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JOURNAL ONKOLOGIE – STUDIE

Durvalumab (MEDI4736) and Tremelimumab in Combination With Either Y-90 SIRT or TACE for Intermediate Stage HCC With Pick-the-winner Design

Rekrutierend

NCT-Nummer:
NCT04522544

Studienbeginn:
Dezember 2020

Letztes Update:
16.02.2021

Wirkstoff:
Tremelimumab, Durvalumab

Indikation (Clinical Trials):
Carcinoma, Hepatocellular

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator:
AstraZeneca

Studienleiter

Salah-Eddin Al-Batran, Prof. Dr.
Study Director
Institut für Klinische Krebsforschung IKF GmbH

Kontakt

Arndt Vogel, Prof. Dr.
Kontakt:
Phone: +49 511 5326
Phone (ext.): 760
E-Mail: Vogel.Arndt@mh-hannover.de
» Kontaktdaten anzeigen

Studienlocations (2 von 2)

Studien-Informationen

Detailed Description:

The IMMUWIN phase II will test the safety and anti-tumor efficacy of the combination of

durvalumab and tremelimumab with either TACE or Y-90 SIRT. Patients will be randomized into

two experimental arms, one receiving SIRT + Durvalumab + Tremelimumab, the other arm

receiving TACE + Durvalumab + Tremelimumab. It will be determined whether the combination of

immunotherapy with SIRT or TACE is more promising.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Capable of giving written informed consent and any locally-required authorization (EU

Data Privacy Directive in the EU) obtained from the subject prior to performing any

protocol-related procedures, including screening evaluations.

2. Age ≥ 18 years at time of study entry.

3. Body weight > 30 kg.

4. Multinodular or large, solitary HCC, not eligible for resection or local ablation.

5. Histologically confirmed diagnosis of HCC.

6. Scheduled to receive locoregional therapy as standard of care.

7. At least one measurable site of disease as defined by RECIST 1.1criteria with spiral

CT scan or MRI.

8. No prior systemic anti-cancer therapy.

9. Child-Pugh A.

10. Performance status (PS) ≤ 1 (ECOG scale).

11. Life expectancy of at least 12 weeks.

12. Adequate blood count, liver-enzymes, and renal function:

- Hemoglobin ≥ 9.0 g/dL, absolute neutrophil count ANC ≥1.5 (or 1.0) x (> 1500 per

mm3), platelets ≥100 (or 75) x 109/L (>75,000 per mm3);

- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN);

- AST (SGOT), ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are

present, in which case it must be ≤5x ULN;

- International normalized ratio (INR) ≤ 1.25.

13. Albumin ≥ 31 g/dL.

14. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40

mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine

collection for determination of creatinine clearance.

15. Female patients with reproductive potential must have a negative urine or serum

pregnancy test within 7 days prior to start of trial and must use two effective forms

of contraception if sexually active.

16. Men who are sexually active with WOCBP must use any contraceptive method with a

failure rate of less than 1% per year. Men receiving IMP and who are sexually active

with WOCBP will be instructed to adhere to contraception for a period of 7 months

after the last dose of investigational products (durvalumab and tremelimumab). Women

who are not of childbearing potential (i.e. who are postmenopausal or surgically

sterile) as well as azoospermic men do not require contraception).

17. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV)

infection, meets the following criteria:

- Patients with HBV or HCV infection should be monitored for viral levels during

study participation;

- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV

DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment

guidelines. Controlled (treated) hepatitis B subjects will be allowed if they

started treatment at the time point of enrollment into the study by the latest

and treatment is continued during study participation and for ≥ 6 months after

end of study treatment;

- HCV patients with advanced HCC are mostly not treated for their HCV infection.

However, patients treated for HCV are considered suitable for inclusion if

antiviral therapy has been completed prior to first administration of study drug.

18. Subject is willing and able to comply with the protocol for the duration of the study

including

Exclusion Criteria:

1. Diffuse HCC or presence of vascular invasion or extrahepatic spread with the following

exception:

o Invasion of a segmental portal vein or hepatic veins.

2. Patients with advanced liver disease as defined below:

o liver cirrhosis with stage Child Pugh B and C.

3. Any contraindications for hepatic embolization procedures:

- Known hepatofugal blood flow;

- Known porto-systemic shunt;

- Impaired clotting test (platelet count < 70 Thsd/L, INR > 1.25);

- Renal failure/insufficiency requiring hemo-or peritoneal dialysis;

- Known severe atheromatosis;

- Total thrombosis or total invasion of the main branch of the portal vein.

