General study presentation NUCOG I - VINGEM

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

2. 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”

3. 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”

4. 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”

5. Trial design Multicenter Randomized (1:1) Phase II screening design

6. End points Primary: PFS improvement of PFS from 5 to 7.5 months

7. 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)

8. 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

9. How to include patients? Inclusion and exclusion

10. 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.

11. 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.

12. 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.

13. 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.

14. Study outline

15. Study outline 50 % Carbo/Gem 50% Vin/Gem

16. 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

17. 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

18. Study outline

19. 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)

20. Screening visit cont. Clinical history and physicalexam Concomittantmedication ECOG/WHO PS Height, weight Bloodpreasure/heart rate Bloodsamples (haematology, electrolytes, hepaticfunction)

21. 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%.

22. TreatmentDay 1 Treatment Day 8 Haematology Electrolytes

23. 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

24. 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

25. 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).

26. Evaluation

27. 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

28. 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.

29. 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

30. Assessment of adverse events and toxicity Before every treatment cycle and at Follow-Up According to CTCAE v 4.0 SAE-form

31. Dose reduction and dose dealys

32. 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)

33. 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.

34. 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

35. Dose reduction cont. Dose reduction of gemcitabine on day 8:

36. Dose reduction cont. Dose reduction of vinflunine and gemcitabine on day 1:

37. Dose reduction cont. Dose reduction of carboplatin and gemcitabine on day 1:

38. 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.

40. Time schedule for study initiation

41. 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

42. Time schedule for study initiation Independent Ethics Committee Sweden – accepted 21st of august Denmark – submitted Norway – submitted Biobank Sweden – accepted 14th of october

43. 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

44. 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

45. 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

46. Monitoring in Denmark GCP unit – Bispebjerg Hospital University of Copenhagen Contact person: Kristina Devantier

48. Endpoints • Antal pat, tid rekrytering/analys etc • Upplägg de två armarna, doser etc • Tidsschemat, • Utvärderingar/rtg + QoL + Tox • Avslutande i studien

49. 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

50. 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