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A Study of Fruquintinib in Combination With Tislelizumab in Advanced Triple Negative Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04577963
Recruitment Status : Recruiting
First Posted : October 8, 2020
Last Update Posted : July 12, 2021
Information provided by (Responsible Party):
Hutchison Medipharma Limited

Brief Summary:

This is an open-label, multi-center, non-randomized, Phase 1b/2 study to assess the safety and efficacy of fruquintinib in combination with tislelizumab in patients with advanced, refractory TNBC. This study will be conducted in 2 parts; a safety lead-in phase (Part 1) and a dose expansion phase (Part 2). The safety lead-in phase will determine the RP2D. The RP2D will be administered to 2 cohorts of patients in the expansion phase.

  • Cohort A: TNBC (IO-treated)
  • Cohort B: TNBC (IO-Naïve)

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Fruquintinib Drug: Tislelizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Phase 1b/2 Study to Evaluate the Safety and Efficacy of Fruquintinib in Combination With Tislelizumab in Patients With Advanced Triple Negative Breast Cancer
Actual Study Start Date : June 1, 2021
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Part 1
Approximately 6-12 patients will be enrolled to receive fruquintinib in combination with tilelizumab and assessed for DLTs during the 28-day DLT observation period
Drug: Fruquintinib
Oral VEGFR inhibitor
Other Name: HMPL-013

Drug: Tislelizumab
PD-1 inhibitor
Other Name: BGB-A317

Experimental: Part 2

Approximately 60 patients with TNBC will be enrolled, up to 30 patients in each cohort. Patients will be enrolled to one of the following two cohorts:

  • Cohort A (TNBC, IO-Treated): Patients must have advanced TNBC who have progressed on at least one cytotoxic therapy in the metastatic setting. Patients must have also received prior therapy with an immune checkpoint inhibitor.
  • Cohort B (TNBC, IO-Naïve): Patients must have advanced TNBC who have progressed on at least one cytotoxic therapy in the metastatic setting. Patients must not have received prior therapy with an immune checkpoint inhibitor.
Drug: Fruquintinib
Oral VEGFR inhibitor
Other Name: HMPL-013

Drug: Tislelizumab
PD-1 inhibitor
Other Name: BGB-A317

Primary Outcome Measures :
  1. Adverse Events by type, frequency, and severity [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
    To assess the safety and tolerability by monitoring AEs characterized by type, frequency, severity per NCI-CTCAE v5.0

  2. Recommended Phase 2 Dose [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
    To confirm the RP2D of fruquintinib in combination with tislelizumab

  3. Objective Response Rate [ Time Frame: Up to 1 year ]
    To evaluate the objective response rate (ORR) as assessed by the investigator in subjects with advanced TNBC when treated with fruquintinib in combination with tislelizumab

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Willing and able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines;
  2. Age ≥18 years;
  3. Have histologically- or cytologically-confirmed advanced or metastatic triple negative breast cancer with ER-negative, PR-negative tumors as defined by local criteria (Her2-negative defined as immunohistochemistry (IHC) 0, 1+, or 2+. If IHC 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing);
  4. Must have progressed on at least 1 cytotoxic therapy in the metastatic setting, with the exception of patients who progressed within 12 months of adjuvant therapy. However, patients may not have received more than 3 prior lines of cytotoxic chemotherapy in the metastatic setting

    • Patients in Cohort A must have received prior therapy with an immune checkpoint inhibitor
    • Patients in Cohort B must not have received prior therapy with an immune checkpoint inhibitor;
  5. Tumor tissue (fresh or archival tumor tissues as formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) for retrospective analysis of PD-L1 expression level and other exploratory biomarkers related to response and resistance. Submission of < 15 unstained slides is permitted, and patients may be enrolled after confirmation with the sponsor;
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
  7. Expected survival of ≥ 12 weeks;
  8. Have measurable disease as defined by RECIST v1.1. Tumors that were treated with radiotherapy are not considered measurable per RECIST v1.1 unless there has been documented progression of those lesions;
  9. Adequate organ function indicated by the following laboratory values;

    1. Absolute neutrophil count (ANC) of ≥ 1.5 × 109/L
    2. Platelet count of ≥ 75 × 109/L
    3. Hemoglobin ≥ 8 g/dL
    4. Serum total bilirubin ≤ 1.5 × ULN (total bilirubin must be < 3 ULN for patients with Gilbert's syndrome)
    5. For patients without liver metastases, must have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; patients with liver metastases, must have ALT and AST ≤ 5 × ULN
    6. Urine protein < 2+ by dipstick or 24-hour urine protein < 1g. Patients with > 1+ proteinuria on urinalysis must undergo 24-hour urine collection
    7. Serum creatinine <1.5 × ULN or creatinine clearance ≥ 60 mL/min per Cockcroft Gault
    8. International normalized ratio (INR) and activated prothrombin time (aPTT) ≤ 1.5 ULN unless the patient is receiving anticoagulation therapy and INR and aPTT values are within the intended therapeutic range;
  10. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 120 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation together with a barrier method (eg, diaphragm, always containing a spermicide), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or sexual abstinence. Oral contraception should always be combined with an additional contraceptive method (ie, barrier method) because of a potential interaction with the study drug. The same criteria are applicable to male patients involved in this clinical trial if they have a partner of childbearing potential, and male patients must always use a condom. All female patients will be considered to have childbearing potential unless the said female patient has had natural menopause, induced artificial menopause or has undergone sterilization (hysterectomy and bilateral salpingo-oophorectomy).

