Summary
Introduction
Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies.
Methods
This was a phase 1, 3+3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination.
Results
The tumor types of the enrolled subjects included esophageal (n=5), biliary tract (n=3), colon (n=3), gastric (n=2), pancreatic (n=1), anal (n=1) and small bowel (n=1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide.
Discussion
Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.
Keywords: Chemotherapy, Gastrointestinal cancers, Irinotecan, SOM230
Introduction
Pasireotide (SOM230) is a somatostatin analogue with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 [1]. It has 40-fold higher affinity for sst5 than octreotide. Pasireotide is approved in US for the treatment of Cushing’s disease and acromegaly. Pasireotide effectively inhibits growth hormone, insulin and insulin-like growth factor 1 (IGF-1). Pasireotide has demonstrated activity in patients with neuroendocrine tumor and is being evaluated in a large randomized phase 3 trial [2]. Hyperglycemia, fatigue and diarrhea are the most common treatment related adverse events. Somatostatin analogues may induce apoptosis through two distinct mechanisms: inhibition of sst3 and decreasing IGF-1 levels [3]. In the rat models, IGF-1 levels are suppressed more potently and consistently with pasireotide than with octreotide [4]. Dose dependent suppression of IGF-1 levels has been demonstrated in human subjects after treatment with pasireotide [5]. IGF-1, through binding to IGF1 receptor (IGF1R) is associated with tumirogenesis, progression and metastases. IGF1R is frequently overexpressed in gastrointestinal malignancies including colon, gastric and small intestinal cancer and play an important role in the development and proliferation of tumor at these sites. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergestic activity in pre-clinical models [6]. Synergistic activity was observed with the combination of irinotecan and IGF-1R blocking agents in orthotopic xenografts [7].
The combination of 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) is frequently utilized in the treatment of gastrointestinal cancers including esophageal, gastric, biliary tract, pancreatic and colorectal cancer [8–11]. Irinotecan in combination with 5-FU is FDA approved for the treatment of metastatic colorectal cancer. In addition, FOLFIRI regimen has demonstrated to have activity in patients with gastric cancer [10]. The combination of 5-FU, irinotecan and oxaliplatin (FOLFIRINOX) is an efficacious regimen for the treatment of highly selected patients with metastatic pancreatic cancer [8]. The primary adverse events of FOLFIRI regimen include cytopenias, nausea, vomiting, diarrhea, fatigue and mucositis.
In this trial, we evaluated the safety and toxicity of the combination of pasireotide with standard FOLFIRI regimen in patients with gastrointestinal malignancies. The primary objective of this study was to determine the maximum tolerated dose of pasireotide with FOLFIRI.
Methods
Patients
Patients were ≥18 years of age with histological diagnosis of metastatic gastrointestinal malignancies for whom FOLFIRI could be considered standard of care treatment. Subjects must have received at least one prior therapy except for small bowel cancer. All patients had measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST), an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≤2, and adequate organ function as defined by neutrophil count ≥1.5×109/L; platelets 100×109/L; hemoglobin >9 g/dL; bilirubin ≤1.5×upper limit of normal (ULN); and aspartate transaminase/alanaine transaminase ≤3×ULN, creatinine ≤1.5×ULN. Women of childbearing potential must have had negative pregnancy test.
Patients were excluded if they had received prior treatment with irinotecan. Concurrent treatment with radiation and irinotecan was allowed if it was administered prior to>4 weeks. Patients with serum cholesterol >300 mg/dL and fasting triglycerides >2.5×ULN, HbA1c >8 % or a fasting plasma glucose>1.5×ULN, antineoplastic therapy or major surgery within 4 weeks of starting the study drug, liver or biliary tract disease, alcohol abuse in last 12 months, pancreatitis, uncontrolled brain metastases, clinical significant cardiac arrhythmias, QTc >140 ms, risk factors for Torsades de Pointes, history of syncope, other active malignancy and any uncontrolled medical illness were excluded. Patients with hypersensitivity to any component of FOLFIRI or somatostatin analogues were not allowed to participate in the trial.
