Clinical trial NCT01091168: Trial of Vinflunine Versus Alkylating Agent in Metastatic Breast Cancer
Official title: Phase III Trial of IV Vinflunine Versus an Alkylating Agent in Patients With Metastatic Breast Cancer Previously Treated With or Resistant to an Anthracycline, a Taxane, an Antimetabolite, and a Vinca-alkaloid (Study L00070 IN 308 B0)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Metastases
Lead sponsor: Pierre Fabre Medicament
Sponsor class: INDUSTRY
First posted: 2010-03-23
Enrollment: 594
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In metastatic breast cancer (MBC) patients who have already received anthracyclines, taxanes, antimetabolites and vinca-alkaloids and have developed drug resistance to these drugs, therapeutic options are very limited. Alkylating agents showed a modest activity in pretreated metastatic breast cancer. This phase III trial will compare the effectiveness and the safety profile of vinflunine to an alkylating agent of physician choice in MBC patients who have exhausted anthracyclines, taxanes, antimetabolites and vinca-alkaloids.

Detailed description: Breast cancer is the most frequently diagnosed cancer in women worldwide and the second leading cause of cancer-related deaths in women.

Patients with metastatic breast cancer (MBC) remains incurable, and current goals of therapy are to ameliorate symptoms, delay disease progression, improve or at least maintain quality of life (QoL), and prolong overall survival (OS).There are a number of agents with established single-agent activity, with the anthracyclines and taxanes considered generally the most active. In addition, several drugs with different mechanisms of action such as antimetabolites and vinca-alkaloids have also demonstrated substantial activity in the metastatic setting as single-agents or in combination.

In patients who progress after having received anthracyclines, taxanes, antimetabolites and vinca- alkaloids, therapeutic options are scarce. In this heavily pretreated population for whom overall survival is not expected to exceed 6 to 7 months, there is a clear need for novel therapies.

Vinflunine (VFL) is a microtubule inhibitor obtained by semi-synthesis, interacts with tubulin at the vinca-binding domain and inhibits tubulin assembly by perturbing microtubule dynamics and mitotic spindles without affecting assembled microtubules. VFL antitumour activity was fully demonstrated against a large and varied panel of murine and xenograft models.

The main haematological toxicity reported was the neutropenia Grade 3-4 (40-50%). The incidence of its complications (febrile neutropenia and neutropenic infection) was less than 8%. The main non-haematological toxicity Grade 3-4 (with an incidence more than 10%) reported were constipation and fatigue.

This was a prospective multicentre, open-label, randomised (1:1), phase III study comparing OS in patients treated with vinflunine versus those treated with an alkylating agent of physician's choice as third line treatment or more for patients with locally recurrent and/or metastatic breast cancer previously treated with and no longer candidate to anthracyclines, antimetabolites, taxanes and vinca- alkaloids..

The primary endpoint for the trial was OS. Patients were assessed for toxicity, tumour response and progression and status (alive-dead) at regular intervals during the study treatment and the follow-up period. Patients were treated until disease progression, unacceptable toxicity, patient or investigator's decision. After the study treatment discontinuation, patients were followed until death.

The VFL dose of 280 mg/m² was the selected dose for this phase III study in patients with heavily pre- treated MBC. Indeed, VFL dose was reduced from 320 to 280 mg/m² in advanced transitional cell carcinoma of urothelial tract patients with performance status (PS) of 1 or with PS of 0 and having received prior pelvic irradiation. This dose was more regularly tolerable in patients with advanced disease stage who were heavily pre-treated.

Eligibility criteria: Inclusion Criteria:(main conditions)

* Female patients 18 to 75 years of age with metastatic breast cancer histologically/cytologically confirmed not amenable to curative surgery or radiotherapy and who have received at least two prior chemotherapy regimens including anthracyclines,taxanes,antimetabolite and vinca-alkaloid and are no longer candidate for these drugs,
* Karnofsky performance score of at least 70 %, adequate haematological, hepatic and renal functions and ECG without clinically relevant abnormality.

Exclusion Criteria:

* Concurrent serious uncontrolled medical disorder,
* known or clinical evidence of brain metastases or leptomeningeal involvement,
* pulmonary lymphangitis or symptomatic pleural effusion or symptomatic ascites,
* history of second primary malignancy,
* HIV infection, preexisting neuropathy,
* pregnancy or breast feeding.

Primary outcomes:
measure: Overall Survival
timeFrame: From baseline up to 3 years 1 month
Secondary outcomes:
measure: Disease Control Rate (DCR)
timeFrame: From baseline up to 3 years 1 month
measure: Progression Free Survival (PFS)
timeFrame: From baseline to cut-off date(27 August 2012), up to 3 years
Other outcomes:
Locations:
city: Buenos aires
country: Argentina
city: Quilmes
country: Argentina
city: Rosario
country: Argentina
city: San Martin
country: Argentina
city: Tucuman
country: Argentina
city: Graz
country: Austria
city: Salzburg
country: Austria
city: Vienna
country: Austria
city: Gomel
country: Belarus
city: Grodno
country: Belarus
city: Minsk
country: Belarus
city: Vitebsk
country: Belarus
city: Brussels
country: Belgium
city: Haine Saint Paul
country: Belgium
city: Yvoir
country: Belgium
city: Angers
country: France
city: Brest
country: France
city: Clermont Ferrand
country: France
city: Dijon
country: France
city: Grenoble
country: France
city: Le Mans
country: France
city: Lille
country: France
city: Limoges
country: France
city: Lorient
country: France
city: Montpellier
country: France
city: Nancy
country: France
city: Nantes
country: France
city: Nice
country: France
city: Paris
country: France
city: Pontoise
country: France
city: Reims
country: France
city: Rouen
country: France
city: Saint Brieuc
country: France
city: Saint Priest en Jarez
country: France
city: Strasbourg
country: France
city: Berlin
country: Germany
city: Dortmund
country: Germany
city: Essen
country: Germany
city: Mainz
country: Germany
city: Munich
country: Germany
city: Trier
country: Germany
city: Ancona
country: Italy
city: Aviano
country: Italy
city: Bolzano
country: Italy
city: Brindisi
country: Italy
city: Frattamaggiore
country: Italy
city: Macerata
country: Italy
city: Orbassano
country: Italy
city: Lisboa
country: Portugal
city: Arkhangelsk
country: Russian Federation
city: Engels
country: Russian Federation
city: Moscow
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saratov
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: Stavropol
country: Russian Federation
city: Tambov
country: Russian Federation
city: Ufa
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Durban
country: South Africa
city: Johannesburg
country: South Africa
city: Pretoria
country: South Africa
city: A coruna
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Sevilla
country: Spain
city: Taichung
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan
country: Taiwan
city: Dnipropetrovsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Khmelnytskyi
country: Ukraine
city: Kyiv
country: Ukraine
city: Burnley
country: United Kingdom
city: Cornwell
country: United Kingdom
city: Derby
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Ipswich
country: United Kingdom
city: Preston
country: United Kingdom
city: Worthing
country: United Kingdom
Study officials:
affiliation: Institut de Recherche Pierre Fabre
name: Karim Keddad, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Cortes J, Perez-Garcia J, Levy C, Gomez Pardo P, Bourgeois H, Spazzapan S, Martinez-Janez N, Chao TC, Espie M, Nabholtz JM, Gonzalez Farre X, Beliakouski V, Roman Garcia J, Holgado E, Campone M. Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2018 Apr 1;29(4):881-887. doi: 10.1093/annonc/mdy051.