Evaluation of Gemcitabine, Cisplatin, Trastuzumab, and Pembrolizumab in HER2-Positive Biliary Tract Cancer: A Phase II Clinical Trial
- Trial ID
- 2023-505722-33-00
- Protocol
- TRAP-BTC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **efficacy** of the combination of standard of care (SOC) treatment using GemCis with trastuzumab and pembrolizumab in patients with previously untreated HER2-positive **biliary tract cancer**, specifically focusing on the objective response rate after 6 months (ORR@6). This is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in a patient population with limited therapeutic options.
Secondary objectives include further characterizing the efficacy of this combination therapy in terms of progression-free survival (PFS) and overall survival (OS). Additionally, the study seeks to assess the safety and tolerability of the treatment regimen, providing a comprehensive understanding of its clinical benefits and risks.
Participants
The clinical trial involves participants diagnosed with **cholangiocarcinoma** or gallbladder carcinoma. The study population includes both male and female subjects who are at least 18 years of age. Participants are required to have a histologically confirmed diagnosis of the specified cancers and must not be eligible for surgery. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including adequate organ function and HER2-positive disease status. Participants must have measurable disease based on RECIST v1.1 criteria. The sponsor has not provided information regarding the total number of participants. The trial considers lifestyle factors such as the requirement for male participants to use contraception and for female participants to not be pregnant or breastfeeding. The study also includes a vulnerable population, although specific details are not disclosed.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of a combination therapy involving **gemcitabine hydrochloride**, **cisplatin**, **trastuzumab**, and **pembrolizumab** in patients with previously untreated HER2-positive **cholangiocarcinoma** or gallbladder carcinoma. This is a non-randomized, single-arm, open-label, multi-center phase II trial. The primary objective is to assess the objective response rate at six months (ORR@6) following treatment initiation. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety assessment based on the incidence and severity of adverse events.
The trial will span an estimated duration from January 2024 to February 2028. Participants will be involved for a maximum treatment period of 24 months. The study will commence with a screening visit to confirm eligibility based on inclusion criteria such as adequate organ function, HER2-positive disease status, and measurable disease according to RECIST v1.1. Participants must provide written informed consent and meet specific health criteria, including a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments of disease progression, adverse events, and compliance with the study protocol. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent by the participant.
The trial involves intravenous administration of the study drugs, with dosing regimens tailored to each participant's body surface area or weight. The maximum daily doses are set at 1000 mg/m² for gemcitabine, 25 mg/m² for cisplatin, 200 mg for pembrolizumab, and 8 mg/kg for trastuzumab. Participants are expected to adhere to contraceptive guidelines during and after the study to prevent pregnancy-related complications. The trial's design ensures a comprehensive evaluation of the treatment's impact on HER2-positive biliary tract cancer, contributing valuable data to the field of oncology.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Gemcitabine hydrochloride** is provided as "Gemcitabin-GRY 1000 mg Pulver zur Herstellung einer Infusionslösung," a powder for the preparation of a **solution for infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 70000 mg/m² over a treatment period of 24 weeks. The administration route is **intravenous**.
**Pembrolizumab** is administered as "KEYTRUDA 25 mg/mL concentrate for solution for infusion." This medication is also delivered as a **solution for infusion** with a maximum daily dose of 200 mg and a total maximum dose of 7000 mg over the same 24-week period. The route of administration is **intravenous**.
**Cisplatin** is provided as "Cisplatin Teva® 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung," an **injection** form. The maximum daily dose is 25 mg/m², with a total maximum dose of 1750 mg/m² over 24 weeks. The administration is conducted via the **intravenous** route.
**Trastuzumab** is administered as "Zercepac 150 mg powder for concentrate for solution for infusion," a **solution for infusion**. The maximum daily dose is 8 mg/kg, with a total maximum dose of 212 mg/kg over the 24-week treatment period. The route of administration is **intravenous**.
