Clinical Trials

Inclusion Criteria: 

Randomized Portion of Trial

• Sign and date the written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
• Male and female patients must be at least 18 years of age. Other age restrictions may apply as per local regulations.
• Male and female patients must be ≥ 30 kg.
• 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.
• Has histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC established by prospective central testing of tumor tissue or, in the absence of central testing availability, by local test result, where permitted.
• Patients must provide an FFPE tumor sample that is no older than 3 years for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, and other correlatives. The mandatory FFPE tumor sample should be from the most recent biopsy but can be either from the primary tumor or metastatic biopsy. Patients with unknown or indeterminate PD-L1 status on central testing may not be randomized. Archival samples taken from a surgical or diagnostic biopsy confirming HER2 status can be accepted. Specimens with limited tumor content and cytology samples are inadequate for defining tumor HER2 or PD-L1 status. Additional details on sample requirement will be defined in the Diagnostic Testing Manual and Central Laboratory Manual.
• Has at least one target lesion assessed by the Investigator based on RECIST v1.1 (randomized portion of trial). 8 Left ventricular ejection fraction ≥ 50% within 28 days before randomization. 9 WHO/ECOG performance status of 0 or 1.
• 10 Adequate organ and bone marrow function within 14 days before randomization (Table 8): See Protocol 
  • Hemoglobin ≥ 9 g/dL • Absolute neutrophil count ≥ 1500/mm3
  • Platelet count ≥ 100000/mm3 • Bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, ≤ 5 × ULN in patients with liver metastases
  • Serum albumin ≥ 2.5 g/dL • Creatinine clearance ≥ 50 mL/min (as calculated using the Cockcroft and Gault equation)
  • International normalized ratio/prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.

Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D1.

• Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of investigational product. Women of childbearing potential are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause (Section 5.3). See Protocol.
• Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, as presented in Table 10, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP (Section 5.3).
• Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study treatment administration. Preservation of ova may be considered prior to enrollment in this study.
• Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening for 6 months after the last dose of IMP. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception, as described in Table 10 (Section 5.3).
• Patients with HBV infection (as characterized by positive HBsAg and/or anti-HBc with detectable HBV DNA [≥ 10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy prior to randomization per institutional practice to ensure adequate viral suppression. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients who test positive for anti-HBc with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10 IU/mL or reaches detectable limits per local laboratory during the course of treatment. Patients with active co-infection of HBV and HCV as evidenced by positive anti-HCV antibody and actively co-infected with HBV and hepatitis D virus are not eligible.
• Adequate treatment washout period before randomization, defined in Table 9: See Protocol

Inclusion Criteria (Safety Run-In)

• Sign and date the written ICF prior to any mandatory study specific procedures, sampling, and analyses.
• Male and female patients must be at least 18 years of age. Other age restrictions may apply as per local regulations.
• Male and female patients must be ≥ 30 kg. 4 Unresectable, previously untreated, locally advanced or metastatic BTC. 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.
• Has histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC established by prospective central testing of tumor tissue or, in the absence of central testing availability, by local test result, where permitted.
• Patients must provide an FFPE tumor sample that is no older than 3 years for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, and other correlatives. The mandatory FFPE tumor sample should be from the most recent biopsy but can be either from the primary tumor or metastatic biopsy. Archival samples taken from a surgical or diagnostic biopsy confirming HER2 status can be accepted. Specimens with limited tumor content and cytology samples are inadequate for defining tumor HER2 or PD-L1 status. Additional details on sample requirement will be defined in the Diagnostic Testing Manual and Central Laboratory Manual
• Left ventricular ejection fraction ≥ 50% within 28 days before randomization.
• WHO/ECOG performance status of 0 or 1. 9 Adequate organ and bone marrow function within 14 days before randomization (Table 8):
  • Hemoglobin ≥ 9 g/dL
  • Absolute neutrophil count ≥ 1500/mm3
  • Platelet count ≥ 100000/mm3
  • Bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, ≤ 5 × ULN in patients with liver metastases.
  • Serum albumin ≥ 2.5 g/dL • Creatinine clearance ≥ 50 mL/min (as calculated using the Cockcroft and Gault equation).
  • International normalized ratio/prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.

Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D1.

• Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test prior to each administration of investigational product. Women of childbearing potential are defined as those who are not surgically sterile (ie, underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause (Section 5.3).
• Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, as presented in Table 10, from the time of screening and must agree to continue using such precautions for 7 months after the last dose of IMP. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP (Section 5.3).
• Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration. Preservation of ova may be considered prior to enrollment in this study.
• Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening for 6 months after the last dose of IMP. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception, as described in Table 10, throughout this period (Section 5.3).
• Patients with HBV infection (as characterized by positive hepatitis B surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (anti-HBc) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy prior to randomization per institutional practice to ensure adequate viral suppression. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Patients who test positive for anti-HBc with undetectable HBV DNA (< 10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10 IU/mL or reaches detectable limits per local laboratory during the course of treatment. Patients with active co-infection of HBV and HCV as evidenced by positive anti-HCV antibody and actively co-infected with HBV and hepatitis D virus are not eligible.
• Adequate treatment washout period before enrolment, defined in Table 9.

Exclusion Criteria (Randomized Portion of Trial and Safety Run-In)

• Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors (eg, anti-PD-1/PD-L1 or CTLA-4) and therapeutic anticancer vaccines.
• Has histologically confirmed ampullary carcinoma.
• Has a history of substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
• Has 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. Patients with clinically inactive brain metastases may be included in the study. Patients with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
• Patients with a 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. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
• 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.
• Has an active autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogren's, sarcoidosis etc) that has required systemic treatment in the past 2 years (eg, with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs), or where there is documented, or a suspicion of pulmonary involvement at the time of screening. Replacement therapy (eg, thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Full details of the disorder should be recorded in the eCRF for patients who are included in the study.
• Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.
• Criteria related to lung disorders:
  • 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 (eg, pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc).
  • Prior pneumonectomy (complete). 10 Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• Active primary immunodeficiency, known uncontrolled active HIV infection or HCV. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrolment if required by local regulations or institutional review board/ethics committee.
• Acute hepatitis A.
• Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan or rilvegostomig. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
  • Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to [randomization/enrollment/Cycle 1 Day 1] and managed with Standard-of-Care treatment) that the Investigator deems related to previous anticancer therapy, such as:
    • Chemotherapy-induced neuropathy
    • Fatigue
    • Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include:
      • Hypothyroidism/hyperthyroidism
      • Type 1 diabetes
      • Hyperglycemia
      • Adrenal insufficiency
      • Adrenalitis
      • Skin hypopigmentation (vitiligo)
• Known allergy or hypersensitivity to study treatment or any of the study drug and/or any of the excipients.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Pregnant or breastfeeding female patients, or patients who are planning to become pregnant.
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence, adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, lentigo maligna that has undergone potentially curative therapy or adequately treated in situ disease without evidence of disease.
• A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Drainage and CART are not allowed within 2 weeks prior to randomization).
• Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids or local steroid injections (eg, 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 or as an anti-emetic (eg, CT scan premedication).
• 21 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for non-cancerrelated conditions (eg, hormone replacement therapy) is allowed.
• History of allogenic organ transplant.

Prior/Concurrent Clinical Study Experience (Only applicable for the randomized portion of the study):

• Previous randomization in the present study or a previous T-DXd or rilvegostomig study regardless of treatment arm assignment.
• 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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 4/30/2024. Questions regarding updates should be directed to the study team contact.