GEN1042 Safety Trial and Anti-tumor Activity in Subjects With Malignant Solid Tumors

Study Overview
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Brief Summary
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To evaluate the safety and anti-tumor activity of GEN1042 in patients with metastatic or locally advanced solid tumors.

Detailed Description
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This is an open-label, multicenter phase 1/2 study designed to assess the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of GEN1042 administered as a monotherapy or in combination in subjects with metastatic or locally advanced solid tumors.

Official Title
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A First-in-Human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety and Anti-tumor Activity of GEN1042 in Subjects With Malignant Solid Tumors

Conditions
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Malignant Solid Tumor, Non Small Cell Lung Cancer (NSCLC), Colorectal Cancer (CRC), Melanoma, Head and Neck Squamous Cell Carcinoma (HNSCC), Pancreatic Ductal Adenocarcinoma (PDAC)

Intervention / Treatment
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* Biological: GEN1042
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: 5-FU
* Drug: Gemcitabine
* Drug: Nab paclitaxel
* Drug: Pemetrexed
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Monotherapy - Dose Escalation and Dose Expansion Parts Subjects with non-CNS solid tumors that is metastatic or unresectable and for whom there is no available standard therapy. Subjects with a confirmed diagnosis of relapsed or refractory, advanced and/or metastatic melanoma, NSCLC, or CRC and for whom there is no available standard therapy Combination Therapy - Dose Expansion Part Subjects with unresectable Stage III or Stage IV melanoma with no prior systemic anticancer therapy for unresectable or metastatic disease. Primary ocular or mucosal melanoma is excluded. Subjects with Stage IV metastatic or recurrent NSCLC with no prior systemic anticancer therapy, no actionable mutation. Subjects with recurrent or metastatic HNSCC with no prior systemic therapy administered in the recurrent or metastatic setting. Subjects with confirmed metastatic PDAC with no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease. General (all phases): Must be age ≥ 18 years of age on the day of signing informed consent, or the legal age of consent in the jurisdiction in which the trial is taking place. Measurable disease according to RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) 0-1 Normal or adequate liver, renal, cardiac and bone marrow function Key Exclusion Criteria: Monotherapy - Dose Escalation and Dose Expansion Parts Treatment with an anti-cancer agent (within 21 days or after at least 5 half-lives of the drug, whichever is shorter), prior to GEN1042 administration Radiotherapy within 14 days prior to first GEN1042 administration Toxicities from previous anti-cancer therapies that have not resolved Combination Therapy - Dose Expansion Part Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major surgery within 3 weeks or at least 5 half-lives of the drug (whichever is shorter) of the first dose of trial treatment. Radiotherapy within 14 days of start of trial treatment or received lung radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment. General (all phases) Subject has an active, known, or suspected autoimmune disease. History of non-infectious pneumonitis that required steroids or currently has pneumonitis. History of ≥ grade 3 allergic reactions to monoclonal antibody (mAb) therapy Subject with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy - Dose Escalation and Dose Expansion parts<br>Escalating doses of GEN1042 monotherapy in subjects with non-central nervous system (CNS) solid malignant tumors followed by monotherapy expansion cohorts at selected dose(s) in subjects with relapsed or refractory, advanced and/or metastatic melanoma, or non-small-cell lung cancer (NSCLC), or colorectal cancer (CRC). | Biological: GEN1042<br>* Intravenous<br>|
| Experimental: Combination Therapy - Dose Expansion Part<br>GEN1042 safety and efficacy will be evaluated in combination with pembrolizumab with or without chemotherapy in treatment-naive subjects with advanced or metastatic melanoma, non-small-cell lung cancer [NSCLC], head and neck squamous cell carcinoma [HNSCC], and pancreatic cancer. | Biological: GEN1042<br>* Intravenous<br>Drug: Pembrolizumab<br>* Intravenous<br>Drug: Cisplatin<br>* Intravenous<br>Drug: Carboplatin<br>* Intravenous<br>Drug: 5-FU<br>* Intravenous<br>Drug: Gemcitabine<br>* Intravenous<br>Drug: Nab paclitaxel<br>* Intravenous<br>Drug: Pemetrexed<br>* Intravenous<br>Drug: Paclitaxel<br>* Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Dose-Limiting Toxicities (DLT) | Occurrence of Dose-Limiting Toxicities (DLT) assessed by the Investigator | First Cycle (21 days) | 
