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Brief Title: NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab and Tremelimumab in Muscle-invasive Urothelial Carcinoma

NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab (MEDI4736) and Tremelimumab in Muscle-invasive Urothelial Carcinoma

INTRODUCTION

  • Org Study ID: NEMIO
  • Secondary ID: N/A
  • NTC ID: NCT03549715
  • Sponsor: Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

BRIEF SUMMARY


This is an open label, phase I/II clinical trial to evaluate the efficacy and safety of 2
cycles of durvalumab without (Arm A) or with (Arm B) tremelimumab in association with ddMVAC
as neoadjuvant therapy in patients with MIUC.

DETAILED DESCRIPTION


Study Population:

Patients with MIUC fit to receive cisplatin.

Study Design:

The trial is designed as a non-comparative, open-label phase I/II study.

Divided in two phases:

The run In phase (I) and a phase II study. During the run-in phase, a limited number of
patients (n=12-18) will be treated with durvalumab + ddMVAC or durvalumab + tremelimumab +
ddMVAC (6-9 patients each). If the toxicity rate is acceptable (not higher than 2 out of 6 or
3 out of 9 patients per arm) the study will continue as a randomized phase II study. During
phase II, the efficacy and safety of durvalumab + ddMVAC and durvalumab + tremelimumab +
ddMVAC

Research hypothesis:

Combination of checkpoint inhibitors (CPI), durvalumab ± tremelimumab, with neoadjuvant
ddMVAC will improve the pathological complete response (pCR) rate in patients with
muscle-invasive urothelial carcinoma (MIUC). No additional toxicity of the combination CPI +
ddMVAC is expected.

Investigational Product(s):

Durvalumab: 1500 mg IV D1 every 28 days Durvalumab will be administered at the hospital every
28 days prior to administration of ddMVAC on D1.

Tremelimumab 75 mg IV D1 every 28 days Tremelimumab will be administered first, with
durvalumab infusion starting approximately 1 hour (maximum 2 hours) after the end of the
tremelimumab infusion.

Translational research:

Mechanism of response/resistance to neoadjuvant treatment will be assessed by comparing
molecular and immunological tumor profiles before treatment (transurethral resection tumor
samples) and after treatment (cystectomy samples). In addition, circulating tumor DNA (ctDNA)
and urine tumor DNA (utDNA) will be analysed during treatment (ctDNA and utDNA) and after
surgery (ctDNA).

Immunological profiles will be established using a specific metagene signature for major cell
types of the tumor microenvironment and chemokines, cytokines and regulatory molecules , and
will be validated using relevant markers by immunohistochemistry (IHC) on formalin-fixed
paraffin-embedded (FFPE) tumor sections.

Metabolomic profiling will also be conducted by analyzing metabolites present in urinary
samples with a Proton-based nuclear magnetic resonance (1H-NMR), and correlations with
prognosis, molecular profile or/and with immunological signature determined.

Finally, correlations between tumor pathological factors (e.g., pTNM, nuclear grade, variant
squamous differentiation or sarcomatoid dedifferentiation) and prognosis will be evaluated
using IHC on FFPE tissue sections.

Sample Size: Approximately 120 patients are planned to be included.


  • Overall Status
    Recruiting
  • Start Date
    December 6, 2018
  • Phase
    Phase 1/Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Toxicity Grade

Primary Outcome 1 - Timeframe: 38 months

Primary Outcome 2 - Measure: pathologic complete response

Primary Outcome 2 - Timeframe: 1 year

CONDITION

  • Infiltrating Bladder Urothelial Carcinoma

ELIGIBILITY


Inclusion Criteria:

1. Written informed consent and any locally required authorization (e.g., EU Data Privacy
Directive in the EU) obtained from the patient prior to performing any
protocol-related procedures, including screening evaluations

2. Age ≥18 years at time of study entry

3. Histologically confirmed MIUC (also termed TCC) of the bladder. Patients with mixed
histologies are required to have a dominant transitional cell pattern (urothelial
carcinoma must be > 50%)

4. Localized MIUC of the bladder with clinical stage T2−T4a and ≤N1 disease ( the single
lymph node must be < 15 mm (short axis) on imaging

5. Patients with urothelial carcinoma of the prostatic urethra

6. Bodyweight >45kg

7. Patients eligible for cisplatin-based neoadjuvant chemotherapy, including:

- Creatinine clearance (CL) >60 mL/min based on the Modification of Diet in Renal
Disease Study (MDRD) formula

- Cardiac left ventricular ejection fraction (LVEF) ≥50%

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

9. Absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the
pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Patients with
clinical stage N1 disease are eligible if the single lymph node measures ≤2 cm in
greatest dimension.

10. Adequate organ and marrow function as defined below (obtained within 14 days prior to
the first study treatment):

- Hemoglobin ≥10.0 g/dL (patients may be transfused to meet this criterion)

- Absolute neutrophil count (ANC) ≥1500 cells/μL (without G-CSF support within 2
weeks prior to Cycle 1, Day 1)

- WBC counts >2500/µL

- Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to Cycle 1,
Day 1)

- Serum bilirubin ≤1.0 x institutional upper limit of normal (ULN). Patients with
known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled.

- AST, ALT, and alkaline dehydrogenase ≤2.5 x ULN

- Partial thromboplastin time/prothrombin time (PTT/PT) ≤1.5 x ULN or international
normalized ratio (INR) <1.7 x ULN

11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy)

- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).

12. Women of childbearing potential and non-sterilized males who are sexually active with
a female partner of childbearing potential must be willing to use contraceptive
methods during the treatment period and for at least 6 months after the last dose of
treatment

13. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

Exclusion Criteria:

1. Urothelial carcinoma of the upper tract

2. Any approved anti-cancer therapy for urothelial carcinoma, including chemotherapy, or
immunotherapy prior to initiation of study treatment. Of note, previous intravesical
BCG injections are allowed if administered for non-muscle invasive urothelial
carcinoma

3. Primary chemoradiation for bladder preservation for urothelial carcinoma of the
bladder

4. Impaired renal function (glomerular filtration rate (GFR)<60 mL/min); GFR should be
assessed by calculation from serum/plasma creatinine (MDRD formula)

5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent

6. Grade 2 or greater hearing loss that contraindicates cisplatin use. Threshold shift of
>25 decibel averaged at 2 contiguous test frequencies in least one ear.

7. Grade 2 or greater peripheral neuropathy

8. Oral anticoagulation treatment (vitamin K antagonist should be replaced by
low-molecular-weight heparin)

9. Treatment with any other investigational agent or participation in another clinical
trial with therapeutic intent within 28 days or five half-lives of the drug

10. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study

11. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable

12. Major surgical procedure (as defined by the Investigator) other than for diagnosis
within 28 days prior to Cycle 1

13. History of prior organ transplantation, including stem cell allografting

14. History of autoimmune disease, including, but not limited to, myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and
type I diabetes mellitus on stable dose of insulin may be eligible for this study

15. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

16. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

17. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1

18. Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction within the previous 6 months, unstable
arrhythmias, or unstable angina

19. History of another primary malignancy within 3 years prior to Cycle 1, Day 1, except
for:

- Localized low-risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤7, and
prostate-specific antigen [PSA] at prostate cancer diagnosis ≤20 ng/mL [if
measured]) treated with curative intent and without PSA recurrence

- Low-risk prostate cancer (defined as Stage T1/T2a, Gleason score <7, and PSA ≤10
ng/mL) who are treatment-naive and undergoing active surveillance

- Patients with malignancies of a risk of metastasis/death (e.g., risk of
metastasis or death <5% at 5 years) are eligible after investigator's approval if
they meet both of the following criteria: Malignancy treated with expected
curative intent, and no evidence of recurrence or metastasis by follow-up imaging
and any disease-specific tumor markers

20. History of leptomeningeal carcinomatosis

21. History of idiopathic pulmonary fibrosis, organizing pneumonia

22. Serum albumin <25 g/L

23. LVEF <50%

24. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 electrocardiograms (ECGs) within 15 minutes at 5 minutes apart

25. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if PCR is negative for HCV RNA

26. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections ( intra
articular injection)

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent

- Steroids as premedication for hypersensitivity reactions (CT scan premedication)

27. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
treatment. Note: Patients, if enrolled, should not receive live vaccine whilst
receiving study treatment and for up to 30 days after the last dose of study treatment

28. Female patients who are pregnant or breastfeeding, or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy or180 days after
the last dose of durvalumab + tremelimumab combination therapy

29. Known allergy or hypersensitivity to chimeric or humanized antibodies or fusion
proteins, or to any of the study drugs or study drug excipients

30. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment

31. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that, in the
opinion of the Investigator, makes the patient unsuitable for participation in the
study.

Gender: All

Minimum Age: N/A

Maximum Age: 18 Years

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Constance THIBAULT, MD

Role: Principal Investigator

Affiliation: Hôpital Européen Georges Pompidou, Oncology department of Pr Stéphane OUDARD

Overall Contact

Name: Constance THIBAULT, MD

Phone: 00 33 1 56 09 23 40

Email: reza-thierry.elaidi-ext@aphp.fr

LOCATION

Facility Status Contact
Facility: Hôpital Européen Georges Pompidou
Paris, Ile De France 75015
France
Status: Recruiting Contact:
Constance THIBAULT, MD
00 33 1 56 09 59 92
constance.thibault@aphp.fr
Facility: Centre Leon Berard
Lyon, 69008
France
Status: Recruiting Contact:
Aude FLECHON, MD

Facility: Centre Antoine Lacassagne
Nice, 06100
France
Status: Recruiting Contact:
Delphine BORCHIELLINI, MD

Delphine.BORCHIELLINI@nice.unicancer.fr
Facility: Hôpital Cochin
Paris, 75679
France
Status: Recruiting Contact:
Olivier HUILLARD, MD

olivier.huillard@aphp.fr
Facility: Hôpitaux universitaires de Strasbourg
Strasbourg, 67000
France
Status: Recruiting Contact:
Philippe BARTHELEMY, MD

philippe.barthelemy@chru-strasbourg.fr
Facility: Institut Claudius Regaud
Toulouse, 31059
France
Status: Recruiting Contact:
Damien POUESSEL, MD