A First-in-human Study of Multiple Doses of BB-1701 in Subjects With Locally Advanced/Metastatic HER2 Expressing Solid Tumors

• ClinicalTrials.gov Identifier: NCT04257110
• Recruitment Status: Recruiting
• First Posted: February 5, 2020
• Last Update Posted: June 10, 2022
• Sponsor: Bliss Biopharmaceutical (Hangzhou) Co., Ltd
• Information provided by (Responsible Party): Bliss Biopharmaceutical (Hangzhou) Co., Ltd

Study Description

Brief Summary:

This is an open-label, first-in-human (FIH), phase 1 dose-escalation and cohort expansion study of BB-1701 in subjects with locally advanced/metastatic HER2 expressing solid tumors. The study consists of 2 parts: dose-escalation (Part 1) and cohort expansion (Part 2). Part 1 consists of dose escalation cohorts for determining the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Part 2 consists of expansion cohorts, including but not limited to breast cancer, gastric/gastroesophageal junction cancer, bladder cancer and colon cancer, for exploring 1 or more RP2Ds or schedules for expanding/deepening the information/knowledge about clinical safety, clinical pharmacokinetics and anti-tumor activity.

Condition or disease	Intervention/treatment	Phase
Locally Advanced/Metastatic HER2 Positive Solid Tumors	Drug: BB-1701	Phase 1

Detailed Description:

This is an open-label, FIH, phase 1 dose-escalation and cohort expansion study of BB-1701 in subjects with locally advanced /metastatic HER2 expressing solid tumors. The study consists of 2 parts: dose-escalation (Part 1) and cohort expansion (Part 2).

Part 1 of this study will follow accelerated titration and traditional "3 + 3" design. Part 2 is a cohort expansion study with HER2 expressing locally advanced/metastatic solid tumors.

Part 2 consists of 4 cohorts:

Cohort 1: Patients with HER2 overexpressing or positive (defined as IHC 3+ or IHC 2+/FISH positive) locally advanced or metastatic breast cancer who have progressed on prior standard therapies including anti HER2 therapy

Cohort 2: Patients with HER2 low expressing (defined as IHC 2+ /FISH negative, or IHC 1+) locally advanced or metastatic breast cancer who have progressed on prior standard therapies.

Cohort 3: Patients with HER2 overexpressing or positive (defined as IHC 3+ or IHC 2+/FISH positive) locally advanced or metastatic gastric cancer or gastroesophageal junction cancer who have progressed on prior standard therapies.

Cohort 4: Patients with HER2 overexpressing or positive (defined as IHC 3+, or IHC 2+/FISH positive) locally advanced or metastatic solid tumors (other than breast cancer and gastric or gastroesophageal junction cancer) who have progressed on prior standard therapies. Patients with HER2 mutation or amplification by NGS can also be enrolled in this cohort.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 208 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A First-in-human, Open Label, Multiple Dose, Dose Escalation and Cohort Expansion Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antitumor Activities of BB-1701 in Subjects With Locally Advanced/Metastatic HER2 Expressing Solid Tumors
• Actual Study Start Date: July 28, 2020
• Estimated Primary Completion Date: August 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Part 1: Dose-escalation; Eight doses levels have been selected for evaluation in the Part 1 of the study. Dose escalation decisions will be determined based on toxicities observed during the first cycle ( 21 days or 28 days).	Drug: BB-1701; BB-1701 will be administered as an intravenous infusion, every 3 weeks or every 4 weeks or every 6 weeks.
Experimental: Part 2: Cohort 1; Breast Cancer with HER2 overexpressing or positive	Drug: BB-1701; BB-1701 will be administered as an intravenous infusion, every 3 weeks or every 4 weeks or every 6 weeks.
Experimental: Part 2: Cohort 2; Breast Cancer with HER2 low expressing	Drug: BB-1701; BB-1701 will be administered as an intravenous infusion, every 3 weeks or every 4 weeks or every 6 weeks.
Experimental: Part 2 Cohort 3; Gastric Cancer or gastroesophageal junction cancer with HER2 overexpressing or positive	Drug: BB-1701; BB-1701 will be administered as an intravenous infusion, every 3 weeks or every 4 weeks or every 6 weeks.
Experimental: Part 2 Cohort 4; Solid Tumors other than Breast Cancer and Gastric Cancer with HER2 overexpressing or positive	Drug: BB-1701; BB-1701 will be administered as an intravenous infusion, every 3 weeks or every 4 weeks or every 6 weeks.

Outcome Measures

Primary Outcome Measures :

1. Number of subjects with adverse events and serious adverse events [ Time Frame: up to 2 years ]
   To evaluate the safety and tolerability of BB-1701
2. Number of subjects with dose limiting toxicity (DLT) [ Time Frame: Cycle 1. Duration of each cycle is 21 days. ]
   Subjects are evaluated for all study drug related and treatment emergent toxicities based on the National Cancer Institute Common Toxicity Criteria for adverse events (NCI-CTCAE)
3. MTD [ Time Frame: Cycle 1. Duration of each cycle is 21 days. ]
   MTD is defined as the highest dose level at which no more than 1 out of 6 subjects experiences a DLT during the first cycle.

Secondary Outcome Measures :

1. Area under the serum concentration time curve from time 0 extrapolated to infinity (AUC0-inf) [ Time Frame: Cycle 1 Day 1. Duration of each cycle is 21 days. ]
   To characterize the pharmacokinetics (PK) of BB-1701
2. Maximum observed plasma concentration (Cmax) [ Time Frame: Pre-dose and post-dose during Cycle 1 through Cycle 8. Duration of each cycle is 21 days. ]
   To characterize the PK of BB-1701
3. Incidence of anti-drug antibodies [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of Cycles 2, 3, 4, 6, and 8. Duration of each cycle is 21 days. ]
   To assess the immunogenicity of BB-1701
4. Objective response [ Time Frame: Every 9 weeks within 6 months and approximately every 12 weeks thereafter (up to 2 years) ]
   To assess the preliminary anti-tumor activity of BB-1701
5. Progression Free Survival [ Time Frame: Every 9 weeks within 6 months and approximately every 12 weeks thereafter (up to 2 years) ]
   To assess the preliminary anti-tumor activity of BB-1701
6. Duration of Response [ Time Frame: Every 9 weeks within 6 months and approximately every 12 weeks thereafter (up to 2 years) ]
   To assess the preliminary anti-tumor activity of BB-1701

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Willing and able to provide written informed consent for the trial.
2. Male or female subject ≥ 18 years.
3. Patients must have a histologically or cytologically confirmed locally advanced unresectable or metastatic HER2 expressing solid tumor(s) for which no curative therapy is available or tolerable
4. Patients with breast cancer who are estrogen receptor (ER) and/or progesterone receptor (PR) positive and in whom hormonal therapy is indicated (e.g., patients with positive ER and/or PR without rapidly progressive or extensive visceral metastases) must have received at least 1 prior line of hormonal therapy
5. Patients must have at least one measurable lesion as defined per RECIST Version 1.1.
6. Patients must have a brain MRI (breast cancer only for part 2 cohort expansion) for the status of brain metastasis within 28 days prior to the first dose. Those with asymptomatic or stable CNS metastases are eligible for participation. However, patients with symptomatic and untreated CNS metastases, or those requiring ongoing treatment for CNS metastases, including steroids (>10 mg of prednisone or 4 mg of dexamethasone) and antiepileptic agents should not be enrolled in the study.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Life expectancy ≥12 weeks.
9. Subjects (women of childbearing potential and males with fertile female partner) must be willing to use currently accepted reliable contraception method throughout the treatment period and for at least seven months following the last dose of study drug.
10. Patients (women of childbearing potential and males with fertile female partner) must be willing to use currently accepted reliable contraception method throughout the treatment period and for at least six months following the last dose of study drug. These measures include, but are not limited to, oral or implantable injections of hormonal contraceptives; intrauterine birth control ring or placement of IUS intrauterine device); or use of barrier methods such as condoms or septum and spermicide products. Postmenopausal women over 50 years of age must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must have a negative pregnancy test ≤ 7 days prior to the first dose of investigational product.
11. Washout period required from the end of prior treatment to the first administration of the study drug
12. Be able to provide a fresh formalin-fixed, paraffin-embedded (FFPE) tumor tissue block, or 5-10 non-staining tumor slides (cohort 4 should be within 2 years) for evaluation or confirmation or exploratory diagnostic tests of HER2 status.

Exclusion Criteria:

1. Is receiving cancer therapy (chemotherapy or other systemic anti-cancer therapies, immunotherapy, radiation therapy, or surgery) at the time of enrollment.
2. Has not recovered from adverse events (e.g., not returned to baseline or grade 0~1) due to a previously administered agent.
3. Had major surgery within 4 weeks before dosing, or will not have fully recovered from surgery; or has surgery planned during the time the subject is expected to participate in the study or within 4 weeks after the last dose of study drug administration
4. Use of any investigational anti-cancer drug within 28 days before the first investigational product administration.
5. Has received prior cumulative doxorubicin dose > 360 mg/m² or equivalent
6. Has grade 2 or higher peripheral neuropathy, or had a history of grade 3 or higher peripheral neuropathy or had a history of treatment discontinuation due to peripheral neuropathy
7. Has an active pneumonitis/interstitial lung disease (ILD), a history of pneumonitis/ILD that required systemic steroids, received radiotherapy to lung field within 12 months before the first dose of study intervention, or current clinically relevant lung disease (e.g. Chronic Obstructive Pulmonary Disease).
8. Has symptomatic or untreated CNS metastases, or those requiring ongoing treatment for CNS metastases, including steroids (>10 mg of prednisone or 4 mg of dexamethasone) and antiepileptic agents.
9. Any other serious underlying medical conditions, including but not limited to, uncontrolled diabetes mellitus, active uncontrolled infection, active gastric ulcer, uncontrolled seizures, cerebrovascular incidents, gastrointestinal bleeding, severe signs and symptoms of coagulation and clotting disorders
10. Patients has clinically significant cardiovascular disease.
11. QTc interval >/= 450 msecs for male or >/= 470 msecs for female [Fridericia's formula: QTcF=QT msec/(RR sec)0.33).
12. Current dyspnea at rest due to complications of advanced malignancy, or other diseases requiring continuous oxygen therapy.
13. Any other serious underlying medical conditions, including but not limited to, psychiatric, psychological, familial or geographical condition that, in the judgment of the investigator, may interfere with the planned staging, treatment and follow-up, affect subject compliance or place the subject at high risk from treatment-related complications.
14. History of seropositive status for human immunodeficiency virus (HIV) at any time before the start of treatment as determined by presence of anti-HIV-1 or anti-HIV-2 antibodies. Testing for seropositive status during Screening will be at the discretion of the investigator in participants without previously reported results.
15. Active hepatitis B, or hepatitis C infection. Participants will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening:
16. History of life-threatening hypersensitivity, or known to be allergic to protein drugs or recombinant proteins or excipients in BB-1701 drug formulation, or intolerance to trastuzumab or eribulin.
17. Females who are pregnant (positive beta-human chorionic gonadotropin positive [β-hCG] test) or breastfeeding.
18. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol.
19. Unwillingness or inability to follow the procedures outlined in the protocol.

Contacts and Locations

Contacts

Contact: Huoling Tang, MD, PhD; +86 13681491604; hltang@blissbiopharma.com

Locations

United States, California

UCSF Helen Diller Family Comprehensive Cancer Center; Recruiting

San Francisco, California, United States, 94158

Contact: Pamela Munster 415-353-9535 earlyphase@ucsf.edu

United States, Tennessee

Sarah Cannon Research; Recruiting

Nashville, Tennessee, United States, 37203

Contact: Erika P. Hamilton

United States, Virginia

The Regents of NEXT Virginia, LLC; Recruiting

Fairfax, Virginia, United States, 22031

Contact: Alexander I. Spira

China, Jiangsu

Jiangsu Province Hospital; Recruiting

Nanjin, Jiangsu, China

Contact: Xiaoxiang Guan

China, Tianjin

Tianjin Medical University Cancer Institute and Hospital; Recruiting

Tianjin, Tianjin, China

Contact: Yehui Shi

China

Cancer Hospital Chinese Academy of Medical Science; Recruiting

Beijing, China, 100021

Contact: Fei Ma 86-13910217780 13910217780@139.com

Sun Yat-sen Memorial Hospital; Recruiting

Guangzhou, China

Contact: Herui Yao

The First Affiliated Hospital of Zhejiang University; Recruiting

Hangzhou, China, 310003

Contact: Nong Xu 86-571-5673-1277 xunongclinictrial@126.com

Sir Run Run Shaw Hospital - Zhejiang University School of Medicine; Recruiting

Hangzhou, China

Contact: Xian wang

Linyi Cancer Hospital; Recruiting

Linyi, China

Contact: Jingfen Wang

Hubei Cancer Hospital; Recruiting

Wuhan, China

Contact: Xinjun liang

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Recruiting

Wuhan, China

Contact: Tao Huang

Sponsors and Collaborators

Bliss Biopharmaceutical (Hangzhou) Co., Ltd

More Information

• Responsible Party: Bliss Biopharmaceutical (Hangzhou) Co., Ltd
• ClinicalTrials.gov Identifier: NCT04257110
• Other Study ID Numbers: BB-1701-101
• First Posted: February 5, 2020
• Last Update Posted: June 10, 2022
• Last Verified: June 2021

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

Keywords provided by Bliss Biopharmaceutical (Hangzhou) Co., Ltd:

Maximum tolerated dose; Recommended Phase 2 dose; First-in-human

Additional relevant MeSH terms:

Neoplasms