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General study presentation NUCOG I - VINGEM. NUCOG meeting Copenhagen 19 th of November 2013 Karin Holmsten , Consultant Department of Oncology Karolinska University Hospital, Stockholm. NUCOG I - VINGEM.

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general study presentation nucog i vingem

General study presentationNUCOG I - VINGEM

NUCOG meeting

Copenhagen 19thof November 2013

Karin Holmsten, Consultant

Department of Oncology

Karolinska University Hospital, Stockholm

slide2

NUCOG I - VINGEM

“A randomized multicenter study of carboplatin/gemcitabine versus vinflunine/gemcitabine as first line treatment in patients with metastatic urothelial carcinoma unfit for cisplatin based chemotherapy due to impaired renal function”

slide3

NUCOG I - VINGEM

“A randomized multicenter study of carboplatin/gemcitabine versus vinflunine/gemcitabine as first line treatment in patients with metastatic urothelial carcinoma unfit for cisplatin based chemotherapy due to impaired renal function”

slide4

NUCOG I - VINGEM

“A randomized multicenter study of carboplatin/gemcitabine versus vinflunine/gemcitabine as first line treatment in patients with metastatic urothelial carcinoma unfit for cisplatin based chemotherapy due to impaired renal function”

trial design
Trial design

Multicenter

Randomized (1:1)

Phase II screening design

end points
End points

Primary: PFS

improvement of PFS from 5 to 7.5 months

end points1
End points

Primary: PFS

Secondary: Overall response rate, ORR (= CR + PR)

Overall survival (OS)

Disease control rate, DCR (=CR + PR + SD)

Safety (Data on safety parameters)

Quality of Life (QoL)

number of patients
Number of patients

Number of patients:

- Accrual rate of 60 patients/year

- 2 years recruitment period

- 1 year of follow-up

120 ptsand a 3 year study period will generate the neded number of PFS events

Key dates:

- Anticipated start of study: Q3, 2013

- Estimated recruitment period: Q3, 2013 – Q1, 2016

Number of centers: >5 NUCOG centers

inclusion criteria
Inclusion criteria
  • Signed informed consent.
  • Histological or cytological confirmed transitional cell carcinoma of the urothelial tract (mixed histology including transitional cell carcinoma are allowed).
  • Unresectable (T4b), locally advanced (lymph node positive (N+)) or metastatic (M1) urothelial carcinoma (including renal pelvic tumours, ureteral tumours, urinary bladder tumours and urethral primary tumours).
  • No prior chemotherapy or other anti-cancer drugs. Patients who have received neoadjuvant or adjuvant platinum containing chemotherapy and who are diagnosed with loco regional recurrent or metastatic disease after 6 months are eligible.
  • Creatinine clearance 30 – 60 ml/min (measured by Iohexol or Cr-EDTA technique).
  • ECOG/WHO Performance Status (PS) 0-1.
inclusion criteria cont
Inclusion criteria cont.
  • ≥ 4 weeks since prior surgery, ≥ 2 weeks since prior radiation therapy.
  • Measurable and/or non-measurable disease using the RECIST criteria defined as
  • CNS metastases and/or leptomeningeal metastases are allowed provided these have been adequately treated with radiotherapy are stable and not generating any symptoms.
  • Spinal cord compression due to metastatic lesions is allowed provided adequate surgery and/or radiotherapy has been delivered, the metastases are stable and not generating any symptoms.
  • No known or suspected allergy to the investigational agents or any agents given in association with this trial.
  • 18 years of age or older.
  • Fertile men and women of childbearing potential must use secure contraception from before 2 months entering the study until 6 months after end of chemotherapy.
exclusion criteria
Exclusion criteria
  • Not fulfilling inclusion criteria as described above
  • Pure non-transitional cell carcinoma of the urothelial.
  • Bleeding tumours.
  • Impaired bone marrow function defined as WBC < 3.0 x 109/L, neutrophils < 1.5 x 109/L, platelets < 125 x 109/L, haemoglobin < 100 g/L.
  • Impaired liver function defined as serum bilirubin > 1.5 x upper limit of normal (ULN) and/or ASAT/ALAT > 2.5 x ULN (> 5 x ULN if known liver metastasis).
  • Electrocardiogram (ECG) with significant modifications suggesting a high risk of occurrence of angina pectoris or high risk of arrhythmia.
  • Other malignancies, except adequately treated basal carcinoma or squamos cell carcinoma of the skin or in-situ cervix carcinoma or incidental prostate cancer (T1a, Gleason score ≤ 6, PSA < 0.5 ng/ml), or any other tumour with a disease free survival of ≥ 5 years.
exclusion criteria cont
Exclusion criteria cont.
  • History of serious or concurrent illness or uncontrolled medical disorder; including, but not restricted to:
    • Active infection requiring antibiotics within 2 weeks before the study inclusion,
    • Unstable diabetes mellitus,
    • Hypercalcaemia >2.9 mmol/L (= grade 2 according to CTCAE v 4.0),
    • Concurrent congestive heart failure NYHA (class III-IV),
    • Unstable angina pectoris, or myocardial infarction within 6 months and/or poorly controlled hypertension,
    • QTc > 450 ms at baseline,
    • Inflammatory bowel disease,
    • Peripheral neuropathy grade 2 according to CTCAE v 4.0,
  • Patients who require treatment with ketoconazole, itraconazole, ritonavir, amprenavir, indinavir, rifampicine (any potent CYP3A4 inhibitor or inducer) or phenytoine.
  • Pregnant or lactating women.
  • Any psychological, familial, sociological, or geographical condition which does not permit protocol compliance and medical follow-up.
study outline1
Study outline

