A Study Evaluating the Safety, Tolerance and Anti-tumor Activity of a Study Drug in Subjects With Advanced Solid Tumors

Advanced Solid Tumor Clinical Trial

Official title:

A Phase 1 Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of HBM4003 in Subjects With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04135261
• Other study ID #: 4003.1
• Status: Completed
• Phase: Phase 1
• Start date: September 24, 2019
• Est. completion date: February 15, 2023

Study information

• Verified date: April 2023
• Source: Harbour BioMed US, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study to evaluate the safety and tolerability of the study drug HBM4003, and to determine the maximum tolerated dose and/or recommended Phase 2 study dose of HBM4003. The study will also look at the anti-tumor activity of HBM4003.The study consists of 2 parts. In Part 1, patients are enrolled into different cohort doses in order to identify the appropriate recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). In Part 2, participants with metastatic/unresectable melanoma will receive the MTD and/or RP2D established in Part 1 of the study. In Part 1 and Part 2, participants will be administered treatment either once per week or once every 3 weeks. NOTE: Participants are no longer being recruited to this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: February 15, 2023
• Est. primary completion date: January 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed informed consent form and willingness to comply with study requirements.
• Part 1 (Dose-escalation): Adult subject = 75 years old with confirmed advanced solid tumors that have progressed after treatment with standard therapies, or for which no effective standard therapy is available, or the subject refuses or has a contraindication to standard therapy.
• Part 2 (Dose-expansion)
• Adult subjects 18 years and above.

Melanoma Cohort:

1. Histologically confirmed metastatic or unresectable melanoma that progressed during or after treatment with a PD-1 inhibitor (excluding bi-specific antibody) with CTLA-4 blocking function.

2. Must have received at least one BRAF inhibitor with/without a MEK inhibitor if positive with BRAF V600-activating mutation.

HCC Cohort:

1. Histologically confirmed metastatic or unresectable hepatocellular carcinoma;

2. Child-Pugh Score of 6 points or less (A5-A6);

3. Patient with HBV infection will be allowed if he/she is receiving appropriate antiviral therapy for hepatitis B virus (HBV) according to institutional standard of care and HBV DNA level is < 2000 UI/mL;

4. Patient with HCV infection will be allowed if he/she is receiving appropriate antiviral therapy for hepatitis C virus (HCV) according to institutional standard of care and HCV antibody returns to negative;

5. Have received at least one anti-VEGF treatment (either anti-VEGFR TKI or anti-VEGF monoclonal antibody) and/or anti-PD-(L)1 treatment.

RCC Cohort:

1. Histologically confirmed metastatic or unresectable renal cell cancer (including both clear cell and non-clear histology);

2. Subjects with clear cell RCC must have failed at least 1 anti-VEGFR TKI treatment and/or anti-PD(L)1 treatment;

3. For subjects with non-clear cell RCC (e.g. PRCC), treatment naive is permitted.

• Must have at least one measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Willing to undergo tumor biopsy unless determined medically unsafe or not feasible.
• For subjects whose last treatment was immunotherapy, must have disease progression confirmed at least 4 weeks after the initial radiographic evidence of progression;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Adequate organ and bone marrow function.
• Females of childbearing potential may participate provided they agree to practice abstinence; and, if heterosexually active, agree to use at least 2 highly effective contraceptive methods throughout the study and for 3 months following the last dose of HBM4003; and have a negative serum pregnancy test.
• Females of non-childbearing potential must be post-menopausal or have been surgically sterilized.
• Male subjects with a female partner of childbearing potential must agree to practice abstinence or to use a physician-approved contraceptive method throughout the study and for 3 months following the last dose of study drug.
• Life expectancy of =12 weeks. Exclusion Criteria: Part 1 and Part 2
• History of severe or not under well controlled allergic diseases, history of severe drug allergy, or are known to be allergic to macromolecular protein preparations or any component of the study drug.
• Receipt of anticancer medications or investigational drugs within the following

intervals before the first administration of the study drug:

1. CTLA-4 antibody any time prior to study drug administration;

2. Any PD-1 or PD-L1 or Programmed cell death protein ligand 2 (PDL2)-directed antibody within 8 weeks of study drug administration;

3. Any cancer vaccines within 3 months prior to first dose of study drug;

4. Live vaccine within 4 weeks prior to first dose of study drug;

5. Any other anticancer therapy within 2 weeks prior to first dose of study drug.

• Not yet recovered from surgery within 28 days prior to first dose of HBM4003 or (immune-related) toxicity related with previous treatment.
• Concomitant medication or treatments:

1. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biological therapy for cancer treatment. Concurrent use of hormones on a stable dose for non-cancer related conditions is acceptable. Androgen deprivation therapy (ADT) for advanced prostate cancers is acceptable. Local treatment of isolated non-target lesions for palliative intent is acceptable;

2. Any traditional anti-tumor herbal medications;

3. Receipt of red blood cells or platelets infusion, granulocyte colony stimulating factor (G-CSF) or granulocyte monocyte colony stimulating factor (GM-CSF) within 1 week of the first dose of HBM4003.

4. Corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 2 weeks of study drug administration; Nasal spray, inhalation, topical corticosteroids or physiological doses of systemic corticosteroids are not included.

• Have other diseases that may affect the effectiveness and safety of the study drug,

such as:

1. Known brain metastases or other central nervous system metastases that is either symptomatic or untreated, that requires concurrent treatment;

2. Active infection requiring treatment with antibiotics within 14 days prior to first dose of HBM4003;

3. Known history of infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), human T lymphotropic virus 1, hepatitis B virus, or active hepatitis C virus;

4. Suspected autoimmune disease, including but not limited to inflammatory bowel disease, autoimmune hepatitis, Guillain-Barre syndrome.

5. Known primary immunodeficiency;

6. Clinically significant gastrointestinal disorders (e.g. diarrhea with significant clinical meaning), active gastrointestinal bleeding, or a history of gastrointestinal perforation, acute diverticulitis, intra-abdominal abscess or gastrointestinal obstruction;

7. Have received allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation, or have received autologous hematopoietic stem cell transplantation within 3 months prior to the first dose of study drug.

8. Subjects with medically confirmed autoimmune coeliac disease are to be excluded. Patients with so-called gluten intolerance or other conditions labelled "coeliac disease" which are not autoimmune in nature and which are well controlled by diet should be medically confirmed as non-autoimmune "coeliac disease" and can be considered for study.

• Subjects with major cardiovascular disease.
• History of other uncured malignant diseases, except for non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ that has been curatively resected, and localized prostate cancer managed by active surveillance.
• Pregnant or breastfeeding women.
• Have experienced immune-related GI adverse events on any prior immunotherapy or toxicity that led to permanent discontinuation of prior immunotherapy.
• Severe cirrhosis, hepatic atrophy, portal hypertension.
• Main portal vein thrombosis present on imaging.
• Any prior or current clinically significant ascites (moderate to massive with significantly abnormal liver function).
• Any history of hepatic encephalopathy within 12 months prior to randomization or require medications to prevent or control encephalopathy.
• Subjects weighting < 30 kg.
• Active or prior documented GI bleeding (e.g. esophageal varices or ulcer bleeding) within 12 months.

Additional criterial for HCC cohort:

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Prior liver transplantation.
• HBV and HCV co-infection, HBV and HEV co-infection, HBV and HDV co-infection. Other protocol-defined inclusion/exclusion criteria may apply.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Drug:
• HBM4003
Intravenous (IV) administration

Locations

Country	Name	City	State
Australia	Monash Health, Monash Medical Centre, 246 Clayton Road	Clayton	Victoria
Australia	St. George Private Hospital, 1 South Street	Kogarah	New South Wales
Australia	Macquarie University, 2 Technology Place	Macquarie	New South Wales
Australia	The Alfred Hospital, Commercial Road	Melbourne	Victoria
China	Cancer Hospital Chinese Academy of Medical Sciences, Oncology Department, No. 17 Panjiayuan Nanli, Chaoyang District	Beijing
China	Peking University First Hospital, Chemotherapy Department, No. 15 cheniandian Hutong, Annei Street, Dongcheng District	Beijing
China	Hunan Cancer Hospital, Intervention Division, 83 Tongzipo Road, Yuelu District	Changsha
China	Hunan Cancer Hospital, Urology Department, 83 Tongzipo Road, Yuelu District	Changsha
China	Zhejiang Cancer Hospital, Department of Head and Neck Medicine for Rare Diseases, No. 1, Banshan Road, Gongshu District	Hangzhou	Zhejiang
China	Zhenjiang Cancer Hospital, Department of Interventional Therapy, No. 1, Banshan Road, Gongshu District	Hangzhou	Zhejiang
China	Tianjin Medical University Cancer Institute and Hospital, Biotherapeutic Department, 17 / F, Block C, West Huan-Hu Rd., Ti Yuan Bei, Hexi District	Tianjin
China	Union Hospital affiliated to Tongji Medical College of HUST, Oncology Department, No. 1277 Jiefang Dadao	Wuhan	Hubei
China	Xuzhou Central Hospital, Oncology Department, No. 199 Jiefang South Road, Quanshan District	Xuzhou
China	Yantai Yuhuangding Hospital, Urology Department, 8th Floor, No. 20 Donglu Road, Zhifu District	Yantai	Shandong
China	The Second People's Hospital of Yibin, Oncology Department, No. 268 South Bank Nanguang Road, Xuzhou District	Yibin	Sichuan
China	Henan Cancer Hospital, Oncology Department, No. 127 Dongming Road, Jinshui District	Zhengzhou
Hong Kong	Queen Mary Hospital, Department of Medicine, 102 Pok Fu Lam Road	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
Harbour BioMed US, Inc.

Countries where clinical trial is conducted

Australia,  China,  Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Proportion of subjects with Dose-Limiting Toxicity (DLT)	Number of subjects who experience DLT events during 28 days (if on QW dosing schedule) or 21 days (if on Q3W dosing schedule)	From Day 1 until disease progression or Day 28, whichever comes first
Primary	Part 2: Objective Response Rate (ORR)	Proportion of subjects with best overall response of complete response (CR) or partial response (PR) per RECIST 1.1	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Objective Response Rate	Proportion of subjects with best overall response of complete response (CR) or partial response (PR) per RECIST 1.1	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Duration of response	Time interval from first occurrence of a documented objective response to the time of disease progression, as determined by the Investigator using RECIST 1.1 or death from any cause, whichever comes first.	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Disease control rate	Proportion of subjects with a best overall response of complete response (CR), partial response (PR) or stable disease (SD).	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Duration of disease control	Time from data of start of treatment to the date of disease progression or death for subjects who had CR or PR or SD during treatment.	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Tumor shrinkage (The percentage of patients with tumor shrinkage)	Greatest tumor shrinkage achieved at any follow-up assessment. Measured by radiological (computed tomography [CT]/Magnetic Resonance Imaging [MRI]) scanning until documented radiographic disease progression according to RECIST 1.1, or loss of clinical benefit after disease progression according to RECIST 1.1	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 1: Cmax (Maximum serum concentration)		Up to 80 days after end of treatment
Secondary	Part 1: Tmax (Time to reach maximum serum concentration)	Plasma	Up to 80 days after end of treatment
Secondary	Part 1: AUC0-inf (Area under the serum concentration versus time curve from time zero to infinity		Up to 80 days after end of treatment
Secondary	Part 1: Vss (Volume of distribution at steady state)	Amount of drug in the body divided by plasma concentration	Up to 80 days after end of treatment
Secondary	Part 1: AUC0-tau (Area under the serum concentration versus time curve from time zero to the dosing interval tau		Up to 80 days after end of treatment
Secondary	Part 1: t1/2 (Terminal half-life)		Up to 80 days after end of treatment
Secondary	Part 1: Clearance (CL)		Up to 80 days after end of treatment
Secondary	Part 1: Cmin (Minimum serum concentration)	Minimum blood plasma concentration reached by drug prior to administration of second dose	Up to 80 days after end of treatment
Secondary	Part 1: Rac(Cmax)	Accumulation ratio calculated from Cmax,ss (maximum (peak) steady state plasma drug concentration during a dosage interval) and Cmax after single dosing	Up to 80 days after end of treatment
Secondary	Part 1: Rac(AUC0-tau)	Accumulation ratio calculated from AUCt,ss and AUC after single dosing	Up to 80 days after end of treatment
Secondary	Part 2: Disease control rate	Proportion of subjects with a best overall response of complete response (CR), partial response (PR) or stable disease (SD).	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 2: Duration of objective response	Time interval from first occurrence of a documented objective response to the time of disease progression, as determined by the Investigator using RECIST 1.1 and iRECIST, or mRECIST for hepatocellular carcinoma (HCC)	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 2: Objective Response Rate	Proportion of subjects with best overall response of complete response (CR) or partial response (PR) per Response Criteria for Use in Trials Testing Immunotherapeutics (iRECIST), or modified RECIST (mRECIST) for HCC	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 2: Duration of disease control	Time from data of start of treatment to the date of disease progression or death for subjects who had CR or PR or SD during treatment.	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.
Secondary	Part 2: Tumor shrinkage (The percentage of patients with tumor shrinkage)	Greatest tumor shrinkage achieved at any follow-up assessment. Measured by radiological (computed tomography [CT]/Magnetic Resonance Imaging [MRI]) scanning until documented radiographic disease progression according to RECIST 1.1, or loss of clinical benefit after disease progression according to RECIST 1.1	Up to day 206 or until disease progression, unacceptable toxicity, withdrawal of consent, lack of treatment benefit, death or termination of study, whichever comes first.

External Links

•   FDA Safety Alerts and Recalls