HMBD-001 in Advanced HER3 Positive Solid Tumours

Study Overview
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Brief Summary
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This clinical trial is evaluating a drug called HMBD-001 (an anti-HER3 monoclonal antibody) in patients with advanced HER3 positive solid tumours. The main aims are to find out the maximum dose of HMBD-001 that can be given safely to patients alone and in combination with other anti-cancer agents, more about the potential side effects of HMBD-001 and how these can be treated and what happens to HMBD-001 inside the body and how it affects cancer cells.

Detailed Description
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HMBD-001 is a type of drug called a monoclonal antibody, which works by targeting a protein called HER3, that is found in high numbers in some types of cancers including those which contain NRG1 gene fusions. By attaching itself to this protein it may then work to kill the cancer cells or to stop them growing. This is a first-in-human clinical trial which has two parts: Part A is a 'dose escalation' phase where small groups of patients will receive increasing doses of HMBD-001 to find the safest dose which best targets cancer cells. In Arm 1, patients will receive HMBD-001 on its own (as a single agent). In Arm 2, patients will receive HMBD-001 given with other anti-cancer drugs (in combination). Part B is a 'dose expansion' phase where larger groups of patients with specific cancer types, known to have high levels of the protein HER3 or a confirmed NRG1 gene fusion will receive the highest doses of HMBD-001 considered to be safe in Part A either alone as single agent or in combination with other anti-cancer drugs. The main aims of the clinical trial are to find out: The highest dose of HMBD-001 alone and in combination with other anti-cancer drugs that can be given safely to patients. More about the potential side effects of HMBD-001 when given alone and in combination with other anti-cancer agents and how they can be managed. What happens to HMBD-001 inside the body and how it affects cancer cells. The potential anti-tumour activity of HMBD-001 as a single agent and in various combination regimens in specific tumour types of HER3 expressing tumours or tumours with NRG1 gene fusions.

Official Title
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HMBD-001 (an Anti-HER3 Monoclonal Antibody) Given Intravenously as a Single Agent and in Combination in Patients With Advanced HER3 Positive Solid Tumours

Conditions
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Bladder Cancer, Triple Negative Breast Cancer, Castration-resistant Prostate Cancer, Cervical Cancer, RAS Wild Type Colorectal Cancer, Endometrial Cancer, Gastric Cancer, Hepatocellular Carcinoma (HCC), Melanoma, Non-small Cell Lung Cancer (NSCLC), Oesophageal Cancer, Ovarian Cancer, Pancreatic Cancer, Squamous Cell Cancer of the Head and Neck

Intervention / Treatment
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* Drug: HMBD-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written (signed and dated) informed consent and be capable of co-operating with HMBD-001 administration and follow-up. Histologically confirmed advanced or metastatic solid tumours resistant or refractory to conventional treatment, or for which no conventional therapy exists or is not considered appropriate by the Investigator or is declined by the patient. Part A Arm 1 Monotherapy Dose Escalation: Patients with tumour types known to overexpress HER3 including: Bladder cancer Triple negative breast cancer Castration resistant prostate cancer Cervical cancer RAS wild type colorectal cancer Endometrial cancer Gastric cancer Hepatocellular carcinoma (HCC) Melanoma Non-small cell lung cancer (NSCLC) Oesophageal cancer Ovarian Cancer Pancreatic cancer Squamous cell cancers of the head and neck Part B Arm 1 Monotherapy Dose Expansion: Patients with castration resistant prostate cancer, RAS wild type colorectal cancer, triple negative breast cancer or squamous cell cancers of the head and neck with confirmed high HER3 expression by Immunohistochemistry (IHC) on pre screening biopsy prior to study enrolment or confirmed existing NRG1 gene fusion. Life expectancy of at least 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Haematological and biochemical indices within the protocol specified ranges. Patients with advanced prostate cancer must have castrate levels of testosterone and have received a next generation hormonal agent (at least one of abiraterone, enzalutamide, apalutamide or darolutamide). Aged 16 years or over at the time consent is given. Exclusion Criteria: Radiotherapy (except for palliative reasons), chemotherapy, endocrine therapy (with the exception of life-long hormone suppression such as luteinising hormone-releasing hormone (LHRH) agents in prostate cancer), immunotherapy or investigational medicinal products during the previous 4 weeks before trial Cycle 1 Day 1. Patients with ongoing toxic manifestations of previous treatments greater than NCI CTCAE Grade 1. Exceptions apply. Patients with symptomatic brain or leptomeningeal metastases should be excluded. Exceptions apply. Women of child-bearing potential (or are already pregnant or lactating). Exceptions apply. Male patients with partners of child-bearing potential. Exceptions apply. Major surgery from which the patient has not yet recovered. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection. Known or suspected hypersensitivity reaction to previous biological therapy that in the opinion of the Investigator is a contraindication for their participation in this study. Concurrent congestive heart failure, prior history of > class II cardiac disease (New York Heart Association [NYHA]), history of clinically significant cardiac ischaemia or prior history of clinically significant cardiac arrhythmia. Patients with significant cardiovascular disease as defined in the protocol are excluded. Patients with an active autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis. Exceptions apply. Patients receiving doses of prednisolone >10mg daily (or equipotent doses of other corticosteroids) within 7 days prior to the first dose of study drug are not eligible unless administered as pre-medication. Patients having received a live vaccination within 4 weeks prior to first dose of HMBD 001. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I/IIa trial of HMBD-001. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator and Medical Advisor would be acceptable. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. Current or prior malignancy which could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Patients with curatively-treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible.

