| Eligibility |
Inclusion Criteria:
1. Understand and voluntarily sign the informed consent form;
2. 18= age = 75 years old, male or female;
3. Arms A and B, including the Dose Escalation Phase (Phase Ib) and Cohort Expansion
Phase (Phase II):
- Patients with histologically or cytologically confirmed recurrent/metastatic
HR-positive and HER2-negative breast cancer;
- HER2 negative must meet one of the following: IHC 0, IHC 1+; IHC2+ should be
further confirmed by in situ hybridization (ISH) to determine HER2 negative, and
different tissue blocks can also be selected for re-testing;
- ER-positive and/or PR-positive: ER-positive requires >10% of tumor cell nuclei in
the whole section to express ER;
- For females, either postmenopausal or premenopausal/perimenopausal can be
enrolled: postmenopausal, defined as meeting at least one of the following
criteria: 1) age = 60 years, 2) age < 60 years, and amenorrhea = 12 months, and
follicle-stimulating hormone and estradiol levels in the postmenopausal range in
the absence of chemotherapy, endocrine therapy, or ovarian function suppression
therapy, 3) prior bilateral oophorectomy. Premenopausal or perimenopausal (i.e.,
does not meet postmenopausal criteria) and meets the following criteria: Started
at least 2 weeks before the first dose of study drug and continuously treated
with luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin or
leuprolide) for the duration of study treatment
- For stage Ib, the patient has disease progression during or after prior endocrine
therapy or other systemic therapy, with no limit on the number of prior lines of
therapy;
- For Group A Phase II, patients meet the following criteria: disease progression
or recurrence during or after prior treatment with AI with or without CDK4/6
inhibitors, =2 lines of systemic therapy in advanced breast cancer, =1 line of
chemotherapy (neoadjuvant/adjuvant chemotherapy is not counted as a line of
chemotherapy), and > after completion of (neo)adjuvant endocrine therapy patients
with recurrence at 12 months must receive 1 to 2 lines of systemic therapy for
advanced disease to be enrolled;
- For Group B stage II, patients who meet: recurrence during or = 12 months after
completion of (neo)adjuvant endocrine therapy or disease progression after
receiving 1st line of endocrine therapy in the advanced stage, = 1st line
chemotherapy in the advanced breast cancer stage are allowed;
4. Arm C, including the Dose Escalation Phase (Phase Ib) and Cohort Expansion Phase
(Phase II):
- Patients with histologically or cytologically confirmed recurrent/metastatic
endometrial and cervical cancer;
- Disease progression or intolerance to standard therapy after receiving =1 line of
systemic therapy;
5. Group D, including the Dose Escalation Phase (Phase Ib) and Cohort Expansion Phase
(Phase II):
¦ Patients with histologically or cytologically confirmed recurrent/metastatic
triple-negative breast cancer or patients with advanced gynecologic tumors (including
patients with epithelial ovarian, fallopian tube or primary peritoneal cancer,
endometrial cancer, and cervical cancer);
- Disease progression or intolerance to standard therapy after receiving =1 line of
systemic therapy;
- For stage II, in the case of ovarian cancer, must be a
platinum-resistant/platinum-refractory patient (defined as disease progression
during or within 6 months of completion of platinum-containing chemotherapy) For
groups A, B, and D, stage Ib can be enrolled regardless of whether PIK3CA is
mutated or not, and stage II should have PIK3CA activating mutations, which are
determined by the central laboratory to be PIK3CA activating mutations by the
sponsor. The test results of the preferred tissue sample are used as the basis
for enrollment, and for patients who are truly unable to provide a tissue sample
that meets the requirements, a positive PIK3CA mutation of the ctDNA test is
allowed as the basis for enrollment.
