Overview
This is an open-label, phase I study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of GQ1005 and preliminary anti-tumor efficacy in HER2 expressing or mutated advanced malignant solid tumor subjects.
Eligibility
Inclusion Criteria:
The general inclusion criteria for dose escalation in Part 1 and dose expansion in Part 2
are as follows:
1. Voluntary agreement to provide written informed consent；
2. Aged 18 years or older, both male and female.
3. The expected survival time is more than 3 months.
4. ECOG performance status Score 0 or 1.
5. LVEF ≥ 50% by ECHO or MUGA scan within 28 days prior to the first dose of study drug.
6. Histologically or cytologically confirmed malignancy with at least 1 measurable lesion
as assessed by RECIST v1.1.
7. Good organ function, confirmed by the following laboratory test results at Screening
and within 7 days prior to the first dose of study drug:
Platelet count ≥ 100,000/mm3; hemoglobin ≥ 9g/dL; ANC ≥ 1500/mm3; Serum CREA ≤ 1.5 ×
ULN, or estimated CREA clearance ≥ 60 mL/min (Cockcroft-Gault equation); ALT and AST ≤
3 × ULN (≤ 5 x ULN if liver metastases are present); Total bilirubin ≤ 1.5 x ULN for
subjects with Gilbert's syndrome or ≤ 2 x ULN for subjects with liver metastases at
baseline; Prothrombin time and activated partial thromboplastin time ≤ 1.5 × ULN;
8. Adequate washout period prior to the first treatment, defined as follows:
Major surgery ≥ 4 weeks; radiotherapy ≥ 4 weeks (≥ 2 weeks if the radiotherapy is
palliative stereotactic radiotherapy without abdominal involvement); seed-radioactive
therapy ≥ 3 months; Nuclein therapy ≥ 3 months; autotransplantation ≥ 3 months;
Hormone therapy ≥ 2 weeks or as per investigator's judgment (breast cancer subjects)
Chemotherapy or targeted therapy (including antibody drug therapy) ≥ 2 weeks
(5-FU-based drugs, folinic acid preparations and/or weekly paclitaxel therapy);
- 2 weeks (or 5 half-lives, whichever is longer) (tyrosine kinase inhibitor);
- 4 weeks (HER2-targeted biological therapy);
- 6 weeks (nitrosourea or mitomycin C);
- 3 weeks (any other chemotherapy/targeted therapy);
- 2 weeks (Chinese patent medicine with clear antitumor indication) antitumor
immunotherapy ≥ 4 weeks; Any investigational drug or treatment ≥ 4 weeks; Strong
inhibitors of cytochrome P450 enzyme 3A4 (CYP3A4) ≥ 1 week; Organic Anion
Transport Polypeptide (OATP) Inhibitors ≥ 1 week;
Inclusion criteria for the dose escalation phase of Part 1 only:
9. Failure of standard treatment, or intolerance, or absence of standard treatment,
confirmed by pathology, HER2 expression (including IHC1+, IHC2+, IHC3+ and/or ISH+)
or subjects with advanced/unresectable or metastatic solid tumors with HER2 exon 19 or
20 mutations (non-small cell lung cancer only). If only ISH, NGS reports are
available, contact the Medical Monitor.
Inclusion criteria for part 2a only:
10. Failure of standard treatment, intolerance, or absence of standard treatment,
confirmed by pathology, HER2 overexpression (IHC 3+ or IHC 2+ and ISH* +)
Advanced/unresectable or metastatic breast cancer.
Inclusion criteria for part 2b only:
11. Advanced breast cancer with low HER2 expression, unresectable, or metastatic breast
cancer that has failed standard treatment, or is not tolerated, or has no standard
treatment, is confirmed by pathology. (IHC 2+ and ISH*- or ISH unknown, or IHC 1+).
Inclusion criteria for part 2c only:
12. Non-small cell lung cancer with a HER2 exon 19 or 20 mutation that has failed, or is
not tolerated, or is confirmed by a documented pathology without standard treatment.
