Overview
This study is a prospective single-arm phase II clinical study. HER2-negative advanced breast cancer patients with FGFR 1-3 alterations who have failed standard therapy will be enrolled in this study once they have signed the informed consent form (ICF) and been identified as eligible in screening. The patients will receive 13.5 mg of pemigatinib once a day (QD) orally following a 2-week administration/1-week interruption regimen. They will be dosed until disease progression or intolerable toxicity. During treatment, clinical tumor imaging evaluation will be performed according to RECIST v1.1 every 6 weeks (± 7 days) and then every 12 weeks (± 7 days) after week 48. Safety will be assessed according to NCI-CTCAE 5.0.
Eligibility
Inclusion Criteria:
Subjects must sign a written ICF prior to the implementation of any procedures related to
the study;
1. Aged ≥ 18 years old;
2. With histologically confirmed locally advanced and/or metastatic breast cancer;
3. With HER-2 negative (according to IHC or ISH test results, interpretation criteria was
referred to 2020 CSCO Breast Cancer Diagnosis and Treatment guidelines), and
① For metastatic patients with HR positive, they must have received endocrine therapy
once before, and previous chemotherapy times ≤3 times
② For patients with HR negative, 1 time ≤ times of previous chemotherapy ≤3 times
4. Have at least one measurable lesion according to RECIST v1.1;
5. With confirmed FGFR1-3 alterations, including but not limited to amplification,
mutation, fusion/rearrangement, etc.;
6. With disease progression after standard therapy, or no response to standard treatment,
or no standard treatment options;
7. ECOG physical performance status score of 0-1;
8. Expected survival time > 3 months;
9. For evidence of sufficient organ functions, the subjects shall meet the following
laboratory parameters:
① Absolute neutrophil count (ANC) ≥ 1.5×109/L without use of granulocyte colony
stimulating factor in recent 14 days;
- Platelet count ≥ 100×109/L without blood transfusion in recent 14 days;
- Hemoglobin > 9 g/dL without blood transfusion or erythropoietin use in
recent 14 days;
- Total bilirubin ≤ 1.5×upper limit of normal (ULN); or total bilirubin >
ULN, direct bilirubin ≤ ULN; ⑤ Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) ≤ 2.5×ULN (ALT or AST ≤ 5×ULN for
patients with liver metastasis); ⑥ Blood creatinine ≤ 1.5×ULN and
creatinine clearance (calculated by Cockcroft-Gault formula) ≥ 50
mL/min; ⑦ Good coagulation function: international normalized ratio
(INR) or prothrombin time (PT) ≤ 1.5×ULN;
10. Women of childbearing potential shall obtain a negative result in the urine or serum
pregnancy test performed within 3 days before the first dose of the investigational
drug (cycle 1, day 1). If the urine pregnancy test result cannot be identified as
negative, a blood pregnancy test is needed. Women of non-childbearing potential are
defined as those who have not had menses for at least 1 year or who have undergone
surgical sterilization or hysterectomy;
11. All subjects at risk of conception (including their partners) shall use contraceptives
with an annual failure rate of less than 1% throughout the entire treatment period up
to 120 days after the last dose of the investigational drug (or 180 days after the
last dose of the chemotherapy drug).
Exclusion Criteria:
1. Diagnosed with malignant tumors other than breast cancer within 5 years before the
first dose, excluding radically cured cutaneous basal cell carcinoma, cutaneous
squamous cell carcinoma, and/or radically resected carcinoma in situ;
2. Previously treated with selective FGFR inhibitors;
3. Have received any other investigational drug treatment or participated in another
interventional clinical trial within 28 days before the first dose of the
investigational drug, or have received anti-tumor drug treatment within 28 days before
the first dose of the investigational drug (including Chinese herbal medicine with
anti-tumor indications);
4. Have not recovered (i.e., reaching ≤ grade 1 or the baseline status, excluding
asthenia and alopecia) from toxicity and/or complications caused by any intervention
before the start of treatment;
5. With known symptomatic central nervous system metastasis and/or carcinomatous
meningitis. Subjects with previously treated brain metastases are eligible if the
disease is stable (no imaging evidence of progression in at least 4 weeks prior to the
first dose of study treatment), there is no evidence of new or enlarging brain
metastases on repeated imaging, and corticosteroids are not required in at least 14
days prior to the first dose of study treatment. Patients with carcinomatous
meningitis should be excluded regardless of their clinically stability;
6. Pregnant or lactating;
7. Known history of allotransplantation or allogeneic hematopoietic stem cell
transplantation;
8. Subjects with abnormal laboratory parameters listed below:
① Serum phosphate > ULN;
② Serum calcium exceeds the normal range, or the calcium concentration corrected for
serum albumin exceeds the normal range when serum albumin exceeds the normal range;
③ Potassium level < lower limit of normal (LLN); potassium levels can be corrected by
supplements at screening.