4. Locoregional therapies ongoing or completed < 4 weeks prior to the baseline scan.

5. History of cardiac disease:

- Congestive heart failure > New York Heart Association (NYHA) class 2;

- Active coronary artery disease (CAD) (myocardial infarction ≥ 6 months prior to

study entry is allowed);

- Cardiac arrhythmias (Grade > 2 NCI-CTCAE Version 5.0) which are poorly controlled

with anti-arrhythmic therapy or requiring pace maker;

- Uncontrolled hypertension;

- Clinically significant gastrointestinal bleeding within 4 weeks prior to start of

study drug.

6. Thrombotic or embolic events such as cerebrovascular accident (including transient

ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months

prior to the first dose of study drug with the exception of thrombosis of a segmental

portal vein.

7. Prior, systemic anti-cancer therapy, radiotherapy administered < 4 weeks prior to

study entry, endocrine- or immunotherapy or use of other investigational agents.

8. 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 (e.g., 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 (e.g., CT scan

premedication)

9. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:

Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to

30 days after the last dose of IP.

10. Major surgery within 4 weeks of starting the study and patients must have recovered

from effects of major surgery.

11. Patients with second primary cancer, except adequately treated basal skin cancer or

carcinoma in-situ of the cervix, unless curatively treated and disease-free for 3

years or longer.

12. Any co-existing medical condition that in the investigator's judgement will

substantially increase the risk associated with the patient's participation in the

study.

13. 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

14. 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, 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 polymerase chain reaction

is negative for HCV RNA

15. History of allogenic organ transplantation.

16. Psychiatric disorders or altered mental status precluding understanding of the

informed consent process and/or compliance with the study protocol.

17. Symptomatic brain metastases. A scan to confirm the absence of brain metastases is

required in the presence of corresponding symptoms.

18. Pregnant or breast-feeding women.

19. Immunocompromised patients, e.g. patients who are known to be serologically positive

for human immunodeficiency virus (HIV).

20. Active or prior documented autoimmune or inflammatory disorders (including

inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with

the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,

or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid

arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this

criterion:

- Patients with vitiligo or alopecia

- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on

hormone replacement

- Any chronic skin condition that does not require systemic therapy

- Patients without active disease in the last 5 years may be included but only

after consultation with the study physician

- Patients with celiac disease controlled by diet alone

21. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the

product.

22. Is currently participating or has participated in a study of an investigational agent

or has used an investigational device within 4 weeks prior to the first dose of study

treatment.

23. Patient who has been incarcerated or involuntarily

Studien-Rationale

Primary outcome:

1. Objective response rate (ORR) [according to RECIST 1.1] at 6 months. (Time Frame - 6 months):
Proportion of allocated subjects with best response of complete or partial response



Secondary outcome:

1. Progression free survival (PFS) (Time Frame - Time from the date of randomization to the date of first observed disease progression or death (approx. 42 months)):
Time from the date of randomization to the date of first observed disease progression (investigator assessment according to RECIST 1.1) or death from any cause.

2. Overall survival (OS) (Time Frame - From the date of treatment Date of enrollment until date of death if applicable (up to 42 months until Study Closure)):
Overall survival will be determined as time from the date of treatment allocation to the date of death.

3. Treatment related SAEs (Time Frame - From first patient included until study closure (approx. 42 months after First Patient Included)):
Treatment related serious adverse events rate (SAE) will be determined. All observed toxicities and side effects will be graded according to NCI CTCAE v5.0 for all patients and the degree of association of each with the study treatment assessed and summarized.

4. Overall response rate (ORR) as best overall response (BOR) during therapy (Time Frame - 13 months):
ORR as BOR during therapy will be defined as the proportion of allocated subjects with best response of complete or partial response from date of randomization until disease progression or death from any cause occurs.

5. Overall response rate (ORR) at 6 months (Time Frame - 6 months):
ORR at 6 months for patients who received single treatment of TACE/SIRT

6. Quality of Life (QoL) (Time Frame - 24 months):
Quality of life will be assessed by the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30 questionnaire) and will be evaluated based on the EORTC QLQ-C30 scoring manual in its most current version at time of data analysis.

Studien-Arme

  • Experimental: SIRT
    Y-90 SIRT + Tremelimumab + Durvalumab
  • Experimental: TACE
    TACE + Tremelimumab + Durvalumab

Geprüfte Regime

  • Tremelimumab:
    300 mg Tremelimumab C1D1
  • Durvalumab:
    1500 mg Durvalumab C1D1 + Q4W (max. 13 cycles)
  • Y-90 SIRT:
    Locoregional therapy will be performed as a standard-of-care procedure
  • TACE:
    Locoregional therapy will be performed as a standard-of-care procedure

Quelle: ClinicalTrials.gov


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