T-DXd + Rilvegostomig for Biliary Tract Cancer

(DESTINY-BTC01 Trial)

Recruiting at 260 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

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

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 48 months

620 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for advanced biliary tract cancer (BTC), which affects the tubes carrying bile from the liver and gallbladder to the small intestine. Researchers are testing whether the combination of drugs T-DXd (trastuzumab deruxtecan) and rilvegostomig, or T-DXd alone, is more effective than the standard treatment of gemcitabine, cisplatin, and durvalumab. The trial targets individuals with HER2-expressing BTC who have not received prior treatment for their advanced cancer. Those recently diagnosed with untreated advanced BTC may be suitable candidates for this trial. As a Phase 3 trial, it represents the final step before FDA approval, providing access to potentially groundbreaking treatments.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that trastuzumab deruxtecan (T-DXd) may effectively treat various cancers, including biliary tract cancer. Studies have found that patients generally tolerate T-DXd well. Most side effects are mild to moderate, such as low white blood cell count and nausea, while serious side effects occur less frequently.

Specific safety information for the combination of T-DXd with rilvegostomig is not widely available. However, since T-DXd is already approved for other uses, some understanding of its safety exists. The ongoing trial continues to study the safety of the combination, but reaching this phase suggests earlier tests deemed it safe enough for further research.

Overall, while T-DXd's safety is known, the combination with rilvegostomig remains under exploration. Joining the trial would contribute to understanding its safety further. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for biliary tract cancer because they offer innovative approaches compared to the standard of care, which typically involves chemotherapy drugs like gemcitabine and cisplatin, often used with durvalumab. Trastuzumab deruxtecan (T-DXd) is unique because it is an antibody-drug conjugate that specifically targets cancer cells expressing the HER2 protein, delivering chemotherapy directly to the tumor and potentially reducing harm to healthy cells. Rilvegostomig, when combined with T-DXd, might enhance the treatment's efficacy by further modulating the immune response against cancer cells. These targeted strategies could offer more effective and possibly less toxic treatment options for patients.

What evidence suggests that this trial's treatments could be effective for biliary tract cancer?

Studies have shown that trastuzumab deruxtecan (T-DXd) holds promise in treating HER2-positive biliary tract cancer (BTC). One study found that over one-third of patients with this cancer type responded well to T-DXd, indicating its potential effectiveness. In this trial, participants may receive T-DXd alone or with rilvegostomig. Although there is less direct evidence for the combination of T-DXd with rilvegostomig, T-DXd has significantly improved outcomes in other cancers, suggesting potential benefits. Researchers are studying these treatments to determine if they outperform the current standard treatment, which includes gemcitabine and cisplatin with durvalumab. Overall, existing research suggests that T-DXd, alone or with rilvegostomig, may be effective for patients with HER2-positive BTC. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

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.

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)

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Rilvegostomig
• Trastuzumab deruxtecan

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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) 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]

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]

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]

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 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]

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 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 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 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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4090

Trastuzumab deruxtecan (T-DXd) in patients (pts) with ... T-DXd showed tumor-agnostic potential, with an objective response rate (ORR) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.02010

Trastuzumab Deruxtecan in Human Epidermal Growth ... T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC.

3. enhertuhcp.com enhertuhcp.com/en/ihc3-plus-metastatic-solid-tumors/efficacy/efficacy-data

Efficacy Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Median follow-up was 11.17 months for non-small cell lung cancer, 9.28 months for colorectal cancer, and 16 months for metastatic solid tumors. 2. fCI is ...

4. daiichisankyo.us daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

Highlights of Prescribing Information effectiveness of fam-trastuzumab deruxtecan-nxki is unknown. Neutralizing antibodies against fam-trastuzumab deruxtecan-nxki were detected in 6% (4/70) of ...

5. jwatch.org jwatch.org/na57893/2024/09/04/trastuzumab-deruxtecan-her2-positive-biliary-cancer

Trastuzumab Deruxtecan for HER2-Positive Biliary Cancer? More than one third of patients with HER2+ biliary cancer had a response to the antibody–drug conjugate T-DXd in a small, single-arm study from Japan.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10730032/

Efficacy and Safety of Trastuzumab Deruxtecan in Patients ... In early-phase studies, T-DXd demonstrated antitumor activity in a range of HER2-expressing malignancies, including colorectal, salivary gland, biliary tract, ...

7. enhertuhcp.com enhertuhcp.com/en/breast/safety

Safety Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) The benefit-risk profile of ENHERTU was established in DESTINY-Breast031. The majority of adverse reactions were Grade 1 or 21,2.