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JOURNAL ONKOLOGIE – STUDIE
DESTINY-BTC01

Phase 3 Study of T-DXd and Rilvegostomig Versus SoC in Advanced HER2-expressing Biliary Tract Cancer

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NCT-Nummer:
NCT06467357

Studienbeginn:
Juni 2024

Letztes Update:
21.06.2024

Wirkstoff:
Gemcitabine, Cisplatin, Durvalumab, Trastuzumab Deruxtecan, Rilvegostomig

Indikation (Clinical Trials):
Biliary Tract Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
AstraZeneca

Collaborator:
Daiichi Sankyo Company, Limited 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo

Kontakt

AstraZeneca Clinical Study Information Center
Kontakt:
Phone: 1-877-240-9479
E-Mail: information.center@astrazeneca.com» Kontaktdaten anzeigen

Studienlocations
(3 von 36)

Alle anzeigen

Studien-Informationen

Brief Summary:

The purpose of this study is to measure the efficacy and safety of T-DXd with rilvegostomig

or T-DXd monotherapy compared with gemcitabine plus cisplatin and durvalumab in patients with

advanced treatment naïve HER2-expressing BTC.

Ein-/Ausschlusskriterien

Key Inclusion Criteria:

- Participants must be ≥ 18 years of age at the time of screening. Other age

restrictions may apply as per local regulations;

- Male and female;

- Unresectable, previously untreated, locally advanced or metastatic BTC. Prior

treatment in the perioperative and/or adjuvant setting is permissible provided there

is > 6 months (180 days) between the end of adjuvant treatment and the diagnosis of

locally advanced or metastatic disease.

- histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC;

- Provision of FFPE tumor sample that is no older than 3 years;

- At least one target lesion assessed by the Investigator based on RECIST v1.1

(randomized portion only);

- WHO/ECOG performance status of 0 or 1;

- Adequate organ and bone marrow function within 14 days before randomization;

- Evidence of post-menopausal status or negative serum pregnancy test for females of

childbearing potential;

Key Exclusion Criteria:

- Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors

and therapeutic anticancer vaccines;

- histologically confirmed ampullary carcinoma;

- history of substance abuse or any other medical conditions such as clinically

significant cardiac or psychological conditions;

- spinal cord compression or clinically active central nervous system metastases,

defined as untreated and symptomatic, or requiring therapy with corticosteroids or

anticonvulsants to control associated symptoms;

- medical history of myocardial infarction within 6 months before

randomization/enrollment, symptomatic congestive heart failure (New York Heart

Association Class II to IV), unstable angina pectoris, clinically important cardiac

arrhythmias, or a recent (< 6 months) cardiovascular event including stroke;

- Serious chronic gastrointestinal conditions associated with diarrhea (eg, active

inflammatory bowel disease); active non-infectious skin disease (including any grade

rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment;

- active autoimmune, connective tissue or inflammatory disorders that has required

systemic treatment in the past 2 years, or where there is documented, or a suspicion

of pulmonary involvement at the time of screening;

- Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec

(males) based on average of the screening triplicate 12-lead ECG;

- History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where

suspected ILD/pneumonitis cannot be ruled out by imaging at screening;

- Lung-specific intercurrent clinically significant illnesses including, but not limited

to, any underlying pulmonary disorder;

- Prior pneumonectomy (complete);

- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals;

- Active primary immunodeficiency, known uncontrolled active HIV infection or HCV;

- Pregnant or breastfeeding female patients, or patients who are planning to become

pregnant;

- Participation in another clinical study with a study intervention or investigational

medicinal device administered in the last 6 months prior to randomization, or

concurrent enrollment in another clinical study, unless it is an observational

(non-interventional) clinical study or during the follow-up period of an

interventional study (only randomized portion).

Studien-Rationale

Primary outcome:

1. Safety Run In: To evaluate the safety and tolerability of T-DXd with rilvegostomig (Time Frame - Until all patients have completed at least 1 full Cycle (each cycle is 21 days)):
Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%.

2. Randomized Portion: To evaluate the efficacy of T-DXd with rilvegostomig vs Standard of Care (SoC) in terms of Overall Survival in the HER2 IHC 3+ population (Time Frame - From date of treatment assignment until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)):
Overall survival (OS) in HER2 IHC 3+ population OS is defined as time from randomization date until the date of death due to any cause. The comparison will include all randomized patients, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the hazard ratio of OS.

