Transcript BGOG-cx1 - Mito Group

Coordinating investigator: Prof Dr. Ignace Vergote
Rationale and objectives
• Rationale
– Dominant role of angiogenesis related to HPV inhibition of
p53 and stabilization of HIF-1 alfa → increase of VEGF.
– Previous studies confirmed activity of anti-angiogenesis
agents in advanced and recurrent cervical cancer.
• Objectives
– Primary:
• Progression free survival (RECIST 1.1)
– Secondary:
• Toxicity and safety
• Response rate and overall survival
• Patient reported health status (QOL-CX24 and QOQ-C30)
Patients (# 120) with histologically or cytologically confirmed squamous,
adenosquamous or adenocarcinoma of the cervix
Advanced stage (FIGO stage IVB)
OR Recurrent/persistent disease
1:1 Randomization IXRS
Nintedanib 200 mg p.o. BID
Placebo p.o. BID
PLUS
PLUS
Paclitaxel 175 mg/m2 + carboplatin
AUC5
Paclitaxel 175 mg/m2 + carboplatin
AUC5
Every 21 days for 6 cycles
Every 21 days for 6 cycles
Nintedanib monotherapy up to 120
weeks
Placebo monotherapy up to 120 weeks
End of Treatment
Randomization
* * * * * *
* No Nintedanib on day 1 of
each cycle!
6 Combi-Cycles
Screening
-28 to –D1
Required CT /MRI scans
(baseline, week 9, 18, 25, 49,61,121)
Maintenance therapy
Treatment duration: up to 120 weeks
3 Weekly Pacl/Carbo + Nintedanib/Placebo
Maintenance therapy with Nintedanib/Placebo
FU 3 y
BGOG-cx1: Locations
European Network of
Gynaecological Oncological Trial
Groups (ENGOT)
Sites participating in:
- Belgium (BGOG)
- Spain (GEICO)
- Germany (NOGGO)
- Italy (MITO / ManGO)
- UK (NCRI)
Target: 120 patients, 30 sites
Study Timelines
Milestone
Estimated timing
First patient in
March 2014
Last patient in
Dec 2017
Last patient out
Dec 2019
Primary analysis
1,5 y after LPI (July 2019)
Secondary analysis
5 y after LPI (Dec 2022)
Accrual overview
Group
Randomized
On treatment
End of
treatment
(chemo+nint)
End of
trial (FU
compl)
BGOG
22
7
9
6
GEICO
15
11
3
1
NOGGO
0
0
0
0
MANGO
0
0
0
0
MITO
0
0
0
0
37/120
18/37
12/37
7/37
Status MITO
• AIFA did not authorize the study
• An amended protocol is being submitted
New exclusion criteria:
• Active or chronic hepatitis C and/or B infection or
known HIV infection (based on medical file, only
for Italy a mandatory screening test for HIV
should be performed for all patients who did not
have this test within the last 3 months before
the study treatment start).
• Extra slides with inclusion and exclusion
criteria follow if needed
Inclusion criteria
• Women age > 18.
• Histologically or cytologically confirmed advanced (FIGO stage
IVB), or recurrent/persistent squamous cell carcinoma,
adenosquamous carcinoma, or adenocarcinoma of the cervix
• ECOG score 0 or 1
• At least one measurable lesion according to RECIST 1.1
criteria.
• Life expectancy of at least 3 months
• Informed consent
Inclusion criteria continued
•
No prior chemotherapy for recurrent cervical cancer, except:
– Prior concomitant cisplatinum chemotherapy during radiotherapy is
allowed (except if recurrence is within 6 months after the end of the
platinum containing chemotherapy).
– Cases primarily treated with neoadjuvant chemotherapy before radical
local surgery are eligible at the time of first recurrence. (except if…)
– Cases primarily treated with neoadjuvant chemotherapy before radical
local surgery followed by adjuvant radiochemotherapy are eligible at the
time of first recurrence (except if …)
– Cases primarily treated with neoadjuvant chemotherapy before radical
local surgery followed by adjuvant radiotherapy are eligible at the time
of first recurrence (except if …)
Exclusion criteria
•
Prior chemotherapy for advanced (FIGO stage IVB) or recurrent disease
(except if…)
•
Prior treatment with nintedanib or any other VEGFR inhibitor.
•
Known hypersensitivity to the trial drugs or to their excipients (including
peanut or soya).
•
Brain or leptomeningeal metastases.
•
Centrally located tumors with radiographic evidence (CT or MRI) of local
invasion of major blood vessels.
•
Tumor infiltrating the mucosa of the bowel or bladder, or known fistulas
between the tumor and the gastrointestinal or urinary tract.
•
Radiographic evidence of cavitary or necrotic tumours
•
Treatment with other investigational drugs or treatment in another clinical
trial within the past 4 weeks before start of therapy or concomitantly with
the trial.
Exclusion criteria continued
•
Therapeutic anticoagulation with drugs requiring INR monitoring (except low dose
heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous
device) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid
<325 mg per day).
•
Major injuries within the past 4 weeks prior to start of study treatment with
incomplete wound healing and/or planned surgery during the on-treatment study
period.
•
History of clinically significant haemorrhagic or thromboembolic event, cerebral
vascular accident, transient ischemic attack or subarachnoid haemorrhage in the past
6 months
•
Known inherited predisposition to bleeding or thrombosis.
•
Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina,
history of infarction within the past 12 months, congestive heart failure, serious cardiac
arrhythmia, pericardial effusion)
Exclusion criteria continued
•
Abnormal renal, liver or bone marrow function defined as:
– Proteinuria CTCAE grade 2 or greater
– Creatinine > 1,5 ULN or GFR < 45 ml/min
– Hepatic function:
• total bilirubin outside of normal limits;
• ALT or AST > 1.5 ULN in pts without liver metastasis.
• For Pts with liver metastases: total bilirubin outside of normal limits, ALT or
AST > 2.5 ULN
– Absolute neutrophil count ( ANC) < 1500/µl, platelets < 100000/µl,
– Haemoglobin < 9.0 g/dl
•
Coagulation parameters:
– International normalised ratio (INR) > 2, prothrombin time (PT) and partial
thromboplastin time (PTT) > 50% of deviation of institutional ULN
Exclusion criteria continued
•
Other malignancies within the past 3 years or other malignancy with recurrence in the
past 3 years or with high risk of recurrence in the first year. In exception nonmelanomatous skin cancer (if adequately treated) , any premalignant (e.g. in situ)
carcinoma, or basocellular carcinoma.
•
Active serious infections in particular if requiring systemic antibiotic or antimicrobial
therapy
•
Active or chronic hepatitis C and/or B infection or known HIV infection (based on
medical file, only for Italy a mandatory screening test for HIV should be
performed for all patients who did not have this test within the last 3 months
before the study treatment start).
•
Gastrointestinal disorders or abnormalities that would interfere with absorption of the
study drug.
•
Serious illness or concomitant non-oncological disease (neurologic, psychiatric,
infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory
abnormality
Exclusion criteria continued
• Patients of child-bearing potential* who are sexually active and unwilling
to use a medically acceptable method of contraception (during the trial
and for at least three months after end of active therapy).
• Pregnancy or breast feeding, female patients must have a negative
pregnancy test (β-HCG test in urine or serum) prior to commencing study
treatment, if applicable.
• Psychological, familial, sociological or geographical factors potentially
hampering compliance with the study protocol and follow-up schedule
• Active alcohol or drug abuse.
*all patients unless those who are surgically sterilised by hysterectomy or bilateral tubal
ligation/salpingectomy, or post-menopausal for at least one year, or above the age of 60.
Randomization
•
After assessment in-and exclusion criteria
•
Patient will be stratified at the end of screening (3 strata):
– Advanced disease Stage IVB
– Recurrent disease with prior neoadjuvant chemo or chemoradiotherapy (p12
protocol)
– Recurrent disease without prior neoadjuvant chemo or chemoradiotherapy (p12
protocol)
In IXRS, the stratification is performed by answering 2 questions:
1) Disease status of the patient (Stage IVB / recurrent)
2) Prior neoadjuvant chemo or chemoradiotherapy (Y / N)