Phase 1 Study of GEN1046 in Combination with Paclitaxel Albumin-Bound, Cisplatin, and Pembrolizumab in Malignant Solid Tumors
- Trial ID
- 2023-509059-15-00
- Protocol
- GCT1046-01
- Sponsor
- Genmab A/S
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **maximum tolerated dose (MTD)** and/or the recommended Phase 2 dose (RP2D) of **GEN1046** in subjects with malignant solid tumors, including endometrial carcinoma, urothelial carcinoma, triple-negative breast cancer, squamous cell carcinoma of the head and neck, or cervical cancer. Establishing the safety profile of GEN1046 and evaluating its clinical efficacy are also key components of the primary objective. These objectives are clinically relevant as they aim to identify a safe and effective dosage for further clinical development, potentially offering a new therapeutic option for patients with these challenging malignancies.
Secondary objectives include:
- Characterizing the pharmacokinetic (PK) profile of GEN1046.
- Evaluating the immunogenicity of GEN1046.
- Assessing the anti-tumor activity of GEN1046.
- Evaluating the safety profile of GEN1046 in combination with docetaxel, pembrolizumab, and platinum-based chemotherapy doublets (pemetrexed + cisplatin or carboplatin; carboplatin + paclitaxel or nab-paclitaxel).
- Further evaluating the clinical efficacy of GEN1046.
Participants
The clinical trial involves a total of **132 participants** diagnosed with various **malignant solid tumors**, including endometrial carcinoma, urothelial carcinoma, triple-negative breast cancer, squamous cell carcinoma of the head and neck, or cervical cancer. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including having a histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable, and for whom no standard therapy is available. The trial also includes individuals with relapsed or refractory, advanced, and/or metastatic conditions who are not candidates for standard therapy. All participants are required to have measurable disease according to RECIST 1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and acceptable hematological, liver, coagulation, and renal functions. The trial population includes a vulnerable population, indicating that additional ethical considerations are in place to ensure participant safety and well-being. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **first-in-human**, open-label, dose-escalation study with expansion cohorts to evaluate the safety and efficacy of GEN1046 in subjects with **malignant solid tumors**. The trial aims to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D), establish the safety profile, and evaluate the clinical efficacy of GEN1046. The study is structured to include both dose escalation and expansion phases, with participants having histologically or cytologically confirmed non-CNS solid tumors that are metastatic or unresectable, and for whom no standard therapy is available. The trial is expected to run from May 15, 2019, to February 1, 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as measurable disease according to RECIST 1.1, acceptable hematological status, liver function, coagulation status, and renal function. Following the screening, participants will be enrolled in either the dose escalation or expansion cohorts. The primary endpoints include the number of participants with dose-limiting toxicity (DLT) and adverse events (AEs), while secondary endpoints focus on pharmacokinetic parameters such as total body clearance, volume of distribution, and maximum observed plasma concentration of GEN1046.
The expected length of participant involvement varies depending on the cohort and response to treatment, with regular follow-up visits to monitor safety and efficacy. Conditions that may lead to early termination from the study include unacceptable toxicity, disease progression, or withdrawal of consent. The trial is conducted under rigorous scientific and ethical standards to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Abraxane** is provided as a 5 mg/ml powder for dispersion for infusion. It contains the active substance **paclitaxel albumin-bound** and is administered via intravenous use. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is classified under the ATC code L01CD01. The administration schedule and dosage frequency are determined based on the trial protocol.
**Cisplatin** is administered as a 1 mg/ml injection BP, formulated as a solution for infusion. The active substance is **cisplatin**, and the product is provided by Sandoz Ltd. It is also administered intravenously, with the dosing schedule tailored to the trial's requirements. Cisplatin is categorized under the ATC code L01XA01.
**KEYTRUDA**, containing the active substance **pembrolizumab**, is available as a 25 mg/mL concentrate for solution for infusion. This product is manufactured by Merck Sharp & Dohme B.V. and is administered intravenously. The dosing regimen is specified in the trial protocol, and the product is used to evaluate its efficacy and safety in the study.
**Carboplatin** is provided as a 10 mg/ml intravenous infusion solution. The active substance is **carboplatin**, and the product is supplied by Hospira UK Limited. It is administered via intravenous use, with the dosage and frequency determined by the clinical trial guidelines. Carboplatin is classified under the ATC code L01XA02.