Secondary outcome:

1. To evaluate the efficacy of T-DXd with rilvegostomig vs Standard of Care in terms of Overall Survival in the ITT population (HER2 IHC 3+/2+) (Time Frame - From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)):
Overall Survival (OS) in ITT population (HER2 IHC 3+/2+) OS definition as above

2. To evaluate the efficacy of T-DXd monotherapy vs Standard of Care in terms of Overall Survival in the HER2 IHC 3+ population (Time Frame - From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)):
Overall Survival (OS) in HER2 IHC 3+ population OS definition as above

3. To evaluate the efficacy of T-DXd monotherapy vs Standard of Care in terms of Overall Survival in the ITT population (Time Frame - From date of randomization until the date of death from any cause (estimated to be assessed up to 48 months after first subject randomized)):
Overall Survival (OS) in ITT population (HER2 IHC 3+/2+) OS definition as above

4. To further evaluate efficacy of T-DXd with rilvegostomig vs Standard of Care in terms of Progression Free Survival in HER2 IHC 3+ and ITT populations (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first (estimated to be assessed up to 48 months)):
Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the hazard ratio of PFS.

5. To further evaluate efficacy of T-DXd monotherapy vs Standard of Care in terms of Progression Free Survival in HER2 IHC 3+ and ITT populations (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first (estimated to be assessed up to 48 months)):
Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the hazard ratio of PFS.

6. To further evaluate the efficacy of T-DXd with rilvegostomig vs Standrad of Care in terms of objective response rate in the HER2 IHC 3+ and ITT populations (Time Frame - Estimated up to 6 months since randomization):
Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression. Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation. The measure of interest is the odds ratio of ORR.

7. To further evaluate the efficacy of T-DXd monotherapy vs Standrad of Care in terms of objective response rate in the HER2 IHC 3+ and ITT populations (Time Frame - Estimated up to 6 months since randomization):
Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression. Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation. The measure of interest is the odds ratio of ORR.

8. To further evaluate efficacy of T-DXd with rilvegostomig vs Standard if Care in terms of duration of response in patients with HER2-expressing BTC in the IHC 3+ and ITT populations (Time Frame - From the date of first documented response until date of documented progression or death due to any cause, whichever occurs first (estimated up to 48 months)):
Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the median DoR.

9. To further evaluate efficacy of T-DXd monotherapy vs Standard if Care in terms of duration of response in patients with HER2-expressing BTC in the IHC 3+ and ITT populations (Time Frame - From the date of first documented response until date of documented progression or death due to any cause, whichever occurs first (estimated up to 48 months)):
Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the median DoR.

10. To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Overall survival in HER2 IHC 3+ and ITT populations. (Time Frame - From the date of randomisation until progression or death due to any cause, whichever occurs first (estimated up to 48 months)):
Overall survival (OS) in HER2 IHC 3+ population OS is defined as time from randomization date until the date of death due to any cause. The comparison will include all randomized patients, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the hazard ratio of OS.

11. To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of PFS in HER2 IHC 3+ and ITT populations. (Time Frame - From the date of randomisation until progression or death due to any cause, whichever occurs first (estimated up to 48 months)):
Progression free survival (PFS) in HER2 IHC 3+ and ITT populations. PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients, regardless of whether the patient withdraws from randomized therapy, receives another anticancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the hazard ratio of PFS.

12. To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Duration of response in HER2 IHC 3+ and ITT populations. (Time Frame - From the date of first response until progression or death due to any cause, whichever occurs first (estimated up to 48 months)):
Duration of response (DoR) in HER2 IHC 3+ and ITT populations DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, or death due to any cause. The analysis will include all randomized patients who have a response, regardless of whether the patient withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression. The measure of interest is the median DoR.

13. To further evaluate the efficacy of T-DXd with rilvegostomig versus T-DXd monotherapy in terms of Objective response rate in HER2 IHC 3+ and ITT populations. (Time Frame - Estimated up to 6 months):
Objective response rate (ORR) in HER2 IHC 3+ and ITT populations ORR is defined as the proportion of patients who achieved CR or PR per RECIST 1.1, confirmed by the investigator. The analysis will include objective response data for all randomized patients from randomization until progression, or up to the last evaluable assessment in the absence of progression. Patients who go off-treatment without a response or progression and then respond while receiving a subsequent therapy will not be included as responders in the ORR calculation. The measure of interest is the odds ratio of ORR.

14. To assess the safety and tolerability of T-DXd with rilvegostomig vs Standard of Care (Time Frame - From first dose of study intervention until 90 days after the last dose except for ILD/pneumonitis, where safety follow-up will be continued until resolution.):
Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%.

15. To assess the safety and tolerability of T-DXd monotherapy vs Standard of Care (Time Frame - From first dose of study intervention until 90 days after the last dose except for ILD/pneumonitis, where safety follow-up will be continued until resolution.):
Safety and tolerability will be evaluated with multiple endpoints including the proportion of treated patients with occurrence of AEs, SAEs, AESIs, and clinically significant change from baseline for Hematology, clinical chemistry, Urinalysis, vital sign including ECG will be summarized, specifically pts with QTcF prolongation greater than grade 3, number of pts with echocardiogram/MUGA results LVEF greater than 10 percentage points to below 50%.

