| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052399 |
| E.1.2 | Term | Neuroendocrine tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059514 |
| E.1.2 | Term | Small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017758 |
| E.1.2 | Term | Gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075333 |
| E.1.2 | Term | Soft tissue sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002240 |
| E.1.2 | Term | Anaplastic thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
To evaluate the safety and tolerability of surufatinib, thereby determining the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of surufatinib in combination with tislelizumab.
Part 2
To evaluate the objective response rate (ORR) as assessed by the investigator in patients with advanced solid tumors when treated with surufatinib in combination with tislelizumab according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 |
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| E.2.2 | Secondary objectives of the trial |
Part 1
• To evaluate the antitumor activity in patients with advanced solid tumors when treated with surufatinib in combination with tislelizumab according to RECIST v1.1
• To characterize the pharmacokinetics (PK) and immunogenicity of tislelizumab and surufatinib in combination
Part 2
• To evaluate further anticancer effects of surufatinib in combination with tislelizumab
• To characterize the safety and tolerability of surufatinib in combination with tislelizumab
• To characterize the PK and immunogenicity of tislelizumab and
surufatinib in combination |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing, able to provide informed consent signed by study patient or legally acceptable representative, as specified by health authorities and institutional guidelines
2.≥18 years of age
3.Part 1:have evaluable lesions(according to Response Evaluation Criteria in Solid Tumors version 1.1[RECIST v1.1])
Part 2:have measurable lesions(according to RECISTv1.1)
4.Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL
5.Serum total bilirubin (TBIL) <1.5 times the upper limit of normal (ULN)
6.Proteinuria <2+ by urinalysis;if proteinuria ≥2+, proteinuria <1 g by 24-hour urinary protein test is required
7.Patients without liver metastases must have alanine aminotransferase (ALT) and/or AST levels≤2.5 times the ULN.Patients with liver metastases must have ALT and AST levels ≤5 times the ULN
8.Creatinine clearance ≥45 mL/min as calculated by the Cockcroft-Gault formula
9.International normalized ratio (INR) ≤1.5×ULN and activated partial thromboplastin time (aPTT) ≤1.5×ULN,unless the patient is currently receiving anticoagulants for prophylactic purposes
10.Have a performance status of 0 or 1 on the ECOG scale
11.Female patients of childbearing potential and male patients with partners of childbearing potential agree to use a highly effective form(s) of contraception that results in a low failure rate when used consistently and correctly
Dose Escalation
12.Histologically or cytologically documented,locally advanced or metastatic solid malignancy of any type that has progressed on or are intolerant of standard therapies and for which no curative therapy exists
Dose Expansion
13.Histologically or cytologically documented, locally advanced or metastatic
a.Cohort A:adenocarcinoma of the colon or rectum that is microsatellite stable.Patients must have progressed on, or had discontinued due to intolerable toxicity to the following agents: fluoropyrimidine, oxaliplatin, irinotecan,an anti-VEGF targeted therapy,and if RAS wild-type and anti epidermal growth factor receptor antibody therapy.Treatment progression is defined as disease progression during or within 3 months after the last dose of standard therapy.Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment.Patients must have been previously treated with fluoropyrimidine-,oxaliplatin-,and irinotecan-based chemotherapy;an anti-VEGF biological therapy;and,if RAS wild-type,an anti-epidermal growth factor receptor antibody therapy
a.Cohort B:progressive, low, or intermediate grade(Grade 1 or Grade 2)NETs of thoracic(B1) or GEP(B2) origins.Patients must have radiological documentation of progression of disease in the last 6 months prior to the initiation of study treatment and must have progressed on at least 1 line of standard therapy for metastatic disease
i.For NETs originating from the thorax
A.Grade 1 is defined as<2 mitoses/10 high-power field(HPF) and no necrosis
B.Grade 2 is defined as2-10/10HPF and/or foci of necrosis
ii.For NETs originating from GEP
A.Grade 1 is defined as <2 mitoses/10 HPF and/or<3% Ki-67 index
B.Grade 2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index
iii.If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade is used to assign classification
iv.Patients who have functioning NETs and have been on a stable dose of an SSA for a minimum of 2 months prior to the first dose of study treatment for control of their secretory symptoms will be eligible
c.Cohort C:SCLC that has progressed on standard first line chemotherapy treatment
d.Cohort D:Adenocarcinoma of the stomach or gastroesophageal junction and have progressed on at least 2 prior lines of therapy.Must be microsatellite stable and have tumor stain for PD-L1 by combined positive score ≥5%
e.Cohort E:ASPS(E1) or UPS(E2).Patients must have radiological documentation of disease progression in the last 3 months prior to the initiation of study treatment and have progressed on at least 1 line of standard therapy or refused standard frontline cytotoxic chemotherapy
f.Cohort F:Anaplastic thyroid cancer(a diagnosis that is noted to be consistent with anaplastic thyroid cancer is acceptable)that is considered not curable by resection.Patients with a BRAFV600E mutation must have previously been treated with 1 line of systemic therapy with a BRAF-targeted therapy.Prior cytotoxic chemotherapy and radiation for local disease control is not considered a prior line of therapy
14.Patients in dose expansion: must be able to provide a minimum of 10 unstained slides for central confirmation of PD-L1 expression and microsatellite stability testing.In the event archived tumor samples not available for testing, patients may opt for a core needle biopsy prior to beginning protocol therapy if medically feasible.Patients in Cohort F must also undergo core needle biopsy
Please refer to protocol for full list of inclusion criteria |
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| E.4 | Principal exclusion criteria |
1. AEs due to previous antitumor therapy has not recovered to CTCAE ≤Grade 1, except alopecia and peripheral neurotoxicity with CTCAE ≤Grade 2
2. Part 2 patients with CRC (Cohort A), NETs (Cohort B), STS (Cohort E), and ATC (Cohort F): previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway
Note: Patients in the Part 1 and patients in Part 2 Cohorts C and D (SCLC and GC) may have received previous treatment with anti-PD-1, anti-PD-L1/L2 antibodies, CTLA-4 antibody, or any other antibody acting on T cell costimulatory or checkpoint pathway;
3. Previous treatment with surufatinib
4. Uncontrollable hypertension, defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg
5. Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, active gastric and duodenal ulcers, ulcerative colitis and other digestive disease, gastrointestinal tumor with active bleeding, or other gastrointestinal
conditions that may cause bleeding or perforation by investigator's discretion
6. History or presence of a serious hemorrhage (>30 mL within 3 months), hemoptysis (>5 mL blood within 4 weeks), or life-threatening thromboembolic event within 6 months
7. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, congestive heart failure according to the New York Heart Association classification ≥2, ventricular arrhythmias which need drug treatment, or left ventricular ejection fraction (LVEF) <50%
8. QT interval corrected by the method of Fredericia (QTcF) ≥480 milliseconds
9. Other malignant tumors within 5 years prior to screening (except cured basal-cell carcinoma or squamous carcinoma at skin and cervical carcinoma in situ)
10. Antitumor therapy received within 2 weeks or 5 half-lives, whichever is shorter, prior to the initiation of the investigational treatment, including, but not limited to, chemotherapy, radical radiotherapy, targeted therapy, immunotherapy, hepatic embolization, cryoablation, and radiofrequency ablation
11. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the study treatment
12. Strong inducers or inhibitors of Cytochrome P450, family 3, subfamily A (CYP3A) taken within two weeks prior to the first study treatment
13. Any clinically significant active infection, including, but not limited to, known human immunodeficiency virus (HIV) infection
14. Known history of active viral hepatitis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with hepatitis c virus (HCV) infection who are currently on treatment
are eligible if they have an undetectable HCV viral load. Patients with an unknown history of viral hepatitis must be screened for HBV with HBs antigen; HBc antibody and HBS antibody; and HBV-DNA, if indicated and for HCV with HCV antibody.
a. Patients with detectable HBsAg or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for >2 weeks before the first dose of study treatment.
b. Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody.
15. Brain metastases and/or leptomeningeal disease and/or spinal cord compression untreated with surgery and/or radiotherapy and without clinical imaging evidence of stable disease (SD) for 14 days or longer. Patients requiring steroids within 4 weeks prior to start of study treatment will be excluded.
16. Used corticosteroids (prednisone or other steroids with equivalent efficacy at a dose of >10 mg/day) or other immunosuppressants for systemic therapy within 2 weeks before the first drug administration. Nasal spray, inhaled, or other topical steroids are allowed (ie, ≤10 mg/day of prednisone or other glucocorticoids at an equivalent dose)
17. For patients with NETs: administration of SSAs in the absence of secretory symptoms discontinued at least 4 weeks before the first dose of study treatment;
18. Active autoimmune diseases or history of autoimmune diseases that may relapse.
19. Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the duration of the study
20. Major surgeries within 60 days prior to first dosing
21. Uncontrollable malignant pleural effusion, ascites, or pericardial effusion.
Please refer to protocol for complete list of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
Safety including dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events (AEs) leading to discontinuation, ECGs, clinical laboratory abnormalities, and vital signs
Part 2
Objective Response Rate (ORR) at 12 weeks |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Part 1: as stated in endpoint and for part 2: ORR at 12 weeks |
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| E.5.2 | Secondary end point(s) |
Part 1
ORR, progression-free survival (PFS), disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), time to response (TTR)
• Concentrations of surufatinib in plasma and tislelizumab in serum
• Incidence of antidrug antibodies (ADA) to tislelizumab
Part 2
• PFS, DCR, CBR, DoR, TTR
• OS: Cohorts A and F
• Safety including TEAEs, SAEs, AEs leading to discontinuation, electrocardiograms (ECGs), clinical laboratory abnormalities, and study drug discontinuation due to AEs
• Concentrations of surufatinib in plasma and tislelizumab in serum
• Incidence of ADA to tislelizumab |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the study assessments in the protocol |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, biomarkers assessments |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the last visit of the last patient in the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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