| Objective Response Rate (ORR) | Defined as proportion of participants who have a confirmed partial or complete response (PR or CR). Determined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | From the start of the study treatment until disease progression/death/ lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first. (an expected average of 10 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects with Adverse Events and Serious Adverse Events | Incidence of Adverse Events and Serious Adverse Events as assessed by NCI CTCAE V5.0 | Baseline up to 90 Days After the Last Dose, assessed up to 36 months after the last subject's first treatment in the trial. | 
| Duration of Object Response (DOR) | Defined as time from the first documentation of objective response (CR or PR) to the date of first PD or death. | From the start of the study treatment until disease progression/death/ lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first. (an expected average of 10 months) | 
| Disease Control Rate (DCR) | Determined by Investigator Using RECIST Version 1.1 | From the start of the study treatment until disease progression/death/ lost to follow-up/start of new anticancer therapy or withdrawal of consent, whichever occurs first. (an expected average of 10 months) | 
| Progression-Free Survival (PFS) | Defined as the time from start of study treatment to first documented progression per RECIST Version 1.1 by investigator assessment or death due to any cause, whichever occurs first. | From the start of the study treatment until disease progression/death whichever occurs first. (an expected average of 10 months) | 
| Overall survival (OS) | Defined as the time from start of study treatment to date of death due to any cause. | From the start of the study treatment until death due to any cause, assessed up to 36 months after the last subject's first treatment in the trial. | 
| Dose Escalation: Maximum Concentration (Cmax) of GEN1042 | Pharmacokinetic (PK) parameters of GEN1042, and incidence of anti-drug antibodies Dose Escalation: Maximum Concentration (Cmax) of GEN1042 | Cycle (Cy) 1 Day (D) 1 before GEN1042 infusion (BI) and End of Infusion (EOI), Cy1 D2, 3, 8, 15, Cy2 BI, EOI on D1, D 2, 3, 8, 15, and then D1 of Cy 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment) (Cy =21 days) | 
| Dose Escalation: Area Under the Concentration Time Curve (AUC) of GEN1042 | Pharmacokinetic (PK) parameters of GEN1042, and incidence of anti-drug antibodies Dose Escalation: Area Under the Concentration Time Curve (AUC) of GEN1042 | Cycle (Cy) 1 Day (D) 1 before GEN1042 infusion (BI) and , End of GEN1042 Infusion (EOI), Cy1 D2, 3, 8, 15, Cy2 BI, EOI on D1, D 2, 3, 8, 15, and then D1 of Cy 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment) (Cy =21 days) | 
| Dose Escalation: Half-life (t1/2) of GEN1042 | Dose Escalation: Half-life (t1/2) of GEN1042 | Cycle (Cy) 1 Day (D) 1 before GEN1042 infusion (BI) and End of Infusion (EOI), Cy1 D2, 3, 8, 15, Cy2 BI, EOI on D1, D 2, 3, 8, 15, and then D1 of Cy 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment) (Cy =21 days) | 
| Dose Expansion: Area Under the Concentration Time Curve (AUC) of GEN1042 | Dose Expansion: Area Under the Concentration Time Curve (AUC) of GEN1042 | Cy 1 BI, EOI on D1, D8, 15, Cy 2 BI, EOI on D1, D8, 15, and then D1 of Cy 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment) (Cy =21 days) | 
| Dose Expansion: Maximum Concentration (Cmax) of GEN1042 | Dose Expansion: Maximum Concentration (Cmax) of GEN1042 | Cy 1 BI, EOI on D1, D8, 15, Cy 2 BI, EOI on D1, D8, 15, and then D1 of Cy 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment) (Cy =21 days) | 
| Dose Escalation: Incidence of ADA response to GEN1042 | Dose Escalation: Incidence of ADA response to GEN1042responses to GEN1042 | BI on Cy 1, 2, 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment), safety follow-up visit (SFU) (30 and 90 days post final dose) (Cy =21 days) | 
| Dose Expansion: Incidence of ADA response to GEN1042 | Dose Expansion: Incidence of ADA response to GEN1042 | BI on Cy 1, 2, 3, 5, 7, 11, 15 and every 4 cycles thereafter (up to end of treatment), SFU (30 and 90 days post final dose) (Cy =21 days) |