T-DXd + Rilvegostomig for Biliary Tract Cancer

(DESTINY-BTC01 Trial)

Recruiting at 170 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: AstraZeneca

Must not be taking: Corticosteroids, Anticonvulsants, Anticancer vaccines, others

Disqualifiers: Cardiac conditions, CNS metastases, Autoimmune disorders, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug T-DXd + Rilvegostomig for Biliary Tract Cancer?

Research shows that trastuzumab, a component of T-DXd, has shown effectiveness in treating HER2-positive biliary tract cancer, with some patients experiencing partial responses or stable disease. Additionally, a case study reported long-term survival in a patient with stage IV gallbladder cancer treated with trastuzumab and chemotherapy. ^{1 2 3 4 5}

Is the treatment T-DXd + Rilvegostomig generally safe for humans?

Trastuzumab deruxtecan (T-DXd) has been studied for safety in various cancers, including breast, gastric, and lung cancers. It is generally considered safe, but like many cancer treatments, it can have side effects, which should be discussed with a healthcare provider. ^{6 7 8 9 10}

What makes the drug T-DXd + Rilvegostomig unique for treating biliary tract cancer?

T-DXd + Rilvegostomig is unique because it targets HER2, a protein that can be overexpressed in some biliary tract cancers, using a combination of an antibody-drug conjugate (T-DXd) and a novel agent (Rilvegostomig). This approach is different from standard treatments like gemcitabine and cisplatin, which do not specifically target HER2. ^{1 11 12 13 14}

Eligibility Criteria

This trial is for adults with advanced HER2-expressing Biliary Tract Cancer (BTC) who haven't had treatment before. Participants must have a specific protein in their cancer cells, which will be checked using special tests like Ventana PD-L1 SP263 assay or Agilent HercepTest™ mAb pharmDx.

Inclusion Criteria

I am post-menopausal or not pregnant.

I am either male or female.

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

Exclusion Criteria

I have had a lung removed.

I do not have active brain metastases requiring steroids or seizure meds.

Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run In

Evaluate the safety and tolerability of T-DXd with rilvegostomig

3 weeks

1 visit (in-person) per cycle

Treatment

Participants receive T-DXd with rilvegostomig or T-DXd monotherapy or standard of care

48 months

Regular visits (in-person) throughout treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Rilvegostomig (Other)
• Trastuzumab deruxtecan (Antibody-drug Conjugate)

Trial Overview The study compares the effectiveness and safety of T-DXd alone or combined with rilvegostomig against standard chemotherapy (gemcitabine plus cisplatin) and durvalumab. It's a Phase 3 trial, meaning it's testing treatments that have shown promise in earlier trials.

Participant Groups

Group I: Trastuzumab deruxtecan + rilvegostomig Experimental Treatment 4 Interventions

Trastuzumab deruxtecan (T-DXd; DS-8201a) in combination with rilvegostomig arm

Group II: Trastuzumab deruxtecan Experimental Treatment 3 Interventions

Trastuzumab deruxtecan (T-DXd; DS-8201a) arm

Group III: Standard of Care Active Control 5 Interventions

Gemcitabine and cisplatin in combination with durvalumab arm

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

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

Collaborator

Trials

3

Recruited

1,900+

Findings from Research

This study identified HER2 as a potential therapeutic target for biliary tract cancer (BTC), with 13% of advanced BTC patients being HER2-positive, suggesting a specific population that could benefit from targeted therapies.

In pre-clinical models, HER2-amplified BTC cell lines showed sensitivity to treatments like trastuzumab and dacomitinib, leading to significant anti-tumor effects, including increased apoptosis and cell cycle arrest, indicating promising efficacy for HER2-targeted strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic implication of HER2 in advanced biliary tract cancer. Nam, AR., Kim, JW., Cha, Y., et al.[2018]

A patient with stage IV gallbladder cancer, which typically has a poor prognosis, achieved a remarkable five-year survival without recurrence after receiving a combination of HER2-targeted therapy (Trastuzumab) and second-line chemotherapy, followed by curative surgery.

This case highlights the potential of targeting HER2 overexpression in gallbladder cancer, suggesting that personalized treatment approaches may improve outcomes even in advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term recurrence free survival in a stage IV gallbladder cancer treated with chemotherapy plus trastuzumab and salvage liver resection. Prieto, M., Gastaca, M., Ruiz, P., et al.[2020]

In a study involving 39 patients with HER2-positive metastatic biliary tract cancer, the combination of pertuzumab and trastuzumab resulted in a promising objective response rate of 23%, indicating potential efficacy for this treatment in a challenging cancer type.

The treatment was generally well tolerated, with 46% of patients experiencing grade 3-4 adverse events, but no treatment-related serious adverse events or deaths were reported, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Javle, M., Borad, MJ., Azad, NS., et al.[2021]

In a study of 210 patients with advanced biliary tract carcinoma, PD-1 monoclonal antibody (PD-1-mAb) combination therapy significantly improved median progression-free survival (mPFS) and median overall survival (mOS) compared to standard chemotherapy in both first-line and second-line treatments.

Specifically, the first-line PD-1-mAb combination group had a mPFS of 7.3 months and mOS of 15.6 months, while the second-line group had a mPFS of 6.1 months and mOS of 11.7 months, indicating that PD-1-mAb combinations are promising treatment options for this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis. Wang, F., Wang, FH., Sun, K., et al.[2022]

In a phase II study involving 77 patients with unresectable biliary tract cancers, the combination of atezolizumab (anti-PD-L1) and cobimetinib (MEK inhibitor) significantly improved progression-free survival (PFS) to a median of 3.65 months compared to 1.87 months for atezolizumab alone.