6. Arm E, including the Dose Escalation Phase (Phase Ib) and Cohort Expansion Phase
(Phase II):
- Patients with histologically or cytologically confirmed recurrent/metastatic
triple-negative breast cancer or epithelial ovarian, fallopian tube, or primary
peritoneal cancer
- Disease progression or intolerance to standard therapy after receiving =1 line of
systemic therapy
- For stage II, in the case of ovarian cancer, must be a
platinum-resistant/platinum-refractory patient (defined as disease progression
during or within 6 months of completion of platinum-containing chemotherapy)
7. Arm F, including the Dose Escalation Phase (Phase Ib) and Cohort Expansion Phase
(Phase II):
¦ Patients with histologically or cytologically confirmed recurrent/metastatic
HER2-positive breast cancer;
¦ Disease progression or intolerance to standard therapy after receiving =1 line of
anti-HER2 therapy;
8. Group G: including Dose Escalation Phase (Phase Ib) and Cohort Expansion Phase (Phase
II):
- Patients with histologically or cytologically confirmed triple-negative breast
cancer, i.e., HER2, ER, PR are all negative;
- Patients with first-diagnosed stage IV (AJCC 8th edition) or recurrent/metastatic
triple-negative breast cancer who are not candidates for surgical treatment, and
have not received prior systemic therapy for advanced disease;
9. Agree to provide tumor tissue and blood samples for PIK3CA mutation testing required
for enrollment:
¦Tumor tissue specimens: fresh or archival unstained sections, preferably from tumor
samples collected after the most recent disease progression or recurrence.
Formalin-fixed, paraffin-embedded (FFPE) unstained sections (at least 5 surgical
samples and 10 needle biopsy samples are recommended) are required. For patients who
are unable to provide tissue samples or the number of sections is insufficient, it is
necessary to communicate with the sponsor whether they can be enrolled;
¦Freshly collected pre-treatment blood sample of at least 10ml
10. All acute toxicities due to prior antineoplastic therapy, surgery, or radiotherapy,
etc., resolved to Grade 0-1 (according to NCI CTCAE version 5.0) or the level
specified by the enrollment/exclusion criteria. Except for alopecia, pigmentation, or
other toxicities that, in the opinion of the investigator, do not pose a safety risk
to the patient and do not affect treatment compliance;
11. At least one measurable lesion (only for Phase II cohort expansion phase) or
non-measurable osteolytic or mixed bone lesion (for breast cancer patients only) that
meets the requirements of RECIST v1.1;
12. Eastern Cooperative Oncology (ECOG) performance status score: 0 or 1;
13. Expected survival = 12 weeks;
14. Ability to swallow oral medications (capsules and tablets) without chewing, breaking,
crushing, opening, or otherwise altering the dosage form of the product;
15. Functions of vital organs, in line with the requirements:
a. No blood transfusion blood products or hematopoietic growth factors to correct the
blood cell count within 14 days before the examination creatinine clearance was
calculated using the Cockcroft/Gault formula: Creatinine clearance (mL/min) =
(140-age)× Body weight (kg) ×(0.85 [females only]) 72 × serum creatinine (mg/dl) c.
For patients with FPG = 100 mg/dL and/or HbA1c = 5.7% (eg, prediabetes threshold)
during the screening period, lifestyle changes such as dietary prescription (eg, small
and frequent meals, low-carb diet, high-fiber diet, etc.) and exercise are recommended
according to ADA guidelines, and endocrinologist consultation is recommended.
d. Patients receiving anticoagulant therapy (such as low molecular weight heparin or
warfarin) should be stable at the dose of anticoagulant drugs for at least 4 weeks
without dose adjustment; e. Only urine routine showed urine protein =2+, and
additional 24-hour urine protein quantification was required
16. Within 7 days before the first dose of study drug, females of childbearing potential
must confirm that the serum HCG test is negative and non-lactating, and female
patients, as well as male patients whose partner is a female of childbearing age, need
to use highly effective contraception during study treatment and within 30 days after
the last dose of JS105 or during the contraceptive period specified in the label of
other antineoplastic drugs, whichever occurs later, (see section 10.3 for the
definition of WOCBP);
Exclusion Criteria:
1. Prior treatment with PI3K/AKT/mTOR inhibitors, prior treatment with fulvestrant and
other SERDs (applicable to phase II of group A and phase II of group B);
2. Patients with known hypersensitivity to JS105 and/or the corresponding group of
combination drug components;
3. Received the following treatments before the first dose of the study drug:
1) Major surgery or radiotherapy within 4 weeks, or anticipated major surgery (except tumor
biopsy) or radiotherapy during the study; 2) Systemic chemotherapy within 4 weeks (6 weeks
for nitrosourea or mitomycin; oral fluorouracil can be shortened to 2 weeks or 5 half-lives
of the drug, whichever is longer), targeted therapy (small molecule targeted drugs can be
shortened to 2 weeks or 5 half-lives of the drug, whichever is longer), immunotherapy or
biological therapy; 3) Receiving endocrine therapy or proprietary Chinese medicine
preparations with anti-tumor indications within 2 weeks.
