Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study

Patient Inclusion Criteria

Patients aged 18 years or older with confirmed advanced or metastatic pancreatic adenocarcinoma were included. Patients were required to have an Eastern Cooperative Oncology Group performance status of ≤1 and adequate liver, renal, and bone marrow function. Prior gemcitabine given concurrently with radiotherapy for localized cancer was permitted. Prior gemcitabine as adjuvant therapy was allowed if ≥3 months had elapsed between the last dose of gemcitabine and detection of recurrent disease.

Patient Exclusion Criteria

Patients previously treated with ipilimumab, CD137 agonists, CTLA‐4 inhibitors or agonists, or anti–PD‐1 therapies were excluded. Prior systemic therapy for advanced pancreatic cancer with gemcitabine was prohibited. Other major exclusion criteria included central nervous system metastatic disease, active autoimmune disease, active infections including human immunodeficiency virus, hepatitis B or C infection, recent vaccine use, or significant comorbid conditions.

The trial was conducted at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and was approved by the institutional review board of Northwestern University Feinberg School of Medicine. It was registered with http://clinicaltrials.gov as NCT01473940 on October 19, 2011. All patients provided written informed consent before enrollment. The study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice and the Declaration of Helsinki.

Study Design and Treatment

This was an open‐label study using a traditional 3 + 3 dose‐escalation design. Enrolled patients received gemcitabine weekly at the assigned dose intravenously over 30 minutes for 7 weeks followed by 1 week off and then subsequent cycles for 3 weeks on and 1 week off. Prior to gemcitabine infusion on weeks 1, 4, 7, and 10, patients received ipilimumab at the assigned dose intravenously over 90 minutes. Thereafter, ipilimumab was given every 12 weeks. Patients were continued on study treatment until unacceptable toxicity, progressive disease, or withdrawal from the study. Each patient was evaluated for dose‐limiting toxicity (DLT) at the end of week 12 of study treatment. Escalation to the next dose level occurred only if there were no DLTs at the previous dose level and thus did not establish the maximum tolerated dose (MTD). An additional expansion cohort at the MTD was included in the study design to generate additional safety and efficacy data. Dose levels included in the study are shown in Table 1.

Dose‐Limiting Toxicity and Maximum Tolerated Dose

Patients were assessed for dose‐limiting toxicity at the end of week 12. All toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. For this study, an immune‐related adverse event (irAE) was defined as an adverse event (AE) of unknown etiology associated with drug exposure and consistent with an immune phenomenon. The MTD was defined as the highest dose at which zero of three patients or one of six patients experienced DLTs.

Major criteria for dose‐limiting toxicity included both hematologic and nonhematologic criteria. The hematologic criteria included grade 4 neutropenia for >7 days, febrile neutropenia with ≥ grade 3 neutropenia, grade 3 thrombocytopenia with ≥ grade 3 hemorrhage, or grade 4 thrombocytopenia. All grade ≥3 nonhematologic toxicities were defined as dose‐limiting toxicities except for hepatic dysfunction related to biliary tract obstruction, grade 3 toxicities lasting <24 hours (e.g., hypomagnesemia corrected with IV magnesium), grade ≥ 3 vomiting without appropriate supportive care, or toxicities clearly related to progressive disease. Any toxicities that resulted in inability to resume treatment for >14 days were considered DLTs.

Safety Assessments

Baseline and screening assessments included history and complete physical examination. Laboratory testing included complete blood counts, comprehensive metabolic profile, amylase, lipase, thyroid‐stimulating hormone (TSH), and carbohydrate antigen 19‐9 (CA19‐9), and baseline imaging and pathology reviews were conducted. Safety assessments were performed before each dose of gemcitabine and ipilimumab and included monitoring and recording all AEs, documentation of concomitant medications, routine laboratory tests, focused history, and physical examinations. Amylase, lipase, and TSH levels were also checked prior to each ipilimumab infusion.

Response Assessment

Imaging was obtained at baseline and response evaluation was done at week 12 by follow‐up imaging using immune‐related response criteria (irRC). All subjects who received at least one dose of study treatment were evaluated for response. Serum CA19‐9 was also measured at baseline and at week 12. For those who achieved a response or stable disease, study treatment was continued, and patients were evaluated for response using imaging and CA19‐9 measurement every 12 weeks until progression, unacceptable toxicity, or study withdrawal.

Correlative Studies

Prior to December 2013, the study included an optional peripheral blood collection. Studies to quantify and monitor regulatory T‐cell number and function, frequency of T‐cell subsets, and pro‐ versus anti‐inflammatory T‐cell function before, during, and after study treatment were planned. However, given that an insufficient number of samples were collected and analyzed, these studies were not completed.

Statistical Analysis

The primary endpoint of the study was to establish the MTD of the combination of ipilimumab and gemcitabine in advanced or metastatic pancreatic adenocarcinoma. Secondary endpoints included the toxicity profile of the combination, objective response rate (ORR) by irRC version 1.0 criteria, median progression‐free survival (PFS), and median overall survival (OS). Accrual began at dose level 1 using the standard 3 + 3 phase I dose‐escalation design 14.

The dose‐escalation schema resulted in a probability of dose escalation that was 91% (49%, 17%, 3%) when the toxicity rate was 10% (30%, 50%, 70%), respectively. For the expansion cohort, dose‐limiting toxicity was monitored by calculating the Bayesian predictive probability of a DLT given the data to date. This was done after each DLT was observed. Once a DLT was observed, patients were removed from the study. If there had been at least a 90% probability that the DLT rate exceeded 33%, then accrual to the expansion cohort would have been terminated.

Adverse events and safety data were analyzed using descriptive statistics. Response assessments were displayed using a waterfall plot, and PFS and OS were calculated using the Kaplan‐Meier method.

Descriptive statistics were calculated for patient characteristics (age, sex, stage of disease, and information about prior treatments). Progression‐free and overall survival were estimated using Kaplan‐Meier calculations. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Baseline Patient Characteristics

From June 11, 2012, to March 23, 2016, 25 patients were screened for study enrollment. Two were ineligible based on lab values, one patient declined enrollment, and one patient never received study treatment for unknown reasons. Twenty‐one patients were enrolled in the study, of whom 13 were in the dose‐escalation phase and 8 in the expansion cohort treated at the established MTD. The median age was 66 years, 62% of patients were female, and 95% had stage IV disease. Fifty‐two percent of patients had one prior line of therapy, and 14% had two prior lines of therapy. Baseline characteristics for the study population are shown in Table 2.

Dose Escalation

In cohort 1, all three patients who were enrolled tolerated the dose well with no DLTs observed. In cohort 2, four patients were enrolled with one patient experiencing multiple serious adverse events (SAEs) but no DLT. The SAEs observed included grade 4 catheter‐related infection, grade 3 hemolytic uremic syndrome, grade 3 thrombocytopenia, and grade 3 retroperitoneal hemorrhage. Because of the number, severity, and rapid onset of SAEs shortly after study enrollment that could not be clearly attributed to study treatment, the patient became nonevaluable for DLTs, requiring an additional patient in this cohort. However, this patient was still included for general adverse event statistics and response assessment.

In cohort 3, three patients were initially enrolled with one experiencing a DLT of grade 3 elevation in alanine transferase (ALT). Per protocol, an additional three patients were enrolled (resulting in six patients in cohort 3). A second DLT of grade 3 diarrhea was recorded in this cohort. Multiple other SAEs were recorded in cohort 3, which are summarized in supplemental online Table 1. This resulted in the MTD being established at the cohort 2 doses, gemcitabine 1,000 mg/m² and ipilimumab 3 mg/kg. An additional eight patients were enrolled at the MTD as an expansion cohort. No DLT was reported in the expansion cohort.