All medications are administered intravenously, and participant compliance is monitored throughout the trial. The study aims to evaluate the efficacy and safety of these treatments in combination for previously untreated HER2-positive biliary tract cancer. No non-experimental treatments, such as placebo or comparator treatments, are specified in this trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate at 6 months (ORR@6)**, which is defined as the proportion of subjects achieving a complete response (CR) or partial response (PR) according to unconfirmed RECIST v1.1 criteria, 6 months after treatment initiation. Secondary endpoints include Progression-Free Survival (PFS), Overall Survival (OS), and PFS rates at 6, 9, and 12 months (PFSR@6, PFSR@9, PFSR@12). PFS is defined as the time from enrollment until the first objectively documented progression according to RECIST v1.1, while OS is defined as the time from enrollment to death from any cause. The PFS rates are calculated as the proportion of patients without progression at the specified time points.
Data collection for these endpoints will be conducted at specified intervals throughout the trial, with efficacy assessments being performed using validated criteria such as RECIST v1.1. The safety of the treatment will also be evaluated by monitoring the incidence, nature, causality, seriousness, and severity of adverse events, using the NCI CTCAE 5.0 guidelines. The trial is designed as an interventional, non-randomized, single-arm, open-label, multi-center phase II study, focusing on the efficacy and safety of the combination treatment of GemCis, trastuzumab, and pembrolizumab in previously untreated HER2-positive biliary tract cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant provides written informed consent.
- Male/female Participants who are at least 18 years of age on the day of signing informed consent.
- Participant is, in the investigator’s judgement, willing and able to comply with the study protocol.
- Participant has histologically confirmed diagnosis of cholangiocarcinoma or gallbladder cancer.
- Participant is not eligible for surgery.
- Participants must have HER2-positive disease defined as either IHC 3+ or IHC 2+, the latter in combination with FISH+, as assessed locally on primary tumor OR positively confirmed by NGS-analysis OR positively confirmed by mRNA
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
- Male Participants must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 7 months after the last dose of study treatment and refrain from donating sperm during this period. Female Participants are eligible to participate if they are not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR A WOCBP who agrees to follow the contraceptive guidance as given in Appendix 3 during the treatment period and for at least 7 months after the last dose of study intervention
- Participant has measurable disease based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- Have adequate organ function as defined in protocol (Table 2).
- Criteria for known Hepatitis B and C positive subjects Hepatitis B and C screening tests are not required unless there is a known history of HBV or HCV infection and/or as mandated by local health authority a. Hepatitis B positive subjects • Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load (< 100 IU/mL) prior to enrollment • Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. b. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. • Participants must have completed curative anti-viral therapy at least 4 weeks prior to enrollment.
Exclusion Criteria
- Participant has received prior systemic anti-cancer therapy. NOTE: Participants who have received up to 4 cycles of prior GemCis or any other anti-cancer treatment prior to initiation of study treatment are eligible for the study. In case of other anti-cancer treatment, at study inclusion patients must be switched to study treatment as defined in protocol section 5.2.
- Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). NOTE: Up to 4 cycles of prior anti-cancer therapy are allowed. In case of other anti-cancer treatment, at study inclusion patients must be switched to study treatment as defined in protocol section 5.2.
- Participant has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- Participant has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- Participant is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. NOTE: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
- Participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Participant has known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
- Participant has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
- Participant has severe hypersensitivity (≥grade 3) to pembrolizumab, trastuzumab, gemcitabine, cisplatin and/or any of their excipients.
- Participant has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- Patient has inadequate cardiac function (LVEF value < 55%) as determined by echocardiography.
- Participant has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Participant has an active infection requiring systemic therapy.
- Participant has a known history of Human Immunodeficiency Virus (HIV) infection.
- Participant has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
- Participant has had an allogenic tissue/solid organ transplant.
- Participant has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Participants who are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 7 months after the last dose of trial treatment.
- Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, previous allogenic bone marrow/blood transplantation or any psychiatric disorder or substance abuse that prohibits obtaining informed consent
- Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
- Patients who are dependent on the sponsor, the investigator or the trial site.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 22 Jan 2024 | 24 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Zercepac 150 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 8 | 24 | PRD8242235 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 200 | 24 | PRD4323105 |
Gemcitabin-GRY 1000 mg Pulver zur Herstellung einer Infusionslösung | Test | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 1000 | 24 | PRD472665 |
Cisplatin Teva® 1 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 25 | 24 | PRD662245 |