Clinical trial NCT01583322: Vargatef in Addition to First Line Chemotherapy With Interval Debulking Surgery in Patients With Ovarian Cancer
Official title: Randomized Double Blind Placebo-controlled Phase II Trial of Vargatef® (Nintedanib) in Addition to First Line Chemotherapy With Interval Debulking Surgery in Patients With Adenocarcinoma of the Ovary, the Fallopian Tube or Serous Adenocarcinoma of the Peritoneum
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Cancer
Keywords: ovarian cancer
debulking surgery
interval debulking
vargatef
nintedanib
maintenance
first line
paclitaxel
carboplatin
Lead sponsor: ARCAGY/ GINECO GROUP
Sponsor class: OTHER
First posted: 2012-04-24
Enrollment: 188
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with extensive and bulky disease are often those whose initial surgery is delayed after 3 or 4 cycles of neo-adjuvant chemotherapy.

In that case, there is, indeed, some concern to administer bevacizumab during the chemotherapy surrounding the interval debulking surgery due to the long half life (14- 21 days) of this monoclonal antibody and the interference of anti angiogenic agents with wound healing.

Vargatef® (Nintedanib) might offer a better alternative to bevacizumab in the neo-adjuvant setting. Vargatef® (Nintedanib) has a much shorter half-life of 7 to 19 hours. Preliminary experience in cancer did not show a trend for increased incidence of fistula or bowel perforation. For more details please refer to the investigator drug brochure for Vargatef® (Nintedanib).

This trial will compare progression-free survival and surgical complications of 188 patients with FIGO stage IIIC/IV treated in first line with either neo-adjuvant chemotherapy (carboplatin \& paclitaxel) and interval debulking surgery or the same treatment + Vargatef® (Nintedanib).


Eligibility criteria: Inclusion Criteria:

* First diagnosis of histological confirmed (cytology alone excluded) epithelial ovarian cancer, fallopian tube or primary peritoneal cancer. Histology should be obtained by laparoscopy (or by laparotomy),
* FIGO-Stages IIIC - IV,
* ECOG performance status \< 2,
* Life expectancy of at least 6 months,
* Primary debulking surgery denied and maximum surgical effort of cytoreduction with the goal of no residual disease planned as interval debulking surgery,
* Interval between diagnosis and enrolment (informed consent) ≤ 8 weeks,
* Adequate hepatic, renal and bone marrow functions:

Platelets \> 100 000 /μL, Hemoglobin \> 9.0 g/dL, Absolute Neutrophil Count (ANC) \> 1500/μL, Prothrombin time and/or partial thromboplastin time \< 50% deviation from normal limits in the absence of therapeutic anticoagulation, Proteinuria \< CTCAE grade 2, Total bilirubin ≤ upper limit of normal (ULN), ALT and/or AST ≤ 2.5 x ULN, Glomerular filtration rate \>40 mL/min,

* Females, age 18 years or older,
* Patient has given written informed consent,

Exclusion Criteria:

* Histological diagnosis of malignant tumour of non-epithelial origin (e.g. germ cell tumour, malignant mixed mullerian tumour, sex cord-stromal tumour) of the ovary, the fallopian tube or peritoneum or borderline tumour of the ovary (tumour of low malignant potential),
* Non-healing wound, ulcer (intestinal tract, skin) or bone fracture,
* Clinical symptoms or signs of gastrointestinal obstruction,
* History of major thromboembolic event, defined as:

  * Pulmonary embolism (PE) within 6 months prior to enrolment,
  * Recurrent pulmonary embolism (history of at least 2 events),
* History of at least 2 unprovoked (without a transient or reversible risk factor) events of proximal deep venous thrombosis,
* Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation, Prothrombin G20210A mutation),
* Patients with perioperative thrombosis including proximal deep vein thrombosis (DVT) or thrombosis of visceral vessels not associated with pulmonary embolism may be included in the trial if stable therapeutic anticoagulation is documented,
* Known inherited or acquired bleeding disorder,
* Significant cardiovascular diseases, including:

  * Hypertension not controlled by medical therapy,
  * Unstable angina within the past 6 months,
  * History of myocardial infarction within the past 6 months,
  * Congestive heart failure \> NYHA II,
  * Clinically relevant cardiac arrhythmia
* Peripheral vascular disease Fontaine stage ≥3,
* Clinically relevant pericardial effusion (e.g. pericardial effusion with echocardiographic or clinical signs of haemodynamic impairment),
* History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 6 months,
* Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including HIV-infection, hepatitis B and/or C infection,
* Poorly controlled diabetes mellitus or other contraindication to high dose corticosteroid therapy,
* Clinical symptoms of brain metastases and/or diagnosis of brain metastases on imaging,
* Pre-existing sensory or motor neuropathy CTCAE ≥ 2, except due to trauma,
* Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug,
* Other malignancy diagnosed within the past 5 years, except:

  * non-melanomatous skin cancer (if adequately treated),
  * cervical carcinoma in situ (if adequately treated),
  * carcinoma in situ of the breast (if adequately treated),
  * prior or synchronous endometrial cancer (if adequately treated), provided the following criteria are met:

    * Disease stage FIGO ≤ IB,
    * No more than superficial myometrial invasion,
    * Not poorly differentiated (less than grade 3, no papillary serous or clear cell histology),
* Prior systemic therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, oral targeted therapy, hormonal therapy),
* Prior radiotherapy to the abdomen or prior radiotherapy to an extra-abdominal target volume that would bear the risk of increased toxicity of chemotherapy,
* Hypersensitivity to Vargatef® (Nintedanib) and/or the excipients of the trial drugs,
* Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease, active ulcers (gastrointestinal tract, skin) or a laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study,
* Patients with preserved reproductive capacity who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner) during the trial and for at least twelve months after end of active therapy,
* Pregnancy or breast feeding,
* Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule,
* Active alcohol or drug abuse,
* Any contraindications for therapy with paclitaxel or carboplatin, e.g. a history of severe hypersensitivity reactions to paclitaxel or platinum-containing compounds and their excipients, or other drugs formulated with Polyoxyl 35 Castor Oil - ELP,
* Treatment with other investigational drugs or participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial.

Primary outcomes:
measure: Median Progression-free Survival (PFS) in each study arm
timeFrame: average of 18 months
Secondary outcomes:
measure: Response rate
timeFrame: 2 months after beginning of treatment
Other outcomes:
Locations:
city: Angers
country: France
facility: Centre Paul Papin
city: Avignon
country: France
facility: Institut Ste Catherine
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Contamine-sur-Arve
country: France
facility: Centre Hospitalier Alpes Leman
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dax
country: France
facility: Centre Hospitalier de Dax
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille - Hôpital Huriez
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Dupuytren
city: Lyon
country: France
facility: Centre Léon bérard
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nantes
country: France
facility: Centre Catherine de Sienne
city: Nantes
country: France
facility: Hôpital Privé du Confluent S.A.S.
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Orléans
country: France
facility: Centre Hospitalier Régional
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: Institut Mutualiste Montsouris-Jourdan
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon-sud
city: Poitiers
country: France
facility: Milétrie - Centre Hospitalier Universitaire de Poitiers
city: Reims
country: France
facility: Institut Jean Godinot
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Brieuc
country: France
facility: Clinique Armoricaine de Radiologie
city: Saint-Cloud
country: France
facility: Hôpital René Huguenin
city: St Herblain
country: France
facility: ICO René Gauducheau
city: Strasbourg
country: France
facility: Hôpital Civil
city: Thonon-les-Bains
country: France
facility: Hôpitaux Du Leman
city: Toulouse
country: France
facility: Centre Claudius Régaud
city: Vandoeuvre-Les-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Institut Claudius Régaud
name: Gwénaël Ferron, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aide N, Fauchille P, Coquan E, Ferron G, Combe P, Meunier J, Alexandre J, Berton D, Leary A, De Rauglaudre G, Bonichon N, Pujade Lauraine E, Joly F. Predicting tumor response and outcome of second-look surgery with 18F-FDG PET/CT: insights from the GINECO CHIVA phase II trial of neoadjuvant chemotherapy plus nintedanib in stage IIIc-IV FIGO ovarian cancer. Eur J Nucl Med Mol Imaging. 2021 Jun;48(6):1998-2008. doi: 10.1007/s00259-020-05092-3. Epub 2020 Nov 21.
citation: Robelin P, Tod M, Colomban O, Lachuer J, Ray-Coquard I, Rauglaudre G, Joly F, Chevalier-Place A, Combe P, Lortholary A, Hamizi S, Raban N, Ferron G, Meunier J, Berton-Rigaud D, Alexandre J, Kaminsky MC, Dubot C, Leary A, Malaurie E, You B. Comparative analysis of predictive values of the kinetics of 11 circulating miRNAs and of CA125 in ovarian cancer during first line treatment (a GINECO study). Gynecol Oncol. 2020 Oct;159(1):256-263. doi: 10.1016/j.ygyno.2020.07.021. Epub 2020 Jul 22.