Safety

Treatment‐related AEs are summarized in Table 3. The most common AEs that occurred in ≥10% of patients were anemia, thrombocytopenia, aspartate aminotransferase (AST)/ALT elevation, leukopenia, fatigue, neutropenia, nausea, rash, alkaline phosphatase elevation, fever, diarrhea, dry mouth, creatinine increase, hyperglycemia, bilirubin elevation, peripheral sensory neuropathy, flu‐like symptoms, chills, hyponatremia, hypokalemia, and anorexia. Grade 3 or higher AEs were observed in 16 patients (76%) with one grade 3 elevation in ALT and one grade 3 diarrhea being the dose‐limiting toxicities at the gemcitabine 1,000 mg/m² and ipilimumab 6 mg/kg doses. 74% of all grade 3 or higher AEs were hematologic toxicities, including the only two grade 4 AEs observed (leukopenia and neutropenia). The most common nonhematologic grade 3 or higher AEs were diarrhea (10%), nausea (10%) and hypokalemia (10%).

Grade 3 or higher immune‐related AEs were observed in 19% of patients. Grade 3 diarrhea occurred in two patients (10%), and grade 3 AST/ALT elevation occurred in two patients (10%). Two of these AEs (one grade 3 ALT elevation and one grade 3 diarrhea) occurred in cohort 3 receiving ipilimumab 6 mg/kg, and two occurred in cohort 2 (one grade 3 AST elevation and one grade 3 diarrhea) receiving ipilimumab 3 mg/kg. There were no other grade 3 or 4 irAEs, including colitis, pneumonitis, rash, endocrine dysfunction, neuritis, and myocarditis. Serious adverse events are reported in supplemental online Table 1.

Response Assessment

Best response was evaluated by irRC criteria in all 21 patients enrolled. A total of three patients achieved a partial response, and seven patients had stable disease as the best response. There were no complete responses, and eight patients had a best response of progressive disease. The three responders had a median age of 66, 33% were female, all were white, and all had metastatic disease at study enrollment. Two had received two prior lines of therapy (both received gemcitabine followed by chemoradiation with 5‐fluorouracil [5‐FU]), and one had received one prior line of therapy (FOLFIRINOX).

The ORR was 14% (3/21). Two of the responses were in cohort 2 (MTD, gemcitabine 1,000 mg/m², ipilimumab 3 mg/kg), and one response occurred in cohort 3 (gemcitabine 1,000 mg/m², ipilimumab 6 mg/kg). Of the seven patients who achieved stable disease, two were in cohort 1 (gemcitabine 750 mg/m², ipilimumab 3 mg/kg), two were in cohort 2, and three were in cohort 3. Their median age was 68, 71% were female, and all seven had metastatic disease. Three were in the upfront setting, three had one prior line of therapy, and one had two prior lines of therapy. The median duration of stable disease was 2.37 months, and the median OS was 8.90 months. These data are displayed in Figure 1. Six patients are not represented in Figure 1 but were included for response assessment: three who died before the first response assessment and three who had progressive disease that was unmeasurable (e.g., peritoneal carcinomatosis). The ORR for patients treated at the MTD was 17% (2/12). All responding patients eventually discontinued study treatment because of progression of disease. A swimmer's plot illustrating these data is shown in Figure 2.

Responses were durable in the three patients who achieved partial responses with a median duration of 11 months. For the two responders in cohort 2, response durations were 8.5 months and 11 months. For the responder in cohort 3, response duration was 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61–4.83 months). Median OS was 6.90 months (95% CI, 2.63–9.57 months). Kaplan‐Meier curves for both PFS and OS are shown in Figure 3. For the 12 patients treated at the MTD, the median PFS and OS were 2.57 and 5.80 months, respectively.

Correlative Studies

Because of an insufficient number of peripheral blood samples collected for analysis, these studies were not performed, and sample collection was terminated in December 2013.