9. With known history of human immunodeficiency virus (HIV) infection or confirmed with
positive immune test results;
10. Presence of severe infection in the active phase or with poor clinical control;
11. Pleural effusion, ascites, or pericardial effusion with obvious clinical symptoms that
require drainage;
12. Acute or chronic active hepatitis B or C infection; hepatitis B virus (HBV) DNA > 2000
IU/mL or 104 copies/mL; hepatitis C virus (HCV) RNA > 103 copies/mL; hepatitis B
surface antigen (HbsAg) and anti-HCV antibody positive concurrently. Those who with
relevant parameters lower than the above criteria after nucleotide antiviral treatment
can be enrolled;
13. With clinically significant or uncontrolled heart diseases, including unstable angina,
acute myocardial infarction within 6 months before the first dose, grade III/IV
congestive heart failure (New York Heart Association), and uncontrolled arrhythmia
(subjects with pacemakers or with atrial fibrillation but well controlled heart rate
are allowed);
14. With ECG changes or medical history considered clinically significant by the
investigator; QTcF interval > 480 ms at screening; for subjects with intraventricular
conduction block (QRS interval > 120 ms), JTc interval can be used instead of QTc
interval (in such cases, JTc must be ≤ 340 ms);
15. With uncontrolled hypertension (systolic pressure > 160 mmHg or diastolic pressure >
100 mmHg) after the optimal medical treatment, or a history of hypertensive crisis or
hypertensive encephalopathy;
16. With hepatic encephalopathy, hepatorenal syndrome, or liver cirrhosis with Child-Pugh
grade B or C.
17. Have received a major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks
prior to the first dose of study treatment, or will receive a major surgery during the
study treatment period;
18. Not fully recovered from toxicity and/or complications of a major surgery before the
commencement of treatment;
19. Pregnant or lactating women, or subjects expected to conceive or give birth during the
study period from the screening visit to the completion of the safety follow-up visit
(90 days after the last dose for male subjects);
20. Have received radiotherapy within 4 weeks before the first dose of the investigational
drug. The subjects must be completely recovered from radiotherapy-related toxicity,
with no need for corticosteroid treatment, and radiation pneumonitis must be excluded.
For palliative radiotherapy for non-CNS diseases, a 2-week washout period is allowed;
21. Have a history of disorders of calcium and phosphorus metabolism or systemic
electrolyte metabolism imbalance with ectopic calcification of soft tissues (excluding
calcification of soft tissues such as skin, kidneys, tendon, or blood vessels without
systemic electrolyte metabolism imbalance caused by injury, disease, and old age);
22. Clinically significant corneal or retinal diseases confirmed by ophthalmological
examination;
23. Have used any potent CYP3A4 inhibitor (see Appendix A for details) or inducer within
14 days or 5 half lives (whichever is shorter) before the first dose of the
investigational drug. Ketoconazole is allowed for external use;
24. With known allergic reactions to pemigatinib or excipients of pemigatinib;
25. Unable or unwilling to swallow pemigatinib or are suffering from significant digestive
system diseases that may interfere with absorption, metabolism, or excretion;
26. Subjects with a history of vitamin D deficiency who require supraphysiological dose of
vitamin D (except dietary vitamin D supplements);
27. Other acute or chronic diseases, psychiatric disorders, or laboratory abnormalities
that may result in an increased risk associated with study participation or
investigational drug administration or interfere with the interpretation of study
results, and disqualify patients from the study in the investigator's judgment.