Trial Title:
First-line Trastuzumab, Gemcitabine, Cisplatin and Nivolumab in Advanced HER2- Positive Biliary Tract Cancer: a Multicenter, Open-label, Single-arm Phase Ib/II Trial (HERBOT)
NCT ID:
NCT05749900
Condition:
HER2 Positive Advanced/Metastatic/Nonresectable Biliary Tract Cancer
Conditions: Official terms:
Biliary Tract Neoplasms
Gemcitabine
Nivolumab
Trastuzumab
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab+Nivolumab+Gemcitabine+Cisplatin
Description:
Phase Ib Nivolumab 360mg IV q 3weeks Gemcitabine 1000mg/m2 IV D1, D8 q 3weeks Cisplatin
25mg/m2 IV D1, D8 q 3weeks Trastuzumab 8mg/kg (C1) then 6mg/kg IV q 3weeks Level -1
Nivolumab 360mg IV q 3weeks Gemcitabine 800mg/m2 IV D1, D8 q 3weeks Cisplatin 25mg/m2 IV
D1, D8 q 3weeks Trastuzumab 8mg/kg (C1) then 6mg/kg IV q 3weeks
Arm group label:
Trastuzumab+Nivolumab+Gemcitabine+Cisplatin
Summary:
Biliary tract cancer is a rare malignant neoplasm including intrahepatic
cholangiocarcinoma (IhCCA), extrahepatic cholangiocarcinoma (EhCCA) and Gallbladder
cancer (GBC). Survival outcome of advanced BTCs are still poor and heterogeneity of
tissue and molecular differences between BTCs limit the clinical studies in BTCs.
Combination therapy of Gemcitabine and Cisplatin has become the standard of care after
the ABC-02 trial. This trial demonstrated that the addition of cisplatin to gemcitabine
improved survival outcomes compared to that with gemcitabine alone. However, the median
overall survival (OS) of Gem/Cis chemotherapy is only about one year.
Anti-Program cell death-1 (anti-PD-1) inhibitor monotherapy including Nivolumab (OPDIVO)
had shown efficacy in refractory, advanced BTC. Various ICIs combined with Gem/Cis as the
1st line treatment in BTCs are under the trials. Combination of Nivolumab and Gem/Cis
showed improved overall survival (15.4 months) in a small sized study (n=30) with
tolerable side effects in advanced BTC patients. Recently reported interim analysis of
phase III TOPAZ-1 trial (NCT03875235) showed Durvalumab, anti-PD-L1 agent, combined with
Gem/Cis showed improvement of overall survival. Considering other studies currently
ongoing, ICIs combined with Gem/Cis are thought to be the future standard of care in 1st
line treatment of advanced stage BTCs.
HER2 amplification/overexpression is presented as many as 15% of total BTC patients.
Basket trial of administration of pertuzumab and trastuzumab combination in previously
treated HER2 positive advanced BTC patients showed promising overall response rate of
23%. Also, multicenter phase II study conducted by Korean investigators (KCSG-HB19-14)
showed promising effect of Trastuzumab combined with modified FOLFOX in Gem/Cis
refractory HER2 positive BTC patients with ORR of 29.4%. Moreover, preclinical data
showed synergistic anti-cancer effect of trastuzumab combined with ICIs in HER2 positive
cancers. Similar data are reported in HER2 positive gastric cancer that phase II and
phase III clinical data showed 1st-line ICIs combined with trastuzumab and cytotoxic
chemotherapy showed promising overall survival outcomes.
In treating HER2-positive advanced BTC, the triple combination of nivolumab, trastuzumab,
and cytotoxic chemotherapy (Gem/Cis) may overcome innate resistance and activate an
immune response to cancer along with inhibiting oncogenic signal from HER2 pathway,
resulting in a synergistic effect with a longer response.
Detailed description:
This phase Ib/II study is designed to see whether
trastuzumab+nivolumab+gemcitabine+cisplatin is active as palliative 1st line treatment
for HER2-positive biliary tract cancer patients.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Subjects with histologically- or cytologically-confirmed biliary tract cancer
(including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and
gall bladder cancer)
2. HER2 positive biliary tract cancer (IHC 3+ or 2+ with ISH + (HER2/CEP17≥2.0) or
ERBB2 gene copy number ≥ 6.0 by NGS)
3. Age (at the time of informed consent): 20 years and older
4. Previously untreated if unresectable/metastatic at initial diagnosis; or recurrent
disease >6 months after curative surgery or adjuvant therapy (allow up to 1 cycle of
gemcitabine-based chemotherapy for advanced/unresectable or metastatic
cholangiocarcinoma prior to enrollment)
5. Explicit and voluntary consent to participate in the study obtained using a signed
and dated informed consent form clearly and fully describing the purpose, potential
risks, and any other critical issues regarding the study
6. Subject with measurable lesions according to RECIST v. 1.1
7. ECOG Performance Status Score 0 or 1
8. Patients with a life expectancy of at least 3 months
9. Patients whose latest laboratory data meet the below criteria within 14 days before
enrollment.
White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 Platelets ≥100,000/mm3
Hemoglobin ≥9.0 g/dL AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal
(ULN) of the study site (or ≤5.0-fold the ULN of the study site in patients with
liver metastases) Total bilirubin ≤1.5-fold the ULN of the study site Creatinine
≤1.5-fold the ULN of the study site or creatinine clearance (either the measured or
estimated value using the Cockcroft-Gault equation) >45 mL/min INR ≤1.5-fold or
prothrombin time ≤1.5-fold the ULN of the study site aPTT ≤1.5-fold the ULN of the
study site
10. Women of childbearing potential (including women with chemical menopause or no
menstruation for other medical reasons) #1 must agree to use contraception#2 from
the time of informed consent until 5 months or more after the last dose of the
investigational product. Also, women must agree not to breastfeed from the time of
informed consent until 5 months or more after the last dose of the investigational
product.
