attack (TIA) or sub-arachnoid haemorrhage within ≤ 6 months prior to first study treatment.
  • Significant cardiac disease: New York Heart Association (NYHA) Class 3 or 4; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty or coronary atrial or ventricular cardiac arrhythmias
  • History of prolonged QT syndrome, or family member with prolonged QT syndrome
  • QTc interval > 470 msec when 3 consecutive ECG values are averaged
  • Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g. sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted
  • Second- or third-degree atrioventricular (AV) block, except: treated with a permanent pacemaker Complete left bundle branch block (LBBB)
  • History of evidence of haemorrhagic disorders, patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorders, coagulopathy or tumour involving major vessels.
  • Participation in another clinical study with experimental therapy within 28 days before start of treatment.
  • Participant must not be simultaneously enrolled in any interventional clinical trial.
  • Women who are pregnant or are lactating
  • Patients unable to be regularly followed for any reason (geographic, familiar, social, psychologic, housed in an institution eg. prison because of a court agreement or administrative order)
  • Subjects that are dependent on the sponsor/CRO or investigational site as well as on the investigator.
  • History of known hypersensibility against any medication used in the study
  • Intolerance / Hypersensitivity reactions to components and excipients of study drugs
  • Peripheral neuropathy of grade >2 per NCI CTCAE, version 4.03, within 4 weeks prior to randomisation
  • Any other condition that, in the opinion of the investigator, may compromise the safety, compliance of the patient, or would preclude the patient from successful completion of the study

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): NCT03783949


Contacts
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Contact: Joke De Roover +32 16 347 419 joke.deroover@uzleuven.be
Contact: Ellen Reynders +32 16 342 996 ellen.reynders@uzleuven.be

Locations
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Austria
Medical University of Innsbruck Not yet recruiting
Innsbruck, Austria, 6020
Contact: Nicole Concin, MD    0043 512 50423 051    nicole.concin@i-med.ac.at   
Principal Investigator: Nicole Concin, MD         
Belgium
UZLeuven Recruiting
Leuven, Vlaams-Brabant, Belgium, 3000
Contact: Joke De Roover    +32 16 347 419    joke.deroover@uzleuven.be   
Contact: Ellen Reynders    +32 16 342 996    ellen.reynders@uzleuven.be   
Principal Investigator: Ignace Vergote, MD         
France
Centre de lutte contre le cancer Francois Baclesse Not yet recruiting
Caen, France, 14076
Contact: Florence Joly, MD    0033 231 455002    f.joly@baclesse.unicancer.fr   
Principal Investigator: Florence Joly, MD         
Centre anticancereux Leon Berard Not yet recruiting
Lyon, France, 69008
Contact: Isabelle Ray-Coquard, MD    0033 478 782888    isabelle.raycoquard@lyon.unicancer.fr   
Principal Investigator: Isabelle Ray-Coquard, MD         
Assistance Publique Hôpitaux de Paris Not yet recruiting
Paris, France, 75004
Contact: Eric Pujade-Lauraine, MD    0033 1 42348 325    eric.pujade-lauraine@htd.aphp.fr   
Principal Investigator: Eric Pujade-Lauraine, MD         
Germany
Universitätsmedizin Berlin Charité Not yet recruiting
Berlin, Germany, 10117
Contact: Regina Schlieder    +4930 - 868 001 40 - 5    regina.schlieder@charite.de   
Principal Investigator: Jalid Sehouli, MD         
Universitätsklinikum Dresden Not yet recruiting
Dresden, Germany, 01069
Contact: Pauline Wimberger, MD    0049 351 45835 08    pauline.wimberger@uniklinikum-dresden.de   
Principal Investigator: Pauline Wimberger, MD         
Kliniken Essen Mitte, Evang. Huyssens- Stiftung/Knappschaft GmbH Not yet recruiting
Essen, Germany, 45136
Contact: Andreas du Bois, MD    0049 201 17434444    prof.dubois@googlemail.com   
Principal Investigator: Andreas du Bois, MD         
Ernst-Moritz-Arndt-Universität Greifswald Not yet recruiting
Greifswald, Germany, 17487
Contact: Alexander Mustea, MD    0049 383 4866532    mustea@uni-greifswald.de   
Principal Investigator: Alexander Mustea, MD         
Universitätsklinikum Hamburg-Eppendorf Not yet recruiting
Hamburg, Germany, 20246
Contact: Barbara Schmalfeldt, MD    0049 40 741052 510    b.schmalfeldt@uke.de   
Principal Investigator: Barbara Schmalfeldt, MD         
Italy
Azienda Ospedaliero Bologna Not yet recruiting
Bologna, Italy, 40138
Contact: Claudio Zamagni, MD    0039 51 2144548    claudio.zamagni@aosp.bo.it   
Principal Investigator: Claudio Zamagni, MD         
Fondazione IRCCS Istituto Nazionale dei tumori Milano Not yet recruiting
Milan, Italy, 20133
Contact: Domenica Lorusso, MD    0039 223 903697    Domenica.Lorusso@istitutotumori.mi.it   
Principal Investigator: Domenica Lorusso, MD         
Università Cattolica del Sacro Cuore Not yet recruiting
Rome, Italy, 00168
Contact: Giovanni Scambia, MD    0039 6 30154979    giovanni.scambia@unicatt.it   
Principal Investigator: Giovanni Scambia, MD         
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
European Commission

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Responsible Party: Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT03783949     History of Changes
Other Study ID Numbers: 2017-004058-40
First Posted: December 21, 2018    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Universitaire Ziekenhuizen Leuven:
Ganetespib
Niraparib

Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Fallopian Tube Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Gemcitabine
Carboplatin
Niraparib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites