Phase 2 Study to Evaluate the Clinical Efficacy and Safety of Sintilimab Plus Low-dose Bevacizumab in Patients With Astrocytoma of Different Relapse Stages
Overview
- Phase
- Phase 2
- Intervention
- Tislelizumab plus Bevacizumab
- Conditions
- Astrocytoma of Brain
- Sponsor
- Henan Provincial People's Hospital
- Enrollment
- 70
- Locations
- 1
- Primary Endpoint
- Overall survival rate at 24 months (Cohort 2)
- Status
- Not yet recruiting
- Last Updated
- 3 years ago
Overview
Brief Summary
This is an ongoing Phase 2, open-label, single-center, non-randomized study of sintilimab (one anti-PD-1 antibody same as nivolumab approved in China) plus bevacizumab administered in a low dosage schedule in adult (≥ 18 years) participants with a clinical relapse or circulating tumor DNA (ctDNA)-level relapse of Astrocytoma. This study has three non-comparative study groups. Cohort 1 and Cohort 2 will receive the same study drug sintilimab 200mg and bevacizumab 3mg/kg every 3 weeks. Cohort 3 will take only standard treatment. A stringent three-step non-randomized process will be used to assign participants to one of the study groups. Neither participants nor doctors but the researcher can choose which group participants are in. No one knows if one study group is better or worse than the other. 70 total participants are expected to participate in this study (25 participants in Cohort 1 and Cohort 2,20 participants in Cohort 3).
Grouping process: After enrollment, under the standard of care, participants will receive regular tumor in situ fluid (fluid within the surgical cavity, TISF) sampling for ctDNA analysis and recceive regular MRI. The researcher will study the TISF ctDNA and imaging dynamics to determine whether the tumor reaches to ctDNA-level (Cohort 1) or clinical relapse (Cohort 2). At the first step, all timely identified as ctDNA-level relapse tumors will be assigned into the Cohort 1 and receive the study drug immediately, those failed to be timely identified will be assigned into the Cohort 2 and receive the study drug after the clinical relapse. At the second step, once Cohort 1 or Cohort 2 reaches the target number, the new participants will be all assigned into the other Cohort. In the third step, if no ctDNA-level or clinical relapse was observed within 60 months after surgery, patients were assigned to Cohort 3 and further analyzed for prognostic biomarkers compared with Cohort 1 and Cohort 2.
Detailed Description
Primary study objectives: -To evaluate the clinical efficacy as measured by the overall survival (OS) rate at 24 months (Cohort 2) and OS rate at 36 months (Cohort 1). Secondary study objectives: * To evaluate the safety/tolerability of the study treatment; To compare the OS, progression-free survival and overall response rate of the two study groups. Exploratory objectives: * To evaluate the correlative biomarkers based on TISF ctDNA. Standard of care: -Surgical removal of tumors followed by adjuvant temozolomide (150-200 mg/m2, days 1-5 every 28 days for up to 12 cycles). The decision to extend TMZ treatment beyond 6 cycles, for up to 12 cycles, was left to the treating investigator. Patients were asked to attend follow-up visits every 3 months after the end of chemotherapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent and HIPAA authorization obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations
- •Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by MRI and tumor in situ fluid (TISF) collection
- •Histologically confirmed diagnosis of Astrocytoma
- •Resection surgery done at the study center (Henan Provincial People's Hospital), with an reservoir intraoperatively implanted connecting the surgical cavity and the subscalp for postoperative noninvasive TISF collection
- •An interval of \> 28 days and full recovery (i.e., no ongoing safety issues) from surgical resection prior to grouping
- •Karnofsky performance status (KPS) of 70 or higher
- •Life expectancy \> 12 weeks
Exclusion Criteria
- •More than two recurrences of Astrocytoma
- •Presence of extracranial metastatic, significant leptomeningeal disease or tumors primarily localized to the brainstem or spinal cord
- •Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
- •Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring chronic and systemic immunosuppressive treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects have any other condition requiring systemic treatment with corticosteroids or other immunosuppressive agents within 14 days. Inhaled or topical steroids and adrenal replacement doses \>10mg daily prednisone equivalent are permitted in absence of active autoimmune disease
- •Previous radiation therapy with anything other than standard radiation therapy (i.e., focally directed radiation) administered as first line therapy
- •Previous treatment with carmustine wafer except when administered as first line treatment and at least 6 months prior to randomization
- •Previous bevacizumab or other VEGF or anti-angiogenic treatment
- •Previous treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy
- •Evidence of \> Grade 1 CNS hemorrhage on the baseline MRI scan
- •Inadequately controlled hypertension (defined as systolic blood pressure ≥160 mmHg and /or diastolic blood pressure ≥100 mmHg) within 7 days of first study treatment
Arms & Interventions
Cohort 1
Subjects with ctDNA-level-relapse Astrocytoma before clinical relapse, determined according to the dynamics of TISF ctDNA.
Intervention: Tislelizumab plus Bevacizumab
Cohort 2
Subjects with clinical-relapse Astrocytoma, determined according to the response assessment in neuro-oncology (RANO) criteria for gliomas.
Intervention: Tislelizumab plus Bevacizumab
Outcomes
Primary Outcomes
Overall survival rate at 24 months (Cohort 2)
Time Frame: Up to 24 months after beginning therapy
OS-24 is the proportion of participants in the analysis population who remain alive for at least 24 months following initiation of study therapy.
Overall survival rate at 36 months (Cohort 1)
Time Frame: Up to 36 months after beginning therapy
OS-36 is the proportion of participants in the analysis population who remain alive for at least 36 months following initiation of study therapy.
Secondary Outcomes
- Overall survival(Up to 5 years after beginning treatment)
- Progression-free survival at 18 months(Up to 18 months after beginning treatment)
- Overall response rate(Up to 5 years after beginning treatment)
- Progression-free survival(Up to 5 years after beginning treatment)
- Duration of response(Up to 5 years after beginning treatment)
- Number of participants with treatment-emergent adverse events(Up to 5 years after beginning treatment)