E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Malignant solid tumors:
Patients with relapsed or refractory, advanced and/or metastatic non-small cell lung cancer (NSCLC), endometrial carcinoma (EC), urothelial carcinoma (UC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), or cervical cancer who are no longer candidates for or refuse (if subjects had access and were eligible for the respective treatments) standard therapy. |
|
E.1.1.1 | Medical condition in easily understood language |
Advanced and/or metastatic non-small cell lung cancer, endometrial carcinoma, urothelial carcinoma, triple-negative breast cancer, squamous cell carcinoma of the head and neck, or cervical cancer |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065143 |
E.1.2 | Term | Malignant solid tumour |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
EC2 to E13: - Determine the MTD and/or the recommended Phase 2 dose (RP2D) - Establish the safety profile of GEN1046
EC1: - Evaluate clinical efficacy
|
|
E.2.2 | Secondary objectives of the trial |
EC2 to EC13: - Characterize pharmacokinetics (PK) profile of GEN1046 - Evaluate immunogenicity of GEN1046 - Evaluate the anti-tumor activity of GEN1046 - Evaluate the safety profile of GEN1046 in combination with docetaxel (EC9 only) - Evaluate the safety profile of GEN1046 in combination with pembrolizumab (1Q3W) (EC11A only) - Evaluate the safety profile of GEN1046 in combination with pembrolizumab (1Q6W) (EC11A only) - Evaluate the safety profile of GEN1046 in combination with pembrolizumab and platinum-based chemotherapy doublets
EC1: - Evaluate safety profile of GEN1046 - Further evaluate clinical efficacy - Characterize PK and immunogenicity of GEN1046 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For Dose Escalation: • Measurable disease according to RECIST 1.1. • Eastern Cooperative Oncology Group (ECOG) 0-1. • Adequate hematologic, coagulation, hepatic and renal function as defined per protocol. • Subjects must 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 Dose Expansion: • Measurable disease according to RECIST 1.1. • Eastern Cooperative Oncology Group (ECOG) 0-1. • Adequate hematologic, coagulation, hepatic and renal function as defined per protocol. • Subjects must have histologically or cytological confirmed diagnosis of relapsed or refractory, advanced and/or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer who are no longer candidates for or refuse standard therapy (if subjects had access and were eligible for the respective treatments).
For detailed inclusion criteria (with specific criteria for expansion cohorts) please refer to the Clinical Trial Protocol. |
|
E.4 | Principal exclusion criteria |
• Subject has uncontrolled intercurrent illness, including but not limited to: • Ongoing or active infection requiring intravenous treatment with anti-infective therapy that has been administered less than 2 weeks prior to first dose, 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 (within 1 year) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for immune-related adverse events (irAEs). • Subjects with a history of grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy treatment should be excluded. Subjects with irAEs below grade 3 that led to discontinuation should be discussed with the sponsor. • Subjects with a prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade are excluded. • 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 GEN1046. • Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. • All subjects should undergo a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to document new or existing CNS lesions. a. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, spinal cord compression (from disease), carcinomatous meningitis or stroke (within the last 6 months). Transient ischemic attack > 1 month prior to screening is allowed. b. Subjects with newly identified or known unstable or symptomatic CNS metastases will be excluded. Subjects with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 28 days from the radiological diagnosis of brain metastases by repeat imaging (that should be performed during trial screening). Subjects should be clinically stable and should not be undergoing acute corticosteroid therapy or steroid taper or have received stereotactic radiation or whole-brain radiation within 14 days prior to C1D1. Chronic steroid therapy is acceptable provided that the dose is stable for the last 14 days prior to C1D1 (≤ 10 mg prednisone daily or equivalent). Note that radiotherapy is not allowed 14 days prior to first dosing and that the irradiated lesion cannot be used for efficacy assessment. • Prior therapy: • Radiotherapy within 14 days prior to first GEN1046 administration or received lung radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects must have recovered from all radiation related toxicities, not require corticosteroids, and not have had radiation pneumonitis. 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 GEN1046 administration. Accepted exceptions are bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab. • Subjects who discontinued treatment due to disease progression within the first 6 weeks of a CPI containing treatment. • Prior treatment with a 4-1BB (CD137) targeted agent. • Prior treatment with a T-cell agonist or anti-CTLA-4 targeted agent within 12 weeks prior to the initiation of treatment. • Toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to grade 1 or less with the exception of alopecia, anorexia, vitiligo, fatigue, hyperthyroidism, hypothyroidism, and peripheral neuropathy. Anorexia, hyperthyroidism, hypothyroidism, and peripheral neuropathy must have recovered to ≤ grade 2.
For detailed exclusion criteria (with specific criteria for expansion cohorts) please refer to the Clinical Trial Protocol. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Dose Escalation: - Dose limiting Toxicities (DLTs) - Adverse events (AEs) and safety laboratory parameters
Dose Expansion EC1: - Objective Response Rate per RECIST 1.1 assessed by Independent Review Committee (IRC)
EC2-EC13: - Dose limiting Toxicities (DLTs) - Adverse events (AEs) and safety laboratory parameters
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose Escalation: - DLTs: dose limiting toxicities will be collected for the first two cycles i.e. DLT period of 42 days. - AEs: screening; Day 1, 2, 3, 8, 15 during Cycles 1-2; Days 1, 8, 15 during Cycle 3-4, Day 1 subsequent Cycles (5-PD); EoT; 4, 8, 12, subsequent every 12 (survival follow-up) Weeks after last dosing.
Dose Expansion: - AEs: screening; Day 1, 2, 3, 8, 15 during Cycles 1-2; Days 1, 8, 15 during Cycle 3-4, Day 1 subsequent Cycles (5-PD); EoT; 4, 8, 12, subsequent every 12 (survival follow-up) Weeks after last dosing.
|
|
E.5.2 | Secondary end point(s) |
Dose Escalation: - PK parameters - Anti-Drug Antibody (ADA) response - Anti-tumor activity, i.e., reduction in tumor size according to RECIST 1.1: - Objective Response Rate (ORR) - Disease Control Rate (DCR) - Duration of Response (DoR)
Dose Expansion: EC1: - Adverse events (AEs) and safety laboratory parameters - Duration of response (DoR), PFS per RECIST 1.1 assessed by IRC - ORR, DoR, PFS per RECIST 1.1 assessed by investigator - Overall survival (OS) - PK parameters (clearance, volume of distribution and area-under-the-concentration-time curve (AUC14days, AUClast and AUCinf), maximum concentration (Cmax), time of Cmax (Tmax), pre-dose trough concentrations (CTrough), and half-life); - Anti-Drug Antibody (ADA) response
EC2-EC13: - PK parameters (clearance, volume of distribution and area-under-the-concentration-time curve (AUC14days, AUClast and AUCinf), maximum concentration (Cmax), time of Cmax (Tmax), pre-dose trough concentrations (CTrough), and half-life) - Anti-Drug Antibody (ADA) response - Anti-tumor activity, i.e., reduction in tumor size according to RECIST 1.1: - Objective Response Rate (ORR) - Disease Control Rate (DCR) - Duration of Response (DoR) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Ukraine |
Georgia |
Israel |
United States |
Czechia |
Hungary |
Italy |
Poland |
Spain |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The trial is considered completed when the last subject dies or withdraws from the trial. However, maximal trial duration is 3 years after the last subject’s first treatment. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |