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JOURNAL ONKOLOGIE – STUDIE

Treatment of Atezolizumab and Derazantinib in Patients With Advanced iCCA With FGFR2 Fusions/Rearrangements

Rekrutierend

NCT-Nummer:
NCT05174650

Studienbeginn:
April 2022

Letztes Update:
23.05.2023

Wirkstoff:
Atezolizumab, Derazantinib

Indikation (Clinical Trials):
Cholangiocarcinoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator:
-

Kontakt

Studienlocations
(3 von 19)

Interdisziplinäres Brustzentrum am Klinikum Esslingen
Hirschlandstraße 97
73730 Esslingen am Neckar
(Baden-Württemberg)
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Henning Wege, Prof.» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

The aim of this phase II study is to explore the safety and anti-tumor efficacy of the

combination of atezolizumab and derazantinib in patients with advanced intrahepatic

cholangiocarcinoma, with ORR as the primary endpoint.

The primary endpoint is the Objective Response Rate (ORR [assessed every 8 weeks (±7 days)]):

Objective response rate (ORR) according to investigator-based RECIST 1.1 assessment, defined

as the proportion of allocated subjects with best response of complete or partial response

within 9 months after the date of first administration of study treatment.

The secondary endpoints are safety and efficacy and will be evaluated by

- Incidence, treatment relationship, seriousness, and severity of all AEs, SAEs, AESIs

according to CTCAE V5.0

- ORR@EOT:

Objective response rate (ORR) according to investigator-based RECIST 1.1 assessment, defined

as the proportion of allocated subjects with best response of complete or partial response

within study treatment.

• PFSR@6, 8 and 10 months: The proportion of patients known to be alive and without confirmed

objective disease progression at 6, 8 and 10 months after first administration of study

treatment, respectively.

• PFS: Time from first administration of study treatment until the date of first objective

disease progression or death.

• OS: Time from first administration of study treatment until death of a patient due to any

cause

Ein-/Ausschlusskriterien

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for the study:

1. Fully informed written consent and locally required authorization (European Union [EU]

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

protocol-related procedures, including screening evaluations.

2. Patients*, age ≥ 18 years at the time of signing the Informed Consent Form.

3. Histologically documented diagnosis of non-resectable iCCA with positively confirmed

FGFR2 fusion/rearrangement via NGS-Analysis.

Note: Only CE-IVD marked NGS-tests are applicable which cover FGFR2 fusions and

rearrangements.

4. Performance status (PS) ≤ 2 (ECOG scale).

5. At maximum one previous line of systemic anti-cancer therapy, (chemotherapy, hormonal,

targeted therapy, experimental therapy) for which treatment was discontinued at least

4 weeks before the first dose of study treatment, or five half-lives of the respective

anti-cancer therapy, whichever is the longer period.

Note: For mABs in previous therapy the restriction to five half-lives does not apply.

6. No prior treatment with any FGFR or immune checkpoint inhibitor (including but not

limited to antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies) apart from

Durvalumab as PD-L1 inhibitor in first line therapy.

7. Body weight > 30 kg AND BMI ≥ 15.

8. At least one measurable site of disease as defined by RECIST 1.1 criteria.

9. Adequate bone marrow and renal function including the following:

- Hemoglobin ≥ 9.0 g/dL (previous transfusion permitted);

- Absolute neutrophil count (ANC) ≥ 1.500 per µL (1.5×109/L);

- Platelet count ≥ 75,000 per µL (75 × 109/L);

- International normalized ratio (INR) between 0.8 × ULN to 1.0 × ULN OR ≤ 3 × ULN

for subjects receving anticoagulant therapy

- Creatinine ≤ 1.5 × ULN OR CLCR ≥ 50 mL/min (as calculated by the Cockcroft-Gault

formula);

- serum phosphate ≤ ULN;

- corrected serum calcium ≥ 1.75 mmol/L (≥ 7.0 mg/dL) AND ≤ 3.1 mmol/L (≤ 12.5

mg/dL);

- serum sodium ≥ LLN.

10. Adequate hepatic function (with stenting for any obstruction, if required) including

the following:

o Total bilirubin ≤ 2 × ULN;

- AST or ALT ≤ 3 × ULN (or ≤ 5 × ULN for subjects with liver metastases);

- Prothrombin time ≥ 60%;

- Albumin ≥ 2.8 g/dL.