4) Other clinical investigational drugs (without placebo) within 4 weeks; 5) Vaccination
with live attenuated vaccine within 4 weeks; 6) Received drug treatment with a known strong
inhibitor or inducer of the isoenzyme CYP3A4 within 7 days (see Appendix 4 for a strong
inhibitor or inducer of the isoenzyme CYP3A4); 7) Need for long-term use or use of
=10mg/day prednisone and equivalent doses of systemic corticosteroids or immunosuppressive
drugs within 2 weeks before the first dose; 4. Previous allogeneic bone marrow
transplantation or solid organ transplantation; 5. Other malignancies other than study
disease within 5 years before the first dose, except for malignancies that can be expected
to heal after treatment (including but not limited to adequately treated thyroid cancer,
cervical carcinoma in situ, basal or squamous cell skin cancer, or ductal carcinoma in situ
of the breast treated with radical surgery); 6. Patients with symptomatic, untreated, or
ongoing central nervous system metastases requiring ongoing treatment (previously treated
patients who have been stable for at least 3 months, have no disease progression as
determined by imaging within 4 weeks before the first dose of the study, and all
neurological symptoms have returned to baseline, have no evidence of new or enlarging brain
metastases, and have stopped using radiation, surgery, or steroids at least 4 weeks before
the first dose of study treatment, may be enrolled); 7. Pleural effusion, pericardial
effusion, or ascites effusion (once a month or more frequent) that is uncontrolled or
requires repeated drainage. Patients who need to be stable for at least 1 week before
enrollment after drainage can be enrolled (stable is defined as no clear increase in
pleural effusion without any intervention); 8. Concomitant and uncontrollable concomitant
diseases, including but not limited to:
1. History of acute pancreatitis, history of chronic pancreatitis, or presence of
pancreatic metastases within one year before screening;
2. Presence of type I diabetes mellitus or history of uncontrolled type II diabetes;
3. Ongoing active infection, unexplained fever > 38.5°C
4. Severe cardiovascular disease, including but not limited to a history of stroke or
transient ischemic attack, angina pectoris, or myocardial infarction within 6 months
before the first dose of study treatment, documented history of congestive heart
failure (New York Heart Association Class II-IV) or cardiomyopathy, uncontrolled
cardiac arrhythmia, active ventricular arrhythmia requiring medication or related
history, symptomatic coronary heart disease or unstable angina;
5. History of interstitial pneumonia, drug-induced pneumonia, radiation pneumonitis
requiring steroid treatment, or active pneumonitis with clinical symptoms, or other
moderate to severe lung diseases that seriously affect lung function;
6. Presence of gastrointestinal insufficiency or gastrointestinal disease that may affect
the swallowing (taking) or absorption of the study drug (e.g., ulcerative disease,
uncontrolled vomiting, diarrhea, malabsorption syndrome, small bowel resection,
history of active inflammatory bowel disease (such as Crohn's disease or ulcerative
colitis), etc.); 9. Known human immunodeficiency virus (HIV) positive patient or
active hepatitis B or C, except for the following:
1) Hepatitis B core antibody (HBcAb) positive and hepatitis B surface antigen (HBsAg)
negative during the screening period can participate in this study; 2) Patients who are
HBsAg positive and whose HBV DNA is less than the lower limit of detection can be enrolled,
and the risk will be assessed by the investigator, if necessary, anti-HBV therapy should be
received throughout the study treatment period to avoid viral activation; 3) Patients with
positive HCV antibody can only be enrolled if the HCV RNA PCR test result is negative; 10.
Female patients who are pregnant, lactating, or intend to become pregnant during the study;
11. Any other clinically significant disease or condition that, in the opinion of the
investigator, could affect protocol compliance (such as a history of psychiatric illness or
substance abuse), or affect the patient's signing of informed consent (such as drug use and
substance abuse), or would be inappropriate to participate in this clinical study.
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