Inclusion criteria for part 2d only:
13. Advanced/unresectable or metastatic solid tumors with HER2 expression that have failed
standard therapy, are not tolerated, or are without standard therapy, and are
confirmed by pathology, with HER2 overexpression preferred. (IHC 3+ or IHC 2+ or ISH
+) Adenocarcinoma of gastric and gastroesophageal junction; Other preferred tumor
types include HER2 overexpression. (IHC 3+ or IHC 2+ or ISH +) Urothelial cancer,
biliary tract cancer, endometrial cancer; Breast cancer and non-small cell lung cancer
are excluded.
- ISH+: FISH or two-color in situ hybridization (DISH).
Exclusion Criteria:
Subjects must not meet any of the following exclusion criteria to be enrolled in the study.
1. Clinically active brain metastases, defined as untreated and symptomatic, or requiring
treatment with steroids or anticonvulsants to control associated symptoms. Subjects
with treated asymptomatic brain metastases who do not require steroid therapy may be
included in the study if they have recovered from the acute toxicity of radiation
therapy.
2. Cardiovascular dysfunction or clinically significant cardiac conditions, including but
not limited to:
- Symptomatic CHF (New York Heart Association classes II to IV) or severe cardiac
arrhythmia requiring treatment
- History of myocardial infarction or troponin levels consistent with myocardial
infarction (defined by the American College of Cardiology guidelines) within 6
months prior to the first dose, and unstable angina pectoris within 6 months
prior to the first dose of study drug;
- QTcF prolongation at Screening >460 milliseconds (ms) (male) and >470 ms (female)
except for right bundle branch block.
3. Clinically significant acute and chronic lung disease. (e.g., interstitial pneumonia,
pulmonary infection, pulmonary fibrosis, and severe radiation pneumonitis), or
subjects with suspected pulmonary disease based on imaging at screening, or subjects
requiring oxygen.
4. People with known hypersensitivity to recombinant humanized anti-HER2 monoclonal
antibody-DXd conjugate drugs and their components or to humanized monoclonal antibody
products.
5. Poorly controlled pleural, ascites, or pericardial effusions.
6. Toxicity that has not resolved from prior antineoplastic therapy, defined as toxicity
(other than alopecia) that has not resolved to ≤ Grade 1 or baseline levels, is at the
discretion of the investigator for the eligibility of subjects with chronic Grade 2
toxicities.
7. The prior anthracycline exposure dose met the following criteria: adriamycin >
500mg/m2; Epirubicin >900mg/m2; Pirarubicin > 950mg/m2; Mitoxanthraquinone >120mg/m2;
other (i.e. liposomal doxorubicin or other anthracycline >equivalent to 500 mg/m2 of
doxorubicin); If more than one anthracycline is used, the cumulative dose must not
exceed the equivalent of 500 mg/m2 of doxorubicin.
8. There is an active infection requiring treatment with intravenous antibiotics,
antivirals, or antifungals.
9. Known HIV infection.
10. Active hepatitis C virus infection. (HCV antibody positive and HCV-RNA higher than the
upper limit of reference value); Active hepatitis B virus infection. (HBsAg positive
and/or HBcAb positive and HBV-DNA quantitation ≥2000 IU/ml);, to be eligible for
enrollment, subjects with chronic hepatitis B will have to agree to monthly DNA
testing and receive appropriate antiviral therapy as indicated.
11. Live vaccine was administered within 30 days prior to the first dose of study drug.
12. Previous or current evidence of any concomitant disease, treatment, or laboratory
abnormality that the investigator believes may confound the results of the trial or
interfere with subject participation and compliance.
13. He has received treatment with an antibody-conjugated drug comprising a topoisomerase
I inhibitor ezotecan derivative.
14. Breastfeeding women or women with confirmed pregnancy by a pregnancy test within 7
days prior to the first treatment.
15. Reluctant to contraception during the study and for at least 7 months after the last
dose of study drug.
16. Subjects with multiple primary malignancies within the past 3 years, with the
exception of fully resected non-melanoma skin cancer, cured disease in situ, cured
contralateral breast cancer.