A phase I/II study of GLIF combination chemotherapy for taxane/platinum-refractory/resistant endometrial cancer (GOGO-EM2)

Patients with taxane/platinum-refractory or -resistant endometrial cancer were eligible for the study. Other eligibility criteria included: age ≥ 20 years, Eastern Cooperative Oncology Group performance status of 0–2, measurable or evaluable disease, a life expectancy ≥ 3 months, and adequate hematological, renal, and hepatic function. Taxane/platinum-resistant or -refractory disease was defined as progression during or within 6 months after a taxane/platinum-based regimen.

The exclusion criteria included: patient with a *28 homozygous or *6 homozygous UGT1A1 gene polymorphism, hypersensitivity to chemotherapeutic drugs, interstitial pneumonia, ascites or pleural effusion that required drainage, active clinically significant inflammatory disease, duplicated cancer, symptomatic brain metastasis, uncontrolled diabetes mellitus, diarrhea, ileus, cardiac disease, edema, or patients whose circumstances did not permit them to complete the study.

The treatment schedule we used is shown in Fig. 1. Adverse treatment effects were graded based on WHO criteria for toxicity. For our phase I study of GLIF therapy, the maximum tolerated dose (MTD) levels of gemcitabine and irinotecan were evaluated. At the starting dose level (Level 0), patients received intravenous gemcitabine (800 mg/m² body surface area) over the course of 30 min, and irinotecan (80 mg/m²) over the course of 90 min, on days 1 and 15, respectively. Levofolinate (100 mg/m² over 120 min) was administered intravenously on days 1, 2, 15, and 16. For 5-FU, an intravenous bolus of 400 mg/m², followed by continuous infusion of 600 mg/m² over the course of 480 min, was administered on days 1, 2, 15, and 16, respectively. This schedule was repeated every 4 weeks. Granulocyte colony-stimulating factor (G-CSF) was used to support hematopoiesis when grade 4 neutropenia, or grade 3 neutropenia with fever, was observed. A 3 + 3 study design was used for dose escalation. The first and second dose escalation indicated 800–1000 mg/m² and 1200 mg/m², respectively, for gemcitabine and 80–100 mg/m² and 120 mg/m², respectively, for irinotecan. The first and second dose reduction indicated 800–600 mg/m² and 500 mg/m², respectively, for gemcitabine, and 80–60 mg/m² and 50 mg/m², respectively, for irinotecan.

Toxicity was assessed after every treatment cycle, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [12]. Dose limiting toxicity (DLT) was defined as when grade 4 thrombocytopenia, grade 3 or 4 febrile neutropenia, or grade 3 or 4 non-hematologic toxicity occurred, or when the patient’s condition, even 14 days after the scheduled day of the subsequent cycle, did not meet the starting criteria, as follows: (i) the pretreatment neutrophil count was < 1500 cells/mm³, (ii) the pretreatment platelet count was < 75,000/mm³, (iii) patients had diarrhea, of any grade, 24 h prior to chemotherapy, (iv) patients had fever ≥ 38 °C, (v) AST or ALT > 2.5 × the upper limit of normal (ULN) was observed, (vi) serum bilirubin > 1.5 × ULN was observed, (vii) pre-treatment serum creatinine level was elevated, or (viii) grade 3/4 non-hematologic toxicity occurred.

For the 3 + 3 design, the first three patients are treated by the starting dose level (Level 0). If no DLT occurs, the dose is escalated for the next cohort of three patients. If one DLT occurs, three additional patients are treated at the same level with dose escalation only if no additional DLT occurs. If two or three DLTs occur, the prior dose level is defined as MTD and recommended as the phase II dose.

Patients received intravenous gemcitabine (800 mg/m² body surface area) over the course of 30 min and irinotecan (80 mg/m²) over the course of 90 min on days 1 and 15, respectively. Levofolinate (100 mg/m²) over 120 min was administered intravenously on days 1, 2, 15, and 16. For 5-FU, an intravenous bolus of 400 mg/m², followed by continuous 600 mg/m² over the course of 480 min, was administered on days 1, 2, 15, and 16, respectively. This schedule was repeated every 4 weeks, until disease progression was confirmed by diagnostic imaging.

Toxicity was assessed every treatment cycle and graded according to CTCAE. Subsequent cycles were delayed up to 2 weeks if (i) the pretreatment neutrophil count was < 1500 cells/mm³, (ii) the pretreatment platelet count was < 75,000/mm³, (iii) patients had diarrhea of any grade 24 h prior to chemotherapy, (iv) patients had fever ≥ 38 °C, (v) AST or ALT > 2.5 × ULN was observed, (vi) serum bilirubin > 1.5 × ULN was observed, (vii) pre-treatment serum creatinine level was elevated, or (viii) grade 3/4 non-hematologic toxicity was observed. Patients who failed to recover adequate counts within a 2-week delay were to discontinue cytotoxic chemotherapy.

Dose adjustments were performed for hematological and other adverse events. A 20% dose reduction of gemcitabine, irinotecan, and 5-FU was done for grade 4 hematologic toxicity in the previous cycle, for diarrhea (grade 2 or worse), or for grade 3 or other non-hematologic toxicity. If these adverse events repeatedly occurred after level 1 dose reduction, another 20% dose reduction was done. The patient had to go off protocol if the following events occurred: (i) disease progression confirmed by a diagnostic imaging, (ii) hematologic/non-hematologic toxicity that violated drug administration criteria—despite a level 2 dose reduction, (iii) allergic reaction (grade 3 or worse), (iv) interstitial pneumonia, (v) hematologic/non-hematologic toxicity failed to recover within a 2-week delay, (vi) grade 4 non-hematologic toxicity, or (vii) patient’s voluntary withdrawal of participation in this study.

The tumor response to treatment was evaluated by CT scan images after three chemotherapy cycles, according to RECIST guidelines, version1.1. Complete response (CR) was defined as disappearance of all target lesions, and partial response (PR) as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions or the appearance of a new lesion, and stable disease (SD) as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Those cases that had confirmed new lesions before completion of three cycles of chemotherapy were also defined as PD.

Primary outcomes were response rate and toxicity. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). PFS was defined as the interval from registration to the date of diseases progression—confirmed by diagnostic imaging. OS was defined as the interval from registration to the last follow-up or death. The median PFS and OS were estimated using the Kaplan–Meier method. Statistical analysis was conducted using JMP Pro 13 statistical software (SAS Institute Inc., Cary, NC, USA).

From November 2011 to July 2015, 30 patients were enrolled, including the 3 patients who received GLIF therapy at the same dose as the recommended phase II dose in the phase I study. Two patients were excluded at this point due to study protocol violations, and the remaining 28 patients were included for analysis. The characteristics of these 28 patients are summarized in Table 2. The median age was 65 years (range 33–76). Staging was undertaken according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system. Seventeen of the 28 patients had advanced-stage diseases (stage III or IV). All patients were histopathologically diagnosed, and the histological subtype included endometrioid carcinoma in 17 patients, serous carcinoma in 4, clear cell carcinoma in 3, poorly differentiated carcinoma in 1, mixed carcinoma in 1, and carcinosarcoma in 2, respectively. Four of the 28 patients had previously received radiotherapy before registering for this study.

In total, 28 patients received 143 cycles of GLIF. Their treatment response, after three cycles of chemotherapy, is shown in Table 3. Response rate (CR + PR) and disease control rate (CR + PR + SD) were 7.1% (2/28) and 39.3% (11/28), respectively. As shown in Fig. 2, the median PFS and OS were 3 months (95% CI 3–7) and 12 months (95% CI 9–17), respectively. All 28 patients had relapsed by the end of this study. Twenty-four of the 28 patients died due to disease progression. Three patients were lost to follow-up, and one patient was still alive with disease. The median follow-up period was 12 months (range 3–41).

The results of hematologic and non-hematologic toxicities are shown in Table 4. Febrile neutropenia or grade 4 neutropenia was observed in 14% (4/28). Dose adjustment due to grade 4 neutropenia was required in two patients (7.1%). Neutropenia (grade ≥ 3) occurred in 50% of the 28 patients (14/28), and grade 3 or 4 thrombocytopenia was not observed. Grade 3 anemia occurred in three patients (10.7%). Grade 3 AST/ALT was observed in one patient (3.6%). Although elevated γ-GTP (grade ≥ 3) was observed in two patients (7.1%), these events were due to disease progression. One patient demonstrated chemotherapy-induced reactivation of hepatitis B virus. No treatment-associated deaths occurred.