Study design and treatment
This is an open label, dose escalation phase 1 clinical trial evaluating the combination of pasireotide and FOLFIRI. The study was approved by the institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Written informed consent was obtained from all patients.
Traditional 3+3 design was utilized for dose escalation. All patients received FOLFIRI regimen on days 1 and 15 of of 28-day cycle consisting of irinotecan 180 mg/m2 IV over 90 min, leucovorin 400 mg/m2 IV over 2 h, 5-fluorouracil 400 mg/m2 bolus followed by 5-fluorouracil 2400 mg/m2 over 46 h. Prior to chemotherapy, patients received ondansetron 16 mg orally and dexamethasone 18 mg orally as antiemetic prophylaxis. pasireotide was administered intramuscularly once every 28 days. The dose of pasireotide for different dose escalation cohorts were 40 (starting dose level), 60, 80, 100 and 120 mg.
Dose limiting toxicities (DLTs) were defined as adverse events (AEs) at least possibly related to the treatment meeting the following criteria during first cycle: 1) Grade ≥3 hematological toxicity lasting for>7 days; 2) Febrile neutropenia; 3) Grade ≥3 non-hematologic AE except nausea, vomiting and diarrhea that is reversed within 5 days with maximal supportive care; or 3) grade 3 hyperglycemia with glucose level>300 mg/ml despite appropriate treatment with insulin or oral anti-diabetic agents.
Safety assessments
All AEs were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Demographic data and medical history were collected at screening. Safety and tolerability were assessed at baseline and every 2 weeks weekly during treatment and included evaluation of patient vital signs, performance status, laboratory (hematology, and blood chemistry). Electrocardiogram and fasting glucose measurement was performed at the beginning of every cycle. Holter monitoring was performed at screening and on day 1 of cycle 1.
Efficacy assessments
Tumor responses were determined by investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Computed tomography scans were used to evaluate tumors at baseline and at the end of even cycles. Patients who did not undergo restaging scans were considered non evaluable for response.
Pharmacodynamics assessment
Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were collected 30–60 min prior to administration of pasireotide on day 1 of cycle 1 and every 2 cycles thereafter. These biomarkers were measured by enzyme-linked immunosorbent (ELISA) assays with reagents from Diagnostic Systems Laboratories, a Beckman Coulter, Inc Company (Webster, TX). The IGF-I assays include an acid-ethanol precipitation of IGF-I–binding proteins to avoid interference of IGFBPs with the IGF-I assay.
Statistical analyses
The primary endpoint of this study was to determine the maximum tolerated dose of pasireotide in combination with FOLFIRI regimen. Secondary endpoints for efficacy included response rate, progression-free survival and overall survival. Standard 3+3 dose escalation design was utilized. There was >71 % chance of dose escalation if the underlying risk of DLT is <20 % and a >91 % chance of escalation if the underlying risk is <10 %. PFS and OS were calculated using Kaplan-Meir curves. For response rate evaluation, only patients who underwent at least one post treatment scans were included. A descriptive analysis was used for biomarker assays.
Results
From November 2011 to January 2014, 16 patients were enrolled in six dose cohorts. Baseline characteristics of the enrolled subjects are mention in Table 1. One patient was taken-off trial prior to completion of first cycle secondary to non-compliance and was replaced for DLT evaluation. The median age was 63 years (range: 27 to 75 years); 5 patients were female and 11 patients were male. All the patients were Caucasians. Three patients had ECOG-PS of 0 and rest of the patients had ECOG-PS of 1. The tumor types of the enrolled subjects included esophageal (n=5), biliary tract (n=3), colon (n=3), gastric (n=2), pancreatic (n=1), anal (n=1) and small bowel (n=1). Nine patients had progressed on 1 prior regimen, and rest had received 2 or 3 prior regimens. The median number of cycles of chemotherapy that patients received was 3 (1–8 cycles).
Table 1.
Baseline characteristics of subjects enrolled in the trial
| Characteristic | N (%) |
|---|---|
| Age, median (range) | 63 (27–75) years |
| Gender | |
| Male | 11 |
| Female | 5 |
| Race | |
| Caucasian | 16 (100 %) |
| ECOG performance status | |
| 0 | 3 |
| 1 | 13 (%) |
| Prior chemotherapy | 16 (100 %) |
| Number of prior regimens, median (range) | 1 (1–3) |
| Tumor type | |
| Esophageal | 5 |
| Biliary tract | 3 |
| Colon | 3 |
| Gastric | 2 |
| Pancreatic | 1 |
| Anal | 1 |
| Small bowel | 1 |
| Number of cycles, median (range) | 3 (1–8) |
Efficacy
Out of 16 patients, 2 patients achieved partial response (colon cancer and esophageal cancer) and 7 patients had stable disease. Six patients progressed at first restaging scans and one patient was non-evaluable as the subject was taken off trial secondary to non-compliance. The clinical benefit rate (PR + SD) was 56 %. Three patients received treatment for≥6 cycles. Two of these patients had colon cancer and one patient had esophageal cancer. Figure 1 represents the waterfall plot demonstrating change in the sum of target lesions. Median PFS was 3.6 months (95 % CI: 2.4–5.5 months) (Fig. 2). The median survival was 7.2 months (95 % CI: 4.3–11.4 months) (Fig. 3). The 6-month PFS and OS was 0.16 (95 % CI: 0.03–0.4) and 0.7 (95 % CI: 0.39–0.88) respectively.
Fig. 1.
Waterfall plot representing the best response using RECIST criteria
Fig. 2.
Progression free survival
Fig. 3.
Overall survival
Toxicity
All 16 patients were evaluable for toxicity. No dose limiting toxicities were observed. The most common AEs that were at least possible related to the study treatment included hyperglycemia (13), neutropenia (10), thrombocytopenia (7), anorexia (7), dehydration (4) and elevated alkaline phosphatase (4) (Table 2). The hematologic toxicities were expected and primarily related to FOLFIRI chemotherapy. Growth factors were administered on as needed basis.
Table 2.
Treatment related adverse events
| Adverse event | Grade 1 N (%) | Grade 2 N (%) | Grade 3 N (%) | Grade 4 N (%) | Total N (%) |
|---|---|---|---|---|---|
| Investigations | |||||
| Alanine aminotransferase increased | 1 (6.3) | – | – | – | 1 (6.3) |
| Alkaline phosphatase increased | 4 (25.0) | – | – | – | 4 (25.0) |
| Aspartate aminotransferase increased | 2 (12.5) | – | – | – | 2 (12.5) |
| Blood bilirubin increased | – | 2 (12.5) | – | – | 2 (12.5) |
| Creatinine increased | 1 (6.3) | – | – | – | 1 (6.3) |
| GGT increased | 1 (6.3) | – | – | – | 1 (6.3) |
| Neutrophil count decreased | 1 (6.3) | 3 (18.8) | 3 (18.8) | 3 (18.8) | 10 (62.5) |
| Platelet count decreased | 6 (37.5) | – | 1 (6.3) | – | 7 (43.8) |
| Weight loss | – | 2 (12.5) | – | – | 2 (12.5) |
| White blood cell decreased | – | 3 (18.8) | – | – | 3 (18.8) |
| Metabolism and nutrition disorders | |||||
| Anorexia | 3 (18.8) | 4 (25.0) | – | – | 7 (43.8) |
| Dehydration | – | 4 (25.0) | – | – | 4 (25.0) |
| Hyperglycemia | 5 (31.3) | 6 (37.5) | 2 (12.5) | – | 13 (81.3) |
| Hypernatremia | 1 (6.3) | – | – | – | 1 (6.3) |
| Hypoalbuminemia | – | 1 (6.3) | – | – | 1 (6.3) |
| Hypocalcemia | 2 (12.5) | – | – | – | 2 (12.5) |
| Hyponatremia | 1 (6.3) | – | – | 1 (6.3) | 2 (12.5) |
| Hypophosphatemia | – | – | 1 (6.3) | – | 1 (6.3) |
| Musculoskeletal and connective tissue disorders | |||||
| Generalized muscle weakness | 2 (12.5) | – | – | – | 2 (12.5) |
| Myalgia | 1 (6.3) | – | – | – | 1 (6.3) |
| Nervous system disorders | |||||
| Dizziness | 1 