Disease	Esophageal cancer
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	One prior regimen
Type of Study	Phase II, single arm
Primary Endpoint	Progression‐free survival
Secondary Endpoints	Overall survival, overall response rate
Additional Details of Endpoints or Study Design
This was an open‐label, single‐arm, phase II clinical trial that enrolled patients with ESCC who had evidence of disease progression after one or more lines of chemotherapy. Enrollment criteria were as follows: patient (aged ≥18 years) with histologically confirmed ESCC that was refractory to more than one chemotherapy regimen (the criteria for progression were based on computed tomography [CT] and magnetic resonance imaging [MRI] evaluation); an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; at least one measurable lesion as defined by RECIST version 1.1 and modified RECIST (mRECIST); and acceptable hematologic, hepatic, and renal function. Patients with uncontrolled blood pressure on medication, with a bleeding tendency, or those receiving thrombolytic therapy or anticoagulants were excluded.
The study protocol was approved by the institutional review board, the Fudan University Shanghai Cancer Center Ethics Committee for Clinical Investigation, and registered on ClinicalTrials.gov as number NCT03274011. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent before participation.
The primary endpoint was PFS. PFS was defined as the time from beginning apatinib therapy until disease progression or death, whichever occurred first. The time period before progression or death was thus considered the PFS. Secondary endpoints included OS (the time from apatinib taking until death from any cause) and investigator‐assessed ORR (the percentage of patients whose best overall response was either a complete response or partial response). The proportion of patients with DCR was defined as complete response (CR), PR, or SD, and objective response was considered a reduction in tumor size. RECIST version 1.1 was used to assess tumor response every 30 days. If patients had obvious tumor necrosis and cavitation of lung metastasis after treatment, the response was also evaluated by mRECIST. Two independent radiologists who were blind to the treatment had to agree on evidence of efficacy.
Pretreatment evaluation included physical examination, baseline laboratory tests (complete blood count; hepatic and renal function, coagulation function), and MRI or CT scan of measurable lesions at baseline. Assessment of toxicity was performed biweekly. Complete blood counts were performed weekly; hepatic, renal, and coagulation function tests were performed monthly. Physical examinations, MRI, or CT scans of measurable lesions were assessed monthly. MRI or CT scans could be scheduled ahead of time if there was evidence of substantial progression. Patients were observed until death or loss to follow‐up.
The primary endpoint was PFS. Previous data report a median PFS of less than 1 month for patients without treatment. The single‐stage study design was built around a null rate of 25% PFS at 2 months and required 33 patients to detect an absolute difference of 25% for a target rate of 50% PFS at 2 months. The trial was designed to have a 5% chance of a type 1 error and 90% power. The study was considered to reach the primary endpoint if 13 or more patients did not progress at 2 months. We expected a dropout or nonevaluable rate of 20%. An estimated 40 patients needed to be enrolled. Analysis of PFS was performed using Kaplan‐Meier for OS. Significance was set at p = .05.
Investigator's Analysis	Active and should be pursued further