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

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

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.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Primary Peritoneal Carcinoma
• Intervention / Treatment: Drug: Niraparib; Drug: Carboplatin; Drug: Paclitaxel; Drug: Gemcitabine; Drug: Ganetespib

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medical University of Innsbruck
• Belgium
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZLeuven
• France
  • Caen, France, 14076
    • Centre de Lutte Contre Le Cancer Francois Baclesse
  • Lyon, France, 69008
    • Centre anticancereux Leon Berard
  • Paris, France, 75004
    • Assistance Publique Hopitaux de Paris
• Germany
  • Berlin, Germany, 10117
    • Universitatsmedizin Berlin Charite
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Dresden, Germany, 01069
    • Universitätsklinikum Dresden
  • Essen, Germany, 45136
    • Kliniken Essen Mitte, Evang. Huyssens- Stiftung/Knappschaft GmbH
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf
• Italy
  • Bologna, Italy, 40138
    • Azienda Ospedaliero Bologna
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori Milano
  • Rome, Italy, 00168
    • Universita Cattolica del Sacro Cuore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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: 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: Ganetespib; Ganetespib dose during chemotherapy will be 150mg/m² (q3w) Ganetespib dose during maintenance treatment will be 100mg/m² (q1w)
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: 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: Ganetespib; Ganetespib dose during chemotherapy will be 150mg/m² (q3w) Ganetespib dose during maintenance treatment will be 100mg/m² (q1w)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival (PFS) by RECIST 1.1	3 years 10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival subgroup analysis	Progression-free survival subgroup analysis	3 years 10 months
Post-progression PFS (PFS2)	Post-progression PFS (PFS2)	3 years 10 months
Time to First Subsequent Therapy (TFST)	Time to First Subsequent Therapy (TFST)	3 years 10 months
Time to Second Subsequent Therapy (TSST)	Time to Second Subsequent Therapy (TSST)	3 years 10 months
Safety: Adverse events (AEs)	Safety: Adverse events (AEs), measure according to NCI CTCAE, version 4.03	3 years 10 months
Objective response rate (ORR)	Objective response rate (ORR)	3 years 10 months
Patients general health, functionality and well-being assessment using QLQ-C30 questionnaire	Patient-reported outcome (PRO) questionnaire (QLQ-C30) will be used to assess patient's general health, functionality and well-being	3 years 10 months
Overall survival (OS)	Overall survival (OS)	3 years 10 months
Patients general health, functionality and well-being assessment using QLQ-ov28 questionnaire	Patient-reported outcome (PRO) questionnaire (QLQ-ov28) will be used to assess patient's general health, functionality and well-being	3 years 10 months
Patients gastro-intestinal symptoms using Gastro-intestinal symptoms questionnaire	Patient-reported outcome (PRO) questionnaire (gastro-intestinal symptoms) will be used to assess patient's gastro-intestinal symptoms	3 years 10 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker analysis	Biomarker analysis on DNA level (e.g. free circulating tumour DNA)	3 years 10 months
Biomarker analysis	Biomarker analysis on RNA level	3 years 10 months
Biomarker analysis	Biomarker analysis on protein level (e.g. circulating tumour cells)	3 years 10 months

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: European Commission

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2018
• Primary Completion (Actual): September 1, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: December 14, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 21, 2018

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Niraparib; Ganetespib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Poly(ADP-ribose) Polymerase Inhibitors; Carboplatin; Paclitaxel; Niraparib; Gemcitabine
• Other Study ID Numbers: 2017-004058-40

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No