Despite the improved PFS, the overall response rates were low in both treatment groups, indicating that biliary tract cancers may be resistant to immune therapies, and combination therapy was associated with increased side effects such as rash and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. Yarchoan, M., Cope, L., Ruggieri, AN., et al.[2023]

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate that has shown efficacy in treating HER2-positive breast and gastric cancers, and it is being evaluated for its effectiveness in biliary tract cancer (BTC), where HER2 positivity occurs in 5-20% of cases.

The ongoing phase II HERB trial aims to assess the safety and efficacy of trastuzumab deruxtecan specifically in patients with unresectable or recurrent HER2-expressing BTC, with the primary goal of measuring the objective response rate in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Ohba, A., Morizane, C., Ueno, M., et al.[2022]

Trastuzumab deruxtecan (T-DXd) is a promising new antibody-drug conjugate that has been approved for treating HER2-positive metastatic breast cancer and gastric cancer, showing potential for use in other solid tumors as well.

T-DXd is expected to become the standard second-line treatment for HER2-positive metastatic breast cancer and may also benefit patients with hormone receptor-positive and triple-negative breast cancer that express low levels of HER2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Perez, J., Garrigós, L., Gion, M., et al.[2022]

In an expanded-access study involving 64 patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas, trastuzumab deruxtecan (T-DXd) was administered safely, with no new safety concerns identified prior to its marketing approval in Japan.

Serious adverse events (SAEs) were reported in 26.6% of patients, with febrile neutropenia being the most common; however, drug-related SAEs led to death in only one patient, indicating a manageable safety profile for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Shitara, K., Yamaguchi, K., Muro, K., et al.[2023]

Trastuzumab deruxtecan (T-DXd) showed promising antitumor activity in patients with advanced HER2-low breast cancer, achieving a 37% objective response rate in a study of 54 patients who had undergone a median of 7.5 prior therapies.

While T-DXd demonstrated efficacy, it also presented significant safety concerns, with 98% of patients experiencing treatment-emergent adverse events, including severe cases of interstitial lung disease (ILD) that led to fatalities, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Modi, S., Park, H., Murthy, RK., et al.[2021]

In a phase II study involving 267 patients with HER2-expressing solid tumors, trastuzumab deruxtecan (T-DXd) showed an overall objective response rate (ORR) of 37.1%, with a median duration of response of 11.3 months, indicating its efficacy in treating these cancers.

Patients with central HER2 IHC 3+ expression had even better outcomes, with an ORR of 61.3% and a median overall survival of 21.1 months, highlighting T-DXd's potential as a targeted therapy for HER2-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Meric-Bernstam, F., Makker, V., Oaknin, A., et al.[2023]

Trastuzumab emtansine (T-DM1) demonstrated preclinical effectiveness against biliary tract cancers (BTC) that overexpress the HER2 receptor, showing higher anti-proliferative activity in cell lines with elevated HER2 levels.

The study found that T-DM1 not only inhibited HER2 signaling but also induced cell death through mechanisms like antibody-dependent cell-mediated cytotoxicity (ADCC) and apoptosis, suggesting its potential as a targeted therapy for HER2-positive BTC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate. Yamashita-Kashima, Y., Yoshimura, Y., Fujimura, T., et al.[2020]

In a study involving 4 patients with advanced HER2-positive biliary tract cancer, the combination of trastuzumab-pkrb and the standard GemCis regimen showed promising preliminary efficacy, with 2 patients achieving a partial response and 2 maintaining stable disease.

The treatment resulted in a median progression-free survival of 6.1 months, and while neutropenia was a common side effect (75% of patients), no serious complications like febrile neutropenia occurred, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of HER2-Targeted Therapy in Advanced Biliary Tract Cancer: A Prospective Pilot Study of Trastuzumab Biosimilar in Combination with Gemcitabine Plus Cisplatin. Jeong, H., Jeong, JH., Kim, KP., et al.[2021]

In a phase II trial involving 90 patients with HER2-positive biliary tract cancers, the combination of gemcitabine-cisplatin and trastuzumab achieved a median progression-free survival (PFS) of 7 months, with a 6-month PFS rate of 75.6%.

The treatment resulted in a 55.5% overall response rate, indicating significant clinical activity, while the presence of isolated TP53 mutations was linked to poorer PFS outcomes, suggesting that genetic profiling could enhance patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2-Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB). Ostwal, V., Mandavkar, S., Bhargava, P., et al.[2023]

In a phase 2 trial involving 34 participants with HER2-positive biliary tract cancer, the combination of trastuzumab and FOLFOX showed a promising overall response rate of 29.4% and a disease control rate of 79.4%, indicating its potential effectiveness as a second-line or third-line treatment.

The treatment was associated with manageable toxicity, with no treatment-related cardiac effects or deaths reported, although some participants experienced significant neutropenia and anemia, suggesting that while the therapy is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14). Lee, CK., Chon, HJ., Cheon, J., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Therapeutic implication of HER2 in advanced biliary tract cancer. [2018]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Long term recurrence free survival in a stage IV gallbladder cancer treated with chemotherapy plus trastuzumab and salvage liver resection. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate. [2020]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Feasibility of HER2-Targeted Therapy in Advanced Biliary Tract Cancer: A Prospective Pilot Study of Trastuzumab Biosimilar in Combination with Gemcitabine Plus Cisplatin. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2-Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB). [2023]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14). [2023]