Advanced Solid Tumors
Conditions
Brief summary
This study is an open-label, multicenter, Phase Ib/II clinical study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of JS105 in combination with other anti-tumor therapies in patients with advanced solid tumors. Patients will be enrolled in two stages: a dose-escalation stage and a dose-expansion stage.
Interventions
DRUGJS105
JS105 is administered once daily, orally
Fulvestrant intramuscularly,The first cycle was injected once in D1 and D15, and then once in each cycle D1, and 28 days was 1 cycle
Dalpiciclib Isetionate Tablets, QD, oral, taken continuously for 21 days, then stopped for 7 days, 28 days for a cycle
DRUGToripalimab Injection
Toripalimab Injection,Intravenous infusion, once every 3 weeks, 21 days for 1 cycle
Paclitaxel for Injection (Albumin Bound),Intravenous infusion, D1, 8, 15 infusion, every 28 days for a cycle
Fluzoparib Capsules is administered once daily, orally
Pyrotinib Maleate Tablets is administered once daily, orally
DRUGCapecitabine Tablets
Capecitabine Tablets is administered once daily, orally
Sponsors
Risen (Suzhou) Pharma Tech Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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);
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events including serious adverse events | Up to 2 years | Abnormal changes in clinical symptoms, vital signs, physical examination, laboratory tests, electrocardiograph and other examinations. |
| Dose-limiting toxicity | At the end of Cycle 1 (each cycle is 28 days) | Incidence and severity of DLT events. |
| MTD | At the end of Cycle 1 (each cycle is 28 days) | Maximum tolerated dose |
| RP2D | At the end of Cycle 1 (each cycle is 28 days) | Recommended phase II dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 2 years | Progression-Free Survival (PFS) as Determined by Investigator according to RECIST v1.1 |
| Overall Survival (OS) | Up to 2 years | Overall Survival (OS) |
| AUC of JS105,dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Area under the curve of JS105,dalpiciclib and fluzoparib |
| Tmax of JS105, dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Time to reach maximum concentration of JS105,dalpiciclib and fluzoparib |
| Vz/F of JS105, dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Apparent volume of distribution of JS105, dalpiciclib and fluzoparib |
| Clearance(CL) of JS105, dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Clearance(CL) of JS105, dalpiciclib and fluzoparib |
| Half-life(T1/2) of JS105, dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Half-life(T1/2) of JS105, dalpiciclib and fluzoparib |
| Cmax of JS105,dalpiciclib and fluzoparib | At pre-defined intervals up to 2 years | Maximum Plasma Concentration (Cmax) of JS105, dalpiciclib and fluzoparib |
| Objective Response Rate (ORR) | Up to 2 years | Objective Response Rate (ORR) as Assessed by Investigator according to RECIST v1.1 |
| Duration of Objective Response (DOR) | Up to 2 years | Duration of Objective Response (DOR) as Assessed by Investigator according to RECIST v1.1 |
| Disease Control Rate(DCR) | Up to 2 years | Disease Control Rate(DCR) |
Other
| Measure | Time frame | Description |
|---|---|---|
| The proportion of patients with PIK3CA mutations in tumor remission | Up to 2 years | The proportion of patients with PIK3CA mutations in tumor remission |
Countries
China
Outcome results
None listed