**Pemetrexed Accord** is a 100 mg powder for concentrate for solution for infusion, containing the active substance **pemetrexed**. Accord Healthcare S.L.U. manufactures this product, and it is administered intravenously. The dosing schedule is outlined in the trial protocol, and the product is used to assess its therapeutic potential in the study.
**Acasunlimab** is a solution for infusion containing the active substance **acasunlimab**, a humanized IgG1 monoclonal antibody against PD-L1 and 4-1BB. It is provided by Genmab and administered intravenously. The dosing regimen is specified in the trial protocol, and the product is evaluated for its safety and efficacy in the study.
**Pazenir** is a 5 mg/ml powder for dispersion for infusion, containing the active substance **paclitaxel albumin-bound**. It is manufactured by Ratiopharm GmbH and administered via intravenous use. The dosing schedule and frequency are determined based on the trial protocol, and the product is used to assess its clinical efficacy and safety.
Efficacy
The clinical trial aims to evaluate the efficacy of **GEN1046** in subjects with malignant solid tumors. Efficacy will be assessed through several primary and secondary endpoints. The primary endpoints include the number of participants with dose-limiting toxicity (DLT) and adverse events (AEs), as well as shifts from baseline in safety laboratory parameters. Additionally, the objective response rate (ORR) will be measured, defined as the percentage of participants achieving a complete response (CR) or partial response (PR) based on the response evaluation criteria in solid tumors (RECIST).
Secondary endpoints will further explore the efficacy of **GEN1046** by evaluating the total body clearance (CL), volume of distribution (Vd), and various pharmacokinetic parameters such as the area under the concentration-time curve (AUC) and maximum observed plasma concentration (Cmax). The trial will also assess the duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). These parameters will be measured at specified time points throughout the trial, using validated scales and laboratory tests to ensure accuracy and reliability in data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- For Dose Escalation: • Have a histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy
- For Expansion: • Have histologically or cytological confirmed diagnosis of relapsed or refractory, advanced and/or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer who are not anymore candidates for standard therapy For separate expansion cohorts: metastatic NSCLC without prior systemic treatment regimens for metastatic disease.
- For Both Dose Escalation and Expansion • Have measurable disease according to RECIST 1.1 • Have Eastern Cooperative Oncology Group (ECOG) 0-1 • Have an acceptable hematological status • Have acceptable liver function • Have an acceptable coagulation status • Have acceptable renal function
Exclusion Criteria
- Have uncontrolled intercurrent illness, including but not limited to: • Ongoing or active infection requiring intravenous treatment with antiinfective therapy, or any ongoing systemic inflammatory condition requiring further diagnostic work-up or management during screening. • Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris or cardiac arrhythmia • Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg, despite optimal medical management • Ongoing or recent evidence of autoimmune disease • History of irAEs that led to prior checkpoint treatment discontinuation • Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade • History of chronic liver disease or evidence of hepatic cirrhosis • History of non-infectious pneumonitis that has required steroids or currently has pneumonitis • History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of acasunlimab • Serious, non-healing wound, skin ulcer (of any grade), or bone fracture • Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke
- Prior therapy: • Radiotherapy within 14 days prior to first dose of acasunlimab. Note: palliative radiotherapy will be allowed. • Treatment with an anti-cancer agent (within 28 days or after at least 5 half-lives of the drug, whichever is shorter), prior to acasunlimab administration. Accepted exceptions are bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab • Toxicities from previous anti-cancer therapies that have not adequately resolved NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Hungary | Not Recruiting | 15 May 2019 | 2 |
 Italy | Not Recruiting | 15 May 2019 | 13 |
 Poland | Not Recruiting | 15 May 2019 | 29 |
 Spain | Not Recruiting | 15 May 2019 | 251 |
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 |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD4323105 |
Cisplatin 1mg/ml Injection BP | Test | INJECTION BP | INTRAVENOUS USE | — | — | PRD8127897 |
Carboplatin 10 mg/ml Intravenous Infusion | Test | INTRAVENOUS INFUSION | INTRAVENOUS USE | — | — | PRD1161259 |
Pemetrexed Accord 100 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD3636606 |
Abraxane 5 mg/ml powder for dispersion for infusion. | Test | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9254303 |
Abraxane 5 mg/ml powder for dispersion for infusion. | Test | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | — | — | PRD9254301 |
Acasunlimab | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD6822274 |
Pazenir 5 mg/ml powder for dispersion for infusion. | Test | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS USE | — | — | PRD7328588 |