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

Sponsor

Genmab (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04083599

Collaborator

BioNTech SE (Industry)

447

Enrollment

Locations

Arms

71.5

Anticipated Duration (Months)

27.9

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Malignant Solid Tumor Non Small Cell Lung Cancer (NSCLC) Colorectal Cancer (CRC) Melanoma Head and Neck Squamous Cell Carcinoma (HNSCC) Pancreatic Ductal Adenocarcinoma (PDAC)	Biological: GEN1042 Drug: Pembrolizumab Drug: Cisplatin Drug: Carboplatin Drug: 5-FU Drug: Gemcitabine Drug: Nab-Paclitaxel Biological: GEN1042	Phase 1/Phase 2

Detailed Description

This is an open-label, multicenter phase 1/2 study designed to assess the safety, pharmacokinetics, pharmacodynamics and activity of GEN1042 administered as a monotherapy or in combination in subjects with metastatic or locally advanced solid tumors. The trial consists of 4 parts: a GEN1042 monotherapy dose escalation (phase 1a), a GEN1042 monotherapy expansion (phase 2a), a combination therapy safety run in (phase 1b), and a combination therapy expansion (phase 2b).

The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) has been determined.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

447 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 17, 2019

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Sep 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GEN1042 monotherapy dose escalation (phase 1a) • All NON-CNS solid tumors	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W).
Experimental: GEN1042 monotherapy expansion (phase 2a) NSCLC Melanoma CRC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W) as per the recommended Phase 2 dose (RP2D) from monotherapy dose escalation.
Experimental: Combination safety run-in (phase 1b) for NSCLC, HNSCC and Melanoma 1L NSCLC 1L HNSCC 1L Melanoma	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W).
Experimental: Combination safety run-in (phase 1b) for HNSCC • 1L HNSCC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W). Drug: Cisplatin Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W. Drug: Carboplatin Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W. Drug: 5-FU Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W.
Experimental: Combination safety run-in (phase 1b) for PDAC • 1L PDAC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W). Drug: Gemcitabine a: GEN1042 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for a total of 8 cycles; b: GEN1042 + pembrolizumab 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for 8 cycles followed by GEN1042 + pembrolizumab 1Q3W Drug: Nab-Paclitaxel a: GEN1042 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for a total of 8 cycles; b: GEN1042 + pembrolizumab 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for 8 cycles followed by GEN1042 + pembrolizumab 1Q3W
Experimental: Combination therapy expansion (phase 2b) for Melanoma • 1L Melanoma	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W).
Experimental: Combination therapy expansion (phase 2b) for NSCLC • 1L NSCLC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W).
Experimental: Combination therapy expansion (phase 2b) for HNSCC with pembrolizumab • 1L HNSCC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W).
Experimental: Combination therapy expansion (phase 2b) for HNSCC with pembrolizumab + chemotherapy • 1L HNSCC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W). Drug: Cisplatin Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W. Drug: Carboplatin Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W. Drug: 5-FU Cis-/carboplatin + 5FU administered intravenously in combination with GEN1042 + pembrolizumab 1Q3W for 6 cycles followed by GEN1042 +pembrolizumab 1Q3W.
Experimental: Combination therapy expansion (phase 2b) for PDAC • 1L PDAC	Biological: GEN1042 GEN1042 administered intravenously every 21 days (1Q3W). Drug: Pembrolizumab Pembrolizumab administered intravenously every 21 days (1Q3W). Drug: Gemcitabine a: GEN1042 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for a total of 8 cycles; b: GEN1042 + pembrolizumab 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for 8 cycles followed by GEN1042 + pembrolizumab 1Q3W Drug: Nab-Paclitaxel a: GEN1042 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for a total of 8 cycles; b: GEN1042 + pembrolizumab 1Q3W+ gemcitabine + nab-paclitaxel 2Q3W for 8 cycles followed by GEN1042 + pembrolizumab 1Q3W

Outcome Measures

Primary Outcome Measures

Occurrence of Dose-Limiting Toxicities (DLT) assessed by the Investigator to be possibly, probably or definitely related to GEN1042 (phase 1a) and GEN1042 combination regimen (phase 1b) [First Cycle (21 days), assessed up to 36 months after the last subject's first treatment in the trial.]
Percentage of Subjects With Dose-Limiting Toxicities (DLT)
Maximum Tolerated Dose (MTD) assessed as the highest dose of GEN1042 administered alone (phase 1a) or in combination regimen (phase 1b) [First Cycle (21 days), assessed up to 36 months after the last subject's first treatment in the trial.]
Maximum Tolerated Dose (MTD) of GEN1042
Recommended Phase 2 Dose (RP2D) based on available safety and dosing information of GEN1042 administered alone (phase 1a) and in combination regimen (phase 1b) [First Cycle (21 days), assessed up to 36 months after the last subject's first treatment in the trial.]
Recommended Phase 2 Dose of GEN1042
Best Overall Response Rate (ORR) assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for dose expansion as monotherapy (phase 2a) and in combination (phase 2b) [Baseline up to PD or start of the next line of treatment or death due to any cause, whichever occurs first, assessed up to 36 months after the last subject's first treatment in the trial.]
Percentage of subjects with best Overall Response Rate (ORR), as determined by Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Secondary Outcome Measures