11. Men must agree to use contraception#2 from the start of study treatment until 7
months or more after the last dose of the investigational product.
-
1. Women of childbearing potential are defined as all women after the onset
of menstruation who are not postmenopausal and have not been surgically
sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral
oophorectomy). Postmenopause is defined as amenorrhea for ≥12 consecutive
months without specific reasons. Women using oral contraceptives,
intrauterine devices, or mechanical contraception such as contraceptive
barriers are regarded as having childbearing potential.
-
2. The subject must consent to use any of the following methods of
contraception: vasectomy or condom for patients who are male or female
subject's partner and tubal ligation, contraceptive diaphragm,
intrauterine device, spermicide, or oral contraceptive for patients who
are female or male subject's partner.
12. EF ≥ 50% via Transthoracic echocardiography or MUGA scan
13. Subjects willing to provide tumor biopsy tissue or excisional biopsy tissue.
14. Subjects with adequate organ function
Exclusion Criteria:
1. Patients treated with systemic chemotherapy, biologic therapy, immunotherapy,
hormone therapy, or clinical trials for unresectable, locally advanced or metastatic
biliary tract cancer. However, the following are excluded.
1. If disease recurrence occurs 6 months after the last dose of adjuvant
chemotherapy, previous adjuvant chemotherapy is permitted.
2. 1 cycle of Gemcitabine-based anticancer therapy for locally advanced or
metastatic cholangiocarcinoma prior to enrollment in this trial is permitted.
2. Patients with multiple primary cancers (with the exception of completely resected
basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ,
intramucosal carcinoma, or superficial bladder cancer, or any other cancer that has
not recurred for at least 5 years)
3. Patients with residual adverse effects of prior therapy or effects of surgery that
would affect the safety evaluation of the investigational product in the opinion of
the investigator or sub-investigator.
4. Patients with current or past history of severe hypersensitivity to any other
antibody products
5. Patients with concurrent autoimmune disease or history of chronic or recurrent
autoimmune disease
6. Patients with a current or past history of interstitial lung disease or pulmonary
fibrosis diagnosed based on imaging or clinical findings. Patients with radiation
pneumonitis may be enrolled if the radiation pneumonitis has been confirmed as
stable (beyond acute phase) without any concerns about recurrence.
7. Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerative
disease
8. Patients with any metastasis in the brain or meninx that is symptomatic or requires
treatment. Patients may be enrolled if the metastasis is asymptomatic and requires
no treatment.
9. Patients with pericardial fluid, pleural effusion, or ascites requiring treatment
10. Patients with uncontrollable, tumor-related pain
11. Patients who have experienced a transient ischemic attack or cerebrovascular
accident within 180 days before enrollment
12. Patients with a history of uncontrollable or significant cardiovascular disease
meeting any of the following criteria:
1. Myocardial infarction within 180 days before enrollment
2. Uncontrollable angina pectoris within 180 days before enrollment
3. New York Heart Association (NYHA) Class III or IV congestive heart failure
4. Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood
pressure ≥150 mmHg or diastolic blood pressure ≥ 90 mmHg lasting 24 hours or
more)
5. Arrhythmia requiring treatment
13. Patients with uncontrollable diabetes mellitus
14. Patients with systemic infections requiring treatment (infection controlled by oral
antibiotics is permitted)
15. Patients who have received systemic corticosteroids (prednisolone or equivalent >
10mg/day) (except for temporary use, e.g., for examination or prophylaxis of
allergic reactions) or immunosuppressants within 28 days before enrollment
16. Patients who have received antineoplastic drugs (e.g., chemotherapy agents,
molecular-targeted therapy agents, or immunotherapy agents) within 28 days before
enrollment
17. Patients who have undergone surgical adhesion of the pleura or pericardium within 28
days before enrollment
18. Patients who have undergone surgery under general anesthesia within 28 days before
enrollment
19. Patients who have undergone surgery involving local or topical anesthesia within 14
days before enrollment
20. Patients who have received radiotherapy within 28 days before enrollment, or
radiotherapy to bone metastases within 14 days before enrollment
21. Patients who have received any radiopharmaceuticals (except for examination or
diagnostic use of radiopharmaceuticals) within 56 days before enrollment
22. Patients with a positive test result for any of the following: HIV-1 antibody, HIV-2
antibody, HTLV-1 antibody, HBs antigen, or HCV antibody
23. Patients with active hepatitis B or C virus (Hepatitis patients can enrolled if HBV
DNA and HCV RNA are controlled to less than 500 and are receiving stable antiviral
treatment.)
24. Women who are pregnant or breastfeeding, or possibly pregnant
25. Patients who have received any other unapproved drug (e.g., investigational use of
drugs, unapproved combined formulations, or unapproved dosage forms) within 28 days
before enrollment
26. Patients who have previously received Nivolumab, anti-PD-1 antibody, anti-PD-L1
antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody or other
therapeutic antibodies or pharmacotherapies for regulation of T-cells
27. Patients judged to be incapable of providing consent for reasons such as concurrent
dementia
28. Other patients judged by the investigator or sub-investigator to be inappropriate as
subjects of this study
29. Patient with current or past history of hypersensitivity to Nivolumab.
Gender:
All
Minimum age:
19 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Severance Hospital, Yonsei University Health System
Address:
City:
Seoul
Country:
Korea, Republic of
Contact:
Last name:
Choong-kun Lee
Phone:
82-2-2228-3122
Email:
cklee512@yuhs.ac
Start date:
March 2023
Completion date:
February 2027
Lead sponsor:
Agency:
Yonsei University
Agency class:
Other
Source:
Yonsei University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05749900