50 % Carbo/Gem

50% Vin/Gem

study outline2
Study outline

Carboplatin – AUC 4.5, Day 1Gemcitabine – 1000 mg/m2, Day 1, 8Cycle length 21 days

50 % Carbo/Gem

Treatment continues until progression, unacceptable toxicity or patients wish to stop treatment

study outline3
Study outline

Carboplatin – AUC 4.5, Day 1Gemcitabine – 1000 mg/m2, Day 1, 8Cycle length 21 days

50 % Carbo/Gem

50% Vin/Gem

Vinflunine – Day 1

250 mg/m2 : a) age > 80 years b) GFR < 30-40 280 mg/m2: GFR 40-60Gemcitabine – 1000 mg/m2, Day 1, 8Cycle length 21 days

Treatment continues until progression, unacceptable toxicity or patients wish to stop treatment

slide19

Screening visit

Inclusion/exclusioncriteria

Informedconsent

ECG

* CT/MR abdomen + CT thorax

Renalfunction (Iohexol or Cr-EDTA)

* within 28 daysbefore 1st drug infusion

QLQ-C30

Central line for infusion (recomended)

slide20

Screening visit cont.

Clinical history and physicalexam

Concomittantmedication

ECOG/WHO PS

Height, weight

Bloodpreasure/heart rate

Bloodsamples (haematology, electrolytes, hepaticfunction)

slide21

Prior toeverycycle

Physicalexam

Weight

Bloodpreasure/heart rate

ECOG/WHO PS

Concomittantmedication

Bloodsamples

haematology

electrolytes*

hepaticfunction

Adverse event

Continuationcriteria

* Cr-EDTA or Iohexol clearance clearance should be done if creatinine increases ≥20%.

slide22

TreatmentDay 1

Treatment

Day 8

Haematology

Electrolytes

continuation criteria
Continuation criteria

A participant will be withdrawn immediately if:

He or she withdraws his/hers informed consent

Unacceptable toxicity not manageable by symptomatic therapy, dose delay or dose modification

He or she does not comply with the instructions given by the study personnel

Tumour progression

Pregnancy

Physician’s decision, including the need of other cancer therapy

slide24

Follow-Up visit

Day 30 ± 2 after last treatment administration

Physicalexam

Weight

Bloodpreasure/heart rate

ECOG/WHO PS

Concomittantmedication

Bloodsamples (haematology, electrolytes, hepaticfunction)

Adverse event

QLQ-C30

follow up period assessment
Follow up period assessment

From 30 days after the last study treatment administration (= Follow-Up visit) until death or decision for study closure.

1) For patients discontinued the study due to progressive disease, survival information will be collected approximately every 3 months until death.

2)For patients who discontinued the study treatment before the occurrence of disease progression, clinical and radiological assessments will be performed every 6th week until disease progression. Then follow up according to above (1).

evaluation1
Evaluation

CT/MR for radiological response measured according to RECIST, after every second cycle

EORTC Quality of Life Questionnaire C 30 (QLQ-C30)

Toxicity according to CTCAE v 4.0

assessment of tumour response
Assessment of tumour response

At baseline and every 6 weeks/2nd treatment cycle

If the patient stops treatment due to unacceptable toxicity or any other reason other than tumor progression, radiological evaluation will continue every 6 week until radiological progress.

If anyobjectiveresponse is documented, the responseshould be confirmedeither at the nextscheduledradiologicalassessment (i.e. after 2 morecyclesoftreatment) or with an additionalassessment 28 daysafter the response has beenobserved.

assessment of quality of life
Assessment of Quality of Life

QLQ-C30: Baseline – beforerandomisation

Every 6 weeks/2nd treatment cycle

Followup visit

Register in eCRF

Collaborationwith Yvonne Brandberg – Professor of Care Sciences with focus on oncology

assessment of adverse events and toxicity
Assessment of adverse events and toxicity

Before every treatment cycle and at Follow-Up

According to CTCAE v 4.0

SAE-form

safety reports
Safety reports

Extra safety check for the first 10 patients

Annual safety report (to the Regulatory Authorities and Ethics Committees)

Trial Safety Committee (independent committee, meet yearly)

dose reduction and dose delay
Dose reduction and dose delay

No dose re-escalation after dose reduction

(re-escalation of day 8 gemictabine is allowed).

In case of 2nd event requiring dose-reduction, the treatment should be stopped.

If > 2 week delay (cycle duration > 5 weeks) the treatment should be discontinued.

dose reduction cont
Dose reduction cont.

To start a new treatment cycle:

- WBC ≥ 3 x 109,

- neutrophils ≥ 1.5 x 109

- platelets ≥ 100 x 109

- All non-haematological toxicity (except alopecia, fatigue, nausea or vomiting) should have recovered to CTCAE grade ≤ 1 or baseline

dose reduction cont1
Dose reduction cont.

Dose reduction of gemcitabine on day 8:

dose reduction cont2
Dose reduction cont.

Dose reduction of vinflunine and gemcitabine on day 1:

dose reduction cont3
Dose reduction cont.

Dose reduction of carboplatin and gemcitabine on day 1:

concomitant treatment
Concomitant treatment

Important - Anti-emetic prophylaxis

Laxatives and dietary measures (opioids!)

Radiotherapy should not be given 14 days before or after treatment with gemcitabine.

Interaction between vinflunine and CYP3A4 inhibitors and inducers

CAVE! Nephrotoxic drugs (carboplatin)

G-CSF is allowed if the recommended dose modifications are insufficient.

time schedule for study initiation1
Time schedule for study initiation

European Medicines Agency – Voluntary Harmonisation Procedure

Accepted the 20th of august 2013

Medical authorities in:

Sweden – accepted the 10th of september

Denmark – accepted the 5th of september

Norway – accepted the 18th of september

time schedule for study initiation2
Time schedule for study initiation

Independent Ethics Committee

Sweden – accepted 21st of august

Denmark – submitted

Norway – submitted

Biobank

Sweden – accepted 14th of october

sponsor and pi s
Sponsor and PI´s
  • Sponsor -
    • Anders Ullén, Karolinska University hospital, Stockholm
  • Principal Investigators:
    • Sweden: Karin Holmsten, Karolinska University hospital, Stockholm
    • Denmark: Helle Pappot, Rigshospitalet, Copenhagen
    • Norway: Lene Ekern Kvavik, Akershus University Hospital, Oslo
time schedule for study initiation in sweden
Time schedule for study initiation in Sweden

Participating centers in Sweden (so far…):

Stockholm – Initation meeting the 5th of december,

Responsible Karin Holmsten

Göteborg – Responsible Elisabeth Öfverholm

Umeå - Responsible Erika Jonsson

Uppsala – Responsible Anna Laurell

National SFUO-meeting 22nd of november

time schedule for study initiation in denmark
Time schedule for study initiation in Denmark

Participating centers in Denmark (so far…):

Rigshospitalet– Initation meeting 15th ofJanuary,

Responsible Helle Pappot

Herlev Hospital – Responsible Lene Sonne

Odense - Responsible Niels Viggo Jensen

Århus – Responsible Mads Agerbæk

Ålborg - Responsible Mette Moe

National Dansk Blærekræftgruppe 6th of April

monitoring in denmark
Monitoring in Denmark

GCP unit – Bispebjerg Hospital

University of Copenhagen

Contact person:

Kristina Devantier

slide48

Endpoints

  • Antal pat, tid rekrytering/analys etc
  • Upplägg de två armarna, doser etc
  • Tidsschemat,
  • Utvärderingar/rtg + QoL + Tox
  • Avslutande i studien
vinflunine in combination with gemcitabine
Vinflunine in combination with Gemcitabine

Dose finding – RD = Vin 320 mg/m2 and Gem 1000 mg/m2

Toxicity – good tolerance profile

No pharmacokinetic interactions

Phase I and Pharmacokinetic Study of iv Vinflunine in Combination with Gemcitbine for Treatment of Advanced Non-small Cell Lung Cancer in Chemonaive Patients. Tournoux-Facon C Et al., J ThoracOncol 2011;6:000-000

dosages in the experimental arm
Dosages in the experimental arm

Dose finding – RD Vin 320 mg/m2, Gem 1000 mg/m2

Toxicity – good tolerance profile

No pharmacokinetic interactions

Phase I and Pharmacokinetic Study of iv Vinflunine in Combination with Gemcitbine for Treatment of Advanced Non-small Cell Lung Cancer in Chemonaive Patients.

Tournoux-Facon C Et al., J ThoracOncol 2011;6:000-000

  • Jasint
number of patients1
Number of patients

Number of patients: 120 pts

Estimated Study duration:2-3 years

Key dates: Anticipated start of study: Q3, 2013

Estimated recruitment period: Q3, 2013 – Q1, 2016

Number of centers: >5 NUCOG centers

slide52

Prior toeverycycle

Physicalexam

Weight

Bloodpreasure/heart rate

ECOG/WHO PS

Concomittantmedication

Bloodsamples

haematology

electrolytes*

hepaticfunction

Adverse event

Continuationcriteria

* Cr-EDTA or Iohexol clearance clearance should be done if creatinine increases ≥20%.

cooperation with pierre fabre pharma norden ab
Cooperation with Pierre Fabre Pharma Norden AB

Economical support:

1) Set-upcosts

Covering initial set-upcosts

2) Monitoring: Covering the monitoringcost for Sweden, Denmark, Norway

3) Fee per patient recievingvinflunin:  

20.000 DKR

randomization and stratification
Randomization and stratification

Centralized randomization by the Clinical Trial Unit, Karolinska, Stockholm.

Stratified on the following factors:

  • PS 0 versus PS1
  • No visceral metastases vs visceral metastases present
randomization and stratification1
Randomization and stratification

Randomization form, faxed to:

the NUGOG I-VINGEM Study Office, KPE, Karolinska University Hospital.

CTO coordinator Karin Hallberg

Fax number +46 8 30 69 89

Computer based, on-line randomization

ae sae and susar
AE, SAE and SUSAR
  • AE = an Adverse Event is any adverse change from baseline condition (CTCAE v 4.0, register in eCRF)
  • SAE = a SeriousAdverse Event (SAE-form)
    • results in death
    • is life-threatening
    • results in persistent or significant disability
    • requires acute or unplanned hospitalisation or prolongation of existing hospitalisation
    • is a congenital anomaly or birth defect
    • medically important event (in which the investigators finds or suggests a significant hazard)
  • SUSAR = Suspected unexpected serious adverse reaction (The sponsor report to the Regulatory Authorities)
serious adverse events sae
Serious adverse events (SAE)

SAE form, faxed within 24 hours, to:

the NUGOG I-VINGEM Study Office, KPE, Karolinska University Hospital.

Coordinator Karin Hallberg

Fax number +46 8 30 69 89