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)]
Pharmacokinetic (PK) parameters of GEN1042, and incidence of anti-drug antibodies Dose Escalation: Area Under the Concentration Time Curve (AUC) of GEN1042
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)]
Pharmacokinetic (PK) parameters of GEN1042, and incidence of anti-drug antibodies Dose Escalation: Maximum Concentration (Cmax) 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 Escalation: Half-life (t1/2) 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: Area Under the Concentration Time Curve (AUC) 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 Expansion: Maximum Concentration (Cmax) of GEN1042
Dose Escalation: Percentage of Participants with Incidence of anti-drug antibody (ADAs) responses 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 Escalation: Percentage of Participants with Incidence of anti-drug antibody (ADAs) responses to GEN1042
Dose Expansion: Percentage of Participants with Incidence of ADA response to GEN104 [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)]
Dose Expansion: Percentage of Participants with Incidence of ADA response to GEN104
Incidence of Adverse Events and Serious Adverse Events as assessed by NCI CTCAE V5.0 for GEN1042 administered alone (phase 1a) and in combination regimen (phase 1b) [Baseline up to 90 Days After the Last Dose, assessed up to 36 months after the last subject's first treatment in the trial.]
Percentage of Subjects with Adverse Events and Serious Adverse Events
Progression-Free Survival (PFS) determined by Investigator using RECIST 1.1 for dose expansion as monotherapy (phase 2a) and in combination (phase 2b) [Baseline up to PD or start of the next line of treatment or death due to any cause, whichever occurs first, assessed up to 36 months after the last subject's first treatment in the trial.]
Progression-Free Survival (PFS), as Determined by Investigator Using RECIST Version 1.1
Duration of Object Response (DOR) determined by Investigator per RECIST 1.1. for dose expansion as monotherapy (phase 2a) and in combination (phase 2b) [Baseline up to PD or start of the next line of treatment or death due to any cause, whichever occurs first, assessed up to 36 months after the last subject's first treatment in the trial.]
Duration of Objective Response, as Determined by Investigator Using RECIST Version 1.1
Overall survival assessed from the start of study treatment to death for dose expansion as monotherapy (phase 2a) and in combination (phase 2b) [From the start of study treatment until death due to any cause, assessed up to 36 months after the last subject's first treatment in the trial.]
Overall Survival
Incidence of Adverse Events and Serious Adverse Events as assessed by NCI CTCAE V5.0 for dose expansion as monotherapy (phase 2a) and in combination (phase 2b) [Baseline up to 90 Days After the Last Dose, assessed up to 36 months after the last subject's first treatment in the trial.]
Percentage of Subjects with Adverse Events and Serious Adverse Events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Phase 1a:

• Subjects with non-CNS solid tumors that is metastatic or unresectable and for whom there is no available standard therapy.

Phase 2a:

• 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

Phase 1b/Phase 2:

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 and tumor demonstrating PD-L1 expression in ≥1% of tumor cells (TPS ≥1%).
Subjects with recurrent or metastatic HNSCC with no prior systemic therapy administered in the recurrent or metastatic setting and tumor demonstrating PD-L1 IHC CPS ≥1.
Subjects with confirmed metastatic PDAC with no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease.

General (all phases):

Dose Escalation and Expansion:

Must be age ≥ 18 years of age
Measurable disease according to RECIST 1.1
Eastern Cooperative Oncology Group (ECOG) 0-1
Normal or adequate liver, renal, cardiac and bone marrow function

Exclusion Criteria:

Phase 1a/Phase 2a

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

Phase 1b/Phase 2

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University Cancer Center	New Haven	Connecticut	United States	06520
2	Levine Cancer Center	Charlotte	North Carolina	United States	28204
3	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
4	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
5	Rigshospitalet (Copenhagen University Hospital)	Copenhagen		Denmark
6	Nationales Centrum fr Tumorerkrankungen NCT	Hamburg		Germany
7	Klinikum der Stadt Ludwigshafen am Rhein gGmbH	Ludwigshafen		Germany
8	Department of Dermatology, University of Mainz	Mainz		Germany
9	UniversitÃ¤tsmedizin Mannheim Dermatologie	Mannheim		Germany
10	Universitaetsklinikum Wuerzburg	Wuerzburg		Germany
11	H. Vall d'Hebron	Barcelona		Spain
12	HM CIOCC Hospital Universitario HM Sanchinarro	Madrid		Spain
13	MD Anderson Cancer Center Madrid	Madrid		Spain
14	START Madrid - Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain
15	Clinica Universidad de Navarra	Pamplona		Spain
16	Royal Marsden NHS Foundation Trust	Sutton		United Kingdom