11. For patients with active hepatitis B virus (HBV):

- HBV DNA ≤ 500 IU/mL obtained within 28 days prior to initiation of study

treatment, AND

- Anti-HBV treatment (per local standard of care; e.g., entecavir) prior to study

entry and willingness to continue treatment for the length of the study.

12. For patients with active hepatitis C virus (HCV):

- Patients positive for hepatitis C virus (HCV) antibody are eligible, also if

polymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).

- However, anti-viral therapy against HCV is only allowed prior to trial but not

during the trial.

13. Negative HIV test.

14. Negative pregnancy test within 72 h prior to dosing.

15. Females of childbearing potential must agree to remain abstinent (refrain from

heterosexual intercourse) or use contraceptive methods that result in a failure rate

of < 1% per year during the treatment period and for at least 5 months or for a period

of at least 5 half-lives of the respective drug/IMP (whichever is longer) after the

last study treatment. A woman is considered to be of childbearing potential if she is

postmenarcheal, has not reached a postmenopausal state (has not had ≥ 12 continuous

months of amenorrhea with no identified cause other than menopause), and has not

undergone surgical sterilization (removal of ovaries and/or uterus). Examples of

contraceptive methods with a failure rate of < 1% per year include bilateral tubal

ligation, male sterilization, hormonal implants, established, proper use of combined

oral or injected hormonal contraceptives, and certain intrauterine devices. The

reliability of sexual abstinence should be evaluated in relation to the duration of

the clinical trial and the preferred and usual lifestyle of the patient. Periodic

abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and

withdrawal are not acceptable methods of contraception.

16. With female partners of childbearing potential, men must remain abstinent or use a

condom plus an additional contraceptive method that together result in a failure rate

of 1% per year from screening to 5 months after the last dose of combination therapy

or for a period of at least 5 half-lives of the respective drug/IMP after the last

dose of combination therapy (whichever is longer). Men must refrain from donating

sperm during this same period. Men with a pregnant partner must agree to remain

abstinent or to use a condom for the duration of the pregnancy to avoid exposing the

embryo.

17. The patient is willing and able to comply with the protocol for the duration of the

study, including hospital visits for treatment and scheduled follow-up visits and

examinations.

18. Must have a life expectancy of at least 12 weeks. *There are no data that indicate

special gender distribution. Therefore, patients will be enrolled in the study

gender-independently.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Mixed cholangiocarcinoma and HCC.

2. Concurrent enrolment in another clinical study, unless it is an observational

(non-interventional) study or a study without a medical intervention (specifically the

PLATON registry [ClinicalTrials.gov identifier: NCT04484636] is allowed).

Note: After the Safety Follow-up (28 days post treatment discontinuation)

participation in another clinical study is allowed.

3. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into

the study; patients must have recovered from effects of any major surgery.

Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions,

per-cutaneous biliary drainage or biliary stenting) is acceptable.

4. 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 active,

uncontrolled, 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.

5. History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease ≥ 3

years before the first dose of IMP and of low potential risk for recurrence;

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence

of disease;

- Adequately treated carcinoma in situ without evidence of disease.

6. 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 5 months after the last dose of combination therapy or for a period of at

least 5 half-lives of the respective drug/IMP after the last dose of combination

therapy (whichever is longer).

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

product.

8. 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.

9. Active or History of autoimmune disease including, but not limited to, myasthenia

gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid

arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's

granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,

vasculitis, or glomerulonephritis.

Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement

hormone, or controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible

based on consultation with the sponsor. Patients with eczema, psoriasis, lichen simplex

chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic

arthritis are excluded) are eligible for the study provided all following conditions are

met:

- Rash must cover < 10% of body surface area;

- Disease is well controlled at baseline and requires only low- potency topical

corticosteroids;

- No occurrence of acute exacerbations of the underlying condition requiring psoralen

plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral

calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12

months.

10. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥

2 pneumonitis.

11. History of active primary immunodeficiency. 12. History of allogeneic bone marrow

transplantation or prior solid organ transplantation.

13. Treatment with systemic immunosuppressive medication (including, but not limited

14. 15. to, corticosteroids, cyclophosphamide, azathioprine, methotrexate,

thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study

treatment, or anticipation of need for systemic immunosuppressive medication during

study treatment, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a

one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of

corticosteroids for a contrast allergy) are eligible for the study.

- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids

for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose

corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible

for the study.

16. Administration of a live, attenuated vaccine within four weeks or for a

period of at least 5 half-lives of the respective drug/IMP (whichever is longer)

prior to start of enrollment, or anticipation that such a live attenuated vaccine

will be required during the study or within 5 months after the last dose of

atezolizumab.

17. Significant cardiovascular disease, such as cardiac disease (New York Heart

Association Class II or greater), myocardial infarction or cerebrovascular

accident within 3 months prior to initiation of study treatment, unstable

arrhythmias, unstable angina, and/or concurrent and clinically significant

abnormalities on electrocardiogram (ECG) at Screening, including QTcF > 450 ms

for males or > 460 ms for females.

18. Clinically significant valvular defect. 19. Unable or unwilling to swallow

the complete daily dose of derazantinib capsules.

20. Clinically unstable central nervous system (CNS) metastases (to be eligible,

subjects must have stable disease > 3 months, confirmed by magnetic resonance

imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases well

controlled by low-dose steroids, anti-epileptics, or other symptom-relieving

medications).

21. Current evidence of clinically significant corneal or retinal disorder,

including but not limited to bullous/band keratopathy, keratoconjunctivitis

(except for keratoconjunctivits sicca), corneal abrasion (except if related to

trauma), inflammation/ulceration, confirmed by ophthalmologic examination.

22. Significant gastrointestinal disorder(s) that could, in the opinion of the

Investigator, interfere with the absorption, metabolism, or excretion of

derazantinib and/or atezolizumab (e.g., Crohn's disease, ulcerative colitis,

extensive gastric resection).

23. Active tuberculosis. 24. Co-infection with hepatitis B and hepatitis C.

Patients who are negative for HCV RNA will be considered non-infected for HCV.

25. Severe bacterial, fungal, viral and/or parasitic infections on therapeutic

oral or IV medication at the time of first dose of study drug administration.

26. Treatment with strong CYP3A4 inducers within 14 days prior to initiation of

study treatment, including rifampin (and its analogues) or St. John's wort.

27. Patient who has been incarcerated or involuntarily institutionalized by court

order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

28. Patients who are unable to consent because they do not understand the nature,

significance and implications of the clinical trial and therefore cannot make a

rational/informed decision after receiving the study information [§ 40 Abs. 1 S.

3 Nr. 3a AMG].

Studien-Rationale

Primary outcome:

1. Primary Objective: Assessment of Efficacy (Time Frame - up to 4 years, at EOS):
Objective Response Rate (ORR) will be assessed every 8 weeks (+/- 7 days) according to RECIST 1.1 criteria



Secondary outcome:

1. Secondary Objective: Assessment of Safety (Time Frame - up to 4 years, at EOS):
All adverse events (including serious adverse events and adverse events of special interest) will be assessed for saftey of study treatment in accordance with CTCAE V 5.0

2. Secondary Objective: Assessment of Efficacy in relation to objection response rate at EOT (Time Frame - up to 4 years, at EOS):
Objective response rate (ORR) according to investigator-based RECIST 1.1 assessment, defined as the proportion of allocated subjects with best response of complete or partial response within study treatment.

3. Secondary Objective: Assessment of Efficacy in relation to progression free survival (Time Frame - up to 4 years, at EOS):
The proportion of patients known to be alive and without confirmed objective disease progression at 6, 8 and 10 months after first administration of study treatment, respectively and time from first administration of study treatment until the date of first objective disease progression or death.

4. Secondary Objective: Assessment of Efficacy in relation to overall survival (Time Frame - 4 years, at EOS):
Time from first administration of study treatment until death of a patient due to any cause

Geprüfte Regime

  • Atezolizumab (Tecentriq):
    Infusion i.v. of atezolizumab on day 1 of a 3-week cycle, first infusion rate over 60 minutes, subsequent infusion rates 30 minutes if tolerated for a maximum of 16 cycles in total
  • Derazantinib (ARQ 087):
    Oral intake of 300 mg derazantinib continuously on day 1 to day 21 of a 3-week cycle for a maximum of 16 cycles in total

Quelle: ClinicalTrials.gov


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