Exclusion Criteria:

  1. Adverse events due to previous anti-tumor therapy that have not recovered to ≤ CTCAE Grade 1, except alopecia and peripheral neurotoxicity with ≤ CTCAE Grade 2;
  2. Other malignancy except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
  3. Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment are excluded;
  4. Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
  5. Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
  6. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
  7. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
  8. Mean corrected QT interval (QTcF) ≥480 milliseconds;
  9. EXCEPT for Cohort B, patients who have previously received any anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody (or any other antibody acting on T cell co-stimulation or checkpoint pathways
  10. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before the first dose of study drug(s), with the following exceptions:

    1. Adrenal replacement (dose ≤ 10 mg daily of prednisone or equivalent)
    2. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal systemic absorption
    3. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen);
  11. Active autoimmune diseases or history of autoimmune diseases that may relapse, with the following exceptions:

    1. Controlled Type 1 diabetes
    2. Hypothyroidism (provided it is managed with hormone-replacement therapy only)
    3. Controlled celiac disease
    4. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or alopecia)
    5. Any other disease that is not expected to recur in the absence of external triggering factors;
  12. Live vaccine ≤ 28 days before the first dose of study drug(s).

    a. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed;

  13. Active infection requiring systemic antibacterial, antifungal, or antiviral therapy (not including antiviral therapy for hepatitis) for ≤ 14 days prior to the first dose of study drug(s) or a positive test for SARS-CoV-2 in the absence or presence of symptoms;
  14. Active tuberculosis that is being treated with anti-tuberculosis therapy or that have received treatment with anti-tuberculosis therapy within one year before the first drug administration;
  15. History or presence of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including but not limited to pulmonary fibrosis, acute lung diseases, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired lung function, and other patients with conditions that may interfere with the detection and treatment of suspected drug-related pulmonary toxicity; radiation pneumonitis in the radiation therapy area is allowed;
  16. Known history of active viral hepatitis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with hepatitis C virus (HCV) infection who are currently on treatment are eligible if they have an undetectable HCV viral load. Patients with an unknown history of viral hepatitis must be screened for HBV with hepatitis B surface antigen (HBsAg) and HBV DNA, if indicated, and for HCV with HCV antibody:

    1. Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for > 2 weeks before the first dose of study drug.
    2. Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody;
  17. Known history of HIV infection;
  18. Major surgery within 60 days before the first drug administration. Patients must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study drug(s);
  19. Patients who had any surgical or invasive therapy (except for puncture biopsy, venous catheterization) within four weeks before the first drug administration; or have unhealed wounds, ulcers or fractures;
  20. Prior allogeneic stem cell transplantation or organ transplantation;
  21. Any of the following cardiovascular risk factors:

    1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before the first dose of study drug(s)
    2. Pulmonary embolism or venous thromboembolis ≤ 6 months before the first dose of study drug(s)
    3. Acute myocardial infarction ≤ 6 months before the first dose of study drug(s)
    4. Heart failure meeting New York Heart Association Classification III or IV ≤ 6 months before the first dose of study drug(s). Left ventricular ejection fraction (LVEF) < 50%
    5. Ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of study drug(s)
    6. Cerebrovascular accident ≤ 12 months before the first dose of study drug(s)
    7. Uncontrolled hypertension that cannot be managed by standard antihypertension medications, which is specified as: systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg ≤ 28 days before the first dose of study drug(s)
    8. Syncope or seizure ≤ 28 days before the first dose of study drug(s);
  22. Inability to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the complete small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction;
  23. Received strong inducers or inhibitors of Cytochrome P450, family 3, subfamily A (CYP3A) taken within two weeks (or 5 times the half-life of the drug, whichever is longer) prior to the first study treatment;
  24. Active gastrointestinal and duodenal ulcers, ulcerative colitis, and other gastrointestinal disease or unresectable tumors with active bleeding, or other conditions that the investigator determines to possibly cause gastrointestinal bleeding, perforation and other conditions; or prior gastrointestinal perforation or gastrointestinal fistula that has not recovered after surgical treatment;
  25. History or presence of hemorrhage from any site (such as melena, hematemesis, hemoptysis, fresh in stool, etc.) within two months before the screening;
  26. History of arterial thrombus or deep vein thrombosis within six months prior to the first drug administration; patients with implanted intravenous infusion pump or catheter related thrombosis or superficial vein thrombosis, except for patients with stable thrombus after routine anticoagulant therapy;
  27. Stroke event and/or transient ischemic attack within 12 months;
  28. Women who are pregnant or lactating;
  29. Known allergy to any of the components of tislelizumab or fruquintinib preparations including tartrazine (E102) and sunset yellow (E110), or have any previous history of severe allergy to monoclonal antibodies.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04577963

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Contact: Alberto Fernandez 973-567-3891
Contact: Keneikia Morgan

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United States, Arkansas
Highlands Oncology Recruiting
Springdale, Arkansas, United States, 72762
Contact: H Holtzen   
Principal Investigator: Thaddeus Beck, MD         
United States, North Carolina
Mission Hospital Cancer Center Recruiting
Asheville, North Carolina, United States, 28806
Contact: C Chay   
Principal Investigator: Christopher Chay, MD         
United States, Tennessee
Tennesse Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: E Hamilton   
Principal Investigator: Erika Hamilton, MD         
Sponsors and Collaborators
Hutchison Medipharma Limited
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Study Director: William Schelman, MD, PhD Hutchison MediPharma International
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Responsible Party: Hutchison Medipharma Limited Identifier: NCT04577963    
Other Study ID Numbers: 2020-013-00US3
First Posted: October 8, 2020    Key Record Dates
Last Update Posted: July 12, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hutchison Medipharma Limited:
Breast cancer
Triple negative
Her2 negative
HR negative
ER negative
PR negative
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases