Clinical trial NCT03816553: SHR-1210 in Combination With Apatinib in Patients With Metastatic, Persistent, or Recurrent Cervical Cancer
Official title: SHR-1210, a Novel Anti-pd-1 Antibody, in Combination With Apatinib in Patients With Metastatic, Persistent, or Recurrent Cervical Cancer: a Single-arm, Open Label, Multi-center, Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Cervical Carcinoma
Metastatic Cervical Cancer
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2019-01-25
Enrollment: 45
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to explore the efficacy and safety of SHR-1210 in combination with apatinib in treating patients with metastatic, persistent, or recurrent cervical cancer.

Detailed description: SHR-1210 is a humanized monoclonal antibody against Programmed death 1(PD-1). Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) selectively inhibits Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2). Patients with metastatic, persistent, or recurrent cervical cancer who failed to first-line chemotherapy +/- bevacizumab will received SHR-1210 200mg (3mg/kg for underweight patients) iv every 2 weeks and apatinib 250mg orally once daily. The efficacy and safety will be observed.

Eligibility criteria: Inclusion Criteria:

1. Patients must have metastatic, recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy;
2. Age ≥ 18 years and ≤ 70 years;
3. Patients must have measurable disease per RECIST 1.1; measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded as ≥ 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI),; a lymph node must be ≥ 15 mm in short axis. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Life expectancy exceeds 3 months;
6. Patients must have had at least one prior systemic chemotherapeutic regimen for management of recurrent, persistent or metastatic carcinoma of the cervix.

   Note: Prior adjuvant therapy is NOT counted as a systemic chemotherapeutic regimen for management of recurrent, persistent or metastatic carcinoma of the cervix; adjuvant therapy includes cisplatin given concurrent with primary radiation therapy (CCRT) and adjuvant chemotherapy given following the completion of concurrent chemotherapy and radiation therapy
7. Patients must have adequate organ function

   * Absolute neutrophil count (ANC) ≥ 1.5×10\^9/L
   * Platelet count ≥ 80 × 10\^9/L
   * Hemoglobin ≥ 90 g/L
   * Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
   * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (however, patients with known liver metastasis who have AST or ALT level ≤ 5 × ULN may be enrolled)
   * Creatinine ≤ 1.5 × ULN or creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula)
   * Baseline albumin ≥ 28 g/L
   * Thyroid-stimulating hormone (TSH) levels ≤ 1 × ULN (however, patients with free Triiodothyronine \[FT3\] or free Thyroxine \[FT4\] levels ≤ 1 × ULN may be enrolled)
8. Written informed consent.

Exclusion Criteria:

1. Histopathologic diagnoses of tumors other than squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.
2. Participated in other clinical trials, or finish other clinical trials within 4 weeks.
3. Prior exposure to immune checkpoint inhibitors, including but not limited to other anti-PD-1 and anti-PD-L1 antibodies, or prior exposure to apatinib.
4. Known history of hypersensitivity to any components of the SHR-1210 formulation, or other monoclonal antibody.
5. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses \> 10 mg/day prednisone or equivalent are prohibited within 2 weeks before study drug administration.
6. Patients with any active autoimmune disease or history of autoimmune disease, including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism, except for subjects with vitiligo or resolved childhood asthma/atopy. Asthma that requires intermittent use of bronchodilators or other medical intervention should also be excluded.
7. Clinically significant cardiovascular diseases, including but not limited to congestive heart failure (New York heart association (NYHA) class \> 2), unstable or severe angina, severe acute myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia which need medical intervention, or QT interval male ≥ 450 ms, female ≥ 470 ms.
8. Arterial thrombus or phlebothrombosis within 6 months.
9. Hypertension that can not be well controlled through antihypertensive drugs (systolic pressure ≥ 140 mm Hg and/or diastolic pressure ≥ 90 mm Hg)
10. Proteinuria ≥ (++) or 24 hours total urine protein \> 1.0 g.
11. Coagulation abnormalities (INR\>2.0、PT\>16s), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy.
12. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events (except for alopecia) due to a previously administered agent.
13. Has known active central nervous system metastases.
14. Patients with a prior invasive malignancy who have had any evidence of disease within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
15. Has an active infection requiring systemic therapy.
16. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease.
17. Hepatitis B virus (HBV) \>2000 IU/ml or DNA ≥ 1×10\^4/ml; or hepatitis C virus (HCV) RNA ≥ 1×10\^3/ml).
18. Has received a live vaccine within 4 weeks prior to the first dose of trial treatment. Note: Injection of inactivated viral vaccines against seasonal influenza are allowed.
19. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 12 months
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 24 months
measure: Overall survival (OS)
timeFrame: Up to approximately 24 months
measure: 6-month PFS rate
timeFrame: From date of enrollment up to 6 months
measure: 9-month OS rate
timeFrame: From date of enrollment up to 9 months
measure: Duration of Response (DCR)
timeFrame: Up to approximately 24 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 24 months
measure: Incidence of Adverse Events (AEs) in the treatment of SHR1210 in combination with apatinib
timeFrame: Up to approximately 24 months
Other outcomes:
measure: Impact of the treatment on Quality of Life (QOL) measured by the Functional Assessment of Cancer Therapy (FACT)-Cervical Trial Outcome of Index (FACT-Cx TOI)
timeFrame: Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months
measure: Pain assessed by Brief Pain Inventory (BPI)
timeFrame: Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months
measure: PD-L1 expression on tumor and immune cells
timeFrame: Up to approximately 24 months
measure: Tumor Mutation Burden (TMB)
timeFrame: Up to approximately 24 months
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
city: Guangzhou
country: China
facility: Guangzhou Panyu Central Hospital
state: Guangdong
city: Guanzhou
country: China
facility: The First affiliated Hospital of Sun Yat-sen University
state: Guangdong
Study officials:
References:
citation: Wang Y, Lai Y, Peng H, Yan S, Liu Z, Tong C, Huang X. Multiparametric immune profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: an exploratory study of the CLAP trial. Clin Transl Oncol. 2023 Jan;25(1):256-268. doi: 10.1007/s12094-022-02945-1. Epub 2022 Sep 17.
citation: Huang X, He M, Peng H, Tong C, Liu Z, Zhang X, Shao Y, Zhu D, Zhang J, Yin JC, Yang F, Lan C. Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial. J Immunother Cancer. 2021 May;9(5):e002223. doi: 10.1136/jitc-2020-002223.
citation: Lan C, Shen J, Wang Y, Li J, Liu Z, He M, Cao X, Ling J, Huang J, Zheng M, Zou G, Yan H, Liu Q, Yang F, Wei W, Deng Y, Xiong Y, Huang X. Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial. J Clin Oncol. 2020 Dec 1;38(34):4095-4106. doi: 10.1200/JCO.20.01920. Epub 2020 Oct 14.