16. To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to Standard of Care based on a summary of symptomatic AEs (Time Frame - Until End of Study (estimated up to 48 months)):
Patient-reported tolerability will be described using the Symptomatic adverse events: Descriptive summary of the proportion of patients reporting symptomatic AEs while on treatment using items from the EORTC Item Library (on EORTC IL form 322).

17. To describe patient-reported tolerability of T-DXd monotherapy in comparison to SoC based on a summary of symptomatic AEs (Time Frame - Until End of Study (estimated up to 48 months)):
Patient-reported tolerability will be described using the Symptomatic adverse events: Descriptive summary of the proportion of patients reporting symptomatic AEs while on treatment using items from the EORTC Item Library (on EORTC IL form 322)

18. To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to T-DXd monotherapy based on a summary of symptomatic AEs and overall side-effect bother (Time Frame - Until End of Study (estimated up to 48 months)):
Symptomatic AEs and overall side-effect bother definitions as above

19. To assess time to deterioration in physical functioning in patients treated with T-DXd with rilvegostomig vs Standard of Care (Time Frame - Until End of Study (estimated up to 48 months)):
Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration. Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold. - The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized.

20. To assess time to deterioration in physical functioning in patients treated with T-DXd monotherapy vs Standard of care (Time Frame - Until End of Study (estimated up to 48 months)):
Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration. Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold. - The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized.

21. To assess time to deterioration in physical functioning in patients treated with T-DXd with rilvegostomig vs T-DXd monotherapy (Time Frame - Until End of Study (estimated up to 48 months)):
Time to deterioration (TTD) in physical function as measured by the PROMIS Short Form v2.0 - Physical Function 8c - TTD is defined as time from the date of randomization to the date of deterioration. Deterioration is defined as the change from baseline that reaches a clinically meaningful deterioration threshold. - The measure of interest is the HR of TTD in physical function. The analysis will include all randomized patients as randomized.

22. To assess the pharmacokinetics of T-DXd, total anti- HER2 antibody, DXd and rilvegostomig in serum (Time Frame - From the time of informed consent until 30 and 90 days after the last dose of T-DXd and rilvegostomig, respectively):
Descriptive analysis of serum concentration of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig in all applicable arms.

23. To investigate the immunogenicity of T-DXd and of rilvegostomig (Time Frame - From the time of informed consent until 30 and 90 days after the last dose of T-DXd and rilvegostomig, respectively):
Descriptive summary of presence of ADAs for T-DXd and rilvegostomig in all applicable arms.

24. To describe patient-reported tolerability of T-DXd with rilvegostomig in comparison to Standard of Care based on overall side-effect bother (Time Frame - Until End of Study (estimated up to 48 months)):
Patient-reported tolerability will be described using the Overall side-effect bother that will be mesured using PGI-TT

25. To describe patient-reported tolerability of T-DXd monotherapy in comparison to SoC based on overall side-effect bother (Time Frame - Until End of Study (estimated up to 48 months)):
Patient-reported tolerability will be described using the Overall side-effect bother that will be assessed will be mesured using PGI-TT

Studien-Arme

  • Experimental: Trastuzumab deruxtecan + rilvegostomig
    Trastuzumab deruxtecan (T-DXd; DS-8201a) in combination with rilvegostomig arm
  • Experimental: Trastuzumab deruxtecan
    Trastuzumab deruxtecan (T-DXd; DS-8201a) arm
  • Active Comparator: Standard of Care
    Gemcitabine and cisplatin in combination with durvalumab arm

Geprüfte Regime

  • Gemcitabine:
    Standard of care chemotherapy by intravenous infusion
  • Cisplatin:
    Standard of care chemotherapy by intravenous infusion
  • Durvalumab:
    Standard of care immunotherapy by intravenous infusion
  • Trastuzumab deruxtecan (DS-8201a; T-DXd):
    Experimental therapy by intravenous infusion
  • Rilvegostomig:
    Experimental therapy by intravenous infusion
  • Agilent HercepTest™ mAb pharmDx:
    A semi-quantitative immunohistochemical assay to determine HER2 overexpression in FFPE breast cancer tissues routinely processed for histological evaluation. Based on a primary monoclonal rabbit antibody which visualises Her2 overexpression utilising a fully automated IHC platform (Dako Omnis).
  • Ventana PD-L1 SP263 assay:
    A qualitative immunohistochemical assay to determine the level of PD-L1 expression in FFPE non-small cell lung cancer (NSCLC) tissues routinely processed for histological evaluation. Based on a rabbit monoclonal anti-PD-L1 clone SP263 which visualises PD-L1 protein using a VENTANA BenchMark ULTRA instrument

Quelle: ClinicalTrials.gov


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