Research Trial to Study Safety of GEN1047 (DuoBody®-CD3xB7H4) in Participants With Malignant Solid Tumors

• ClinicalTrials.gov Identifier: NCT05180474
• Recruitment Status: Recruiting
• First Posted: January 6, 2022
• Last Update Posted: July 27, 2022
• Sponsor: Genmab
• Information provided by (Responsible Party): Genmab

Study Description

Brief Summary:

The drug that will be investigated in the study is an antibody, GEN1047. Since this is the first study of GEN1047 in humans, the main purpose is to evaluate safety. Besides safety, the study will determine the recommended GEN1047 dose to be tested in a larger group of participants and assess preliminary clinical activity of GEN1047. GEN1047 will be studied in a broad group of cancer patients, having different kinds of solid tumors. All participants will get GEN1047. The study consists of two parts: Part 1 tests increasing doses of GEN1047 ("escalation"), followed by Part 2 ("expansion") which tests the recommended GEN1047 dose from Part 1.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Uterine Cancer; Ovarian Cancer; Squamous Non Small Cell Lung Cancer (NSCLC-SCC)	Biological: GEN1047 is a bispecific antibody that induces T-cell mediated cytotoxicity of B7H4-positive cells.	Phase 1; Phase 2

Detailed Description:

The trial is an open-label, multi-center safety trial of GEN1047. The trial consists of two parts: a dose escalation part ("escalation" - phase 1) and an expansion part ("expansion" - phase 2a). The goal of the dose escalation part is to find out if GEN1047 is safe in patients with specific solid tumors and to find the best dose. The best dose is the so-called Recommended Phase 2 Dose (RP2D). The expansion part of the trial (phase 2a) will be initiated once the RP2D has been determined from phase 1.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 220 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1047 in Subjects With Malignant Solid Tumors
• Actual Study Start Date: December 13, 2021
• Estimated Primary Completion Date: January 31, 2025
• Estimated Study Completion Date: January 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; Open Label, single arm where GEN1047 will be administered.	Biological: GEN1047 is a bispecific antibody that induces T-cell mediated cytotoxicity of B7H4-positive cells.; GEN1047 will be administered as an intravenous infusion. The dose-levels will be determined by the starting dose and the escalation steps taken in the trial.

Outcome Measures

Primary Outcome Measures :

1. Escalation: Dose Limiting Toxicities (DLTs) [ Time Frame: DLTs are evaluated during the first cycle (21 days) in each cohort ]
   To evaluate the safety of GEN1047 and determine the recommended phase 2 dose
2. Escalation: Adverse Events (AEs) [ Time Frame: Throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   To evaluate the safety and tolerability of GEN1047 throughout the treatment period of trial participants
3. Escalation: Number of participants with clinically significant shifts from baseline in clinical laboratory parameters [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Clinical laboratory parameters assessed: Hematology, biochemistry, coagulation, urinalysis, hepatitis B, T3 and T4, CA-125 (Cancer-antigen 125; only participants with ovarian cancer)
4. Expansion: Evaluate anti-tumor activity of GEN1047 [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
   Reduction in tumor size according to response assessment (Objective Response Rate)

Secondary Outcome Measures :

1. Escalation and expansion: To characterize the pharmacokinetic (PK) properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Rate at which the drug is removed from the body (clearance)
2. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Amount of drug in the body (volume of distribution)
3. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Area-under-the-concentration-time curve (AUC0-C last) and from time 0 to last quantifiable sample (AUC0-C infinity)
4. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Maximum (peak) concentration (Cmax) after dosing
5. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Time after dosing at which Cmax was observed (Tmax)
6. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Time after dosing at which the lowest drug concentration is observed before the next dose is administered, pre-dose trough concentration (CTrough)
7. Escalation and expansion: To characterize the PK properties of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Elimination half-life of the drug (T1/2)
8. Escalation and expansion: Evaluate immunogenicity of GEN1047 [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
   Anti-drug antibody response (ADA)
9. Escalation: Evaluate anti-tumor activity of GEN1047 [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
   Reduction in tumor size according to response assessment (Objective Response Rate)
10. Escalation and expansion: Evaluate preliminary anti-tumor activity of GEN1047 (efficacy) [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
    Disease control rate (DCR)
11. Escalation and expansion: Evaluate preliminary anti-tumor activity of GEN1047 (efficacy) [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
    Duration of response (DOR)
12. Escalation and expansion: Evaluate preliminary anti-tumor activity of GEN1047 (efficacy) [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
    Time to response (TTR)
13. Expansion: Evaluate preliminary efficacy of GEN1047 [ Time Frame: Response assessment will be evaluated through trial completion, up to 5 years after the first visit of the last participant ]
    Progression free survival (PFS)
14. Expansion: Evaluate preliminary efficacy of GEN1047 [ Time Frame: Survival will be monitored from first dose of GEN1047 until death, up to 5 years after the first visit of the last participant ]
    Overall survival (OS)
15. Expansion: AEs [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
    To evaluate the safety and tolerability of GEN1047 throughout the treatment period of trial participants
16. Expansion: Number of participants with clinically significant shifts from baseline in clinical laboratory parameters [ Time Frame: Collected throughout the trial until the end of the safety follow-up period (30 days after last dose) ]
    Clinical laboratory parameters assessed: Hematology, biochemistry, coagulation, urinalysis, hepatitis B, T3 and T4, CA-125 (only participants with ovarian cancer)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

Dose escalation part:

• Participants must have histologically or cytologically confirmed solid tumor(s) in any of the following selected indications for which there is no further available standard therapy likely to confer clinical benefit (or participant is not a candidate or has previously refused such earlier available therapy), and for whom, in the opinion of the investigator, experimental therapy with GEN1047 may be beneficial (breast cancer, uterine cancer, ovarian cancer, NSCLC-SCC).

Expansion part:

• Participant must have an advanced or metastatic, pathologically confirmed diagnosis of one of the following tumors for which there is no further available standard therapy likely to confer clinical benefit (or participant is not a candidate or has previously refused such available therapy), and for whom, in the opinion of the investigator, experimental therapy with GEN1047 may be beneficial (breast cancer, uterine cancer, ovarian cancer, NSCLC-SCC). For all indications: Participants may have received up to 4 prior systemic treatment regimens for advanced/metastatic disease (maintenance treatment is considered being part of 1 treatment line).

Both, dose escalation and expansion part:

• Participant must sign and ICF, prior to any screening procedures

• Participants with ovarian cancer:

  • Must have documented progressive disease.
  • CA-125 positivity according to the Gynecologic Cancer Intergroup Guideline (GCIG) with a pretreatment sample that is at least twice the upper limit of the reference range.
• Either recurrence after, or progression on or lack of response to established standard of care (SOC) anticancer therapies; or are deemed intolerant to or ineligible for, standard curative therapy in the recurrent setting.
• At least 1 measurable lesion per RECIST v1.1. The measurable lesion(s) must be outside the field of radiation therapy (RT) if there was prior treatment with RT.
• Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0 to 1
• Should provide a tumor tissue sample during the Screening period and prior to C1D1.
• Must have acceptable laboratory parameters as specified in the protocol.
• Provide all pre-trial CT scans since failure of last prior therapy (eg, documenting radiographic progression), if available.

Key Exclusion Criteria (dose escalation and expansion part):

• Exclusions related to cardiovascular disease

  • Symptomatic congestive heart failure (grade III or IV as classified by the New York Heart Association), unstable angina pectoris or cardiac arrhythmia.
  • History of myocardial infarction within 6 months prior to planned start of GEN1047.
  • Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management. Prolonged QTc interval >480 milliseconds using Fridericia's QT correction formula.
  • Any other cardiac disease(s) not listed that, in the opinion of the investigator, is/are clinically significant and/or unacceptable.

• Exclusions related to the central nervous system

  • Participant has any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (within the last 6 months) or symptomatic brain metastases, spinal cord compression (from disease), or stroke. (Transient ischemic attack >1 month prior to Screening is allowed.)
  • Participants with known unstable CNS metastases and any active or history of carcinomatous meningitis will be excluded. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 28 days by repeat imaging prior to C1D1. Participants should be clinically stable and should not be undergoing 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, corresponding to a maximum administration exposure of ≤140 mg within 14 days).
  • A participant with new or progressive brain metastases. Spinal cord metastasis is acceptable. However, participants with spinal cord compression should be excluded.

• Participant has been exposed to any of the following prior therapies within the specified timeframes:

  • Radiotherapy: Radiotherapy within 14 days prior to first GEN1047 administration. Palliative radiotherapy will be allowed.
  • The use of RANK-L inhibitors and bisphosphonates (if on stable dose for at least 4 weeks) is permitted while participating in this trial. However, the initiation of growth factors and bisphosphonates is not allowed during the first 4 weeks of GEN1047 administration, unless agreed upon by the investigator and sponsor medical monitor.
  • Treatment with any investigational or non-investigational anticancer agent (including investigational vaccines) or used an invasive investigational medical device within 28 days or 5 half-lives, whichever is shorter, before the planned first dose of GEN1047 or is currently enrolled in an interventional trial.
  • Prophylaxis with live, attenuated vaccines within 28 days prior to first dose of GEN1047; or prophylaxis with the first and/or subsequent injection(s) of SARS-CoV-2 nucleic acid vaccine within 28 days prior to first dose of GEN1047.
  • Chronic systemic immunosuppressive corticosteroid doses, ie, prednisone >10 mg daily (or equivalent) or a cumulative dose >140 mg prednisone within 14 days (or equivalent) before the first GEN1047 administration. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
  • Has received granulocyte colony-stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support within 2 weeks prior to the first GEN1047 administration or being chronically transfusion dependent.
  • Any prior therapy with an antibody targeting CD3 or other T cell activating surface marker.
• Toxicities from previous anticancer therapies that have not resolved to baseline levels or to ≤ grade 1, except for alopecia, anorexia, vitiligo, fatigue, hyperthyroidism, hypothyroidism, and peripheral neuropathy. Anorexia, hyperthyroidism, hypothyroidism, and peripheral neuropathy must have recovered to ≤ grade 2.
• Has ongoing or active infection requiring IV treatment with anti-infective therapy that has been administered <2 weeks prior to first dose.
• Has a history of non-infectious pneumonitis that has required steroids, or currently has any grade of pneumonitis.
• Has a serious, non-healing wound, or skin ulcer (of any grade).
• Has a history of organ allograft (except for corneal transplant)
• Autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first GEN1047 administration.
• Chimeric antigen receptor (CAR)-T cell therapy within 30 days prior to first GEN1047 administration.

• Has a known past or current malignancy other than inclusion diagnosis, except for:

  • Cervical carcinoma of Stage 1B or less.
  • Non-invasive basal cell or squamous cell skin carcinoma.
  • Non-invasive, superficial bladder cancer.
  • Prostate cancer with a current PSA level <0.1 ng/mL.
  • Any curable cancer with a complete response of >2 years duration.
• A history of ≥ grade 3 allergic reactions to antibody therapy or has known allergies, hypersensitivity, or intolerance to GEN1047 or its excipients.
• A history of ≥ grade 3 cytokine release syndrome or ≥ grade 3 immune effector cell-associated neurotoxicity syndrome to antibody therapy, CAR-T cell therapy, or other immune effector cell therapy

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Contacts

Contact: Genmab Trial Information; +4570202728; clinicaltrials@genmab.com

Locations

Denmark

Rigshospitalet (Copenhagen University Hospital); Recruiting

Copenhagen, Denmark, 2100

France

Institut Curie; Recruiting

Paris, France, 75248

Institut Gustave Roussy; Recruiting

Villejuif, France, 75005

Spain

Hospital Universitari Vall d'Hebron; Recruiting

Barcelona, Spain, 8035

START Madrid-CIOCC; Recruiting

Madrid, Spain, 28050

Clinica Universidad de Navarra; Recruiting

Pamplona, Spain, 31008

Sponsors and Collaborators

Genmab

More Information

• Responsible Party: Genmab
• ClinicalTrials.gov Identifier: NCT05180474
• Other Study ID Numbers: GCT1047-01; 2021-001790-23 ( EudraCT Number )
• First Posted: January 6, 2022
• Last Update Posted: July 27, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Uterine Neoplasms; Neoplasms by Site; Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Antibodies; Antibodies, Bispecific; Immunologic Factors; Physiological Effects of Drugs