Ages Eligible for Study
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Minimum Age: 16 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Arm 1 Dose Escalation (single agent)<br>Groups of patients will receive increasing doses of HMBD-001 as a single agent to find a safe dose that best targets cancer cells. Approximately 26 patients with tumours known to express HER3 will be entered into this arm. | Drug: HMBD-001<br>* Intravenous infusion given over a 21 or 28 day cycle dependent on dosing frequency. Number of cycles: 6 or until disease progression or unacceptable toxicity develops.<br>|
| Experimental: Part B Arm 1 Dose Expansion (single agent)<br>An expansion cohort of up to 25 patients with a confirmed HER3 positive or confirmed NRG1 fusion rearrangement RAS wild type colorectal cancer, castration resistant prostate cancer, triple negative breast cancer or squamous cell head and neck cancer will receive the HMBD-001 single agent RP2D as determined in Part A Arm 1. | Drug: HMBD-001<br>* Intravenous infusion given over a 21 or 28 day cycle dependent on dosing frequency. Number of cycles: 6 or until disease progression or unacceptable toxicity develops.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II dose (Part A) | Recommended dose of HMBD-001 given a) as a single agent and b) in combination with selected anticancer agent(s) with an estimated Dose Limiting Toxicity (DLT) rate that is closest to 25% using a one-stage Bayesian Continual Reassessment Method (CRM) | When sufficient patients have had the opportunity to complete 1 Cycle (max 28 days) | 
| Number of grade 3, 4 and 5 adverse events related to HMBD-001 (Part A & B) | Number of grade 3, 4 and adverse events related to HMBD-001 given a) as a single agent and b) in combination with selected anti-cancer agent(s) graded according to National Cancer Institute Common Criteria for Adverse Events (NCI CTCAE) Version 5.0 | When sufficient patients have had the opportunity to complete 1 Cycle (max 28 days) | 
| Number of patients achieving a complete response (CR) or partial response (PR) to HMBD-001 in the chosen tumour types (Part B) | Number of patients achieving a complete response (CR) or partial response (PR) to HMBD-001 based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in the chosen tumour types | From baseline radiological disease assessment until 28 days after last dose of HMBD-001 (max 30 weeks) per patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of HMBD-001 (Part A & B) | Maximum observed plasma concentration (Cmax) of HMBD-001 | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Area under the curve (AUC) of HMBD-001 (Part A & B) | Area under the curve (AUC) of HMBD-001 | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Terminal elimination half-life (t½) of HMBD-001 (Part A & B) | Terminal elimination half-life (t½) of HMBD-001 | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Time taken to reach maximum observed concentration (Tmax) of HMBD-001 (Part A & B) | Time taken to reach maximum observed concentration (Tmax) of HMBD-001 | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Steady state volume of distribution of HMBD-001 in plasma (Part A and B) | Volume of distribution of HMBD-001 in plasma | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Total body clearance of HMBD-001 (Part A and B) | Total body clearance of HMBD-001 | From first dose of HMBD-001 until 24 weeks after first dose of HMD-001 | 
| Number of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (Part A and B) | Number of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 | From baseline radiological disease assessment until 28 days after last dose of HMBD-001 (max 30 weeks) per patient | 
| Number of Patients whose cancer has not progressed at 12 and 24 months (Part A & B) | Number of Patients whose cancer has not progressed at 12 and 24 months | From first dose of HMBD-001 until 24 months after first dose of HMBD-001 | 
| Number of patients who are still alive at 12 and 24 months (Part A & B) | Number of patients who are still alive at 12 and 24 months | From first dose of HMBD-001 until 24 months after first dose of HMBD-001 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Monoclonal Antibody, HER3, NRG1, NRG1 Fusion, NRG1 gene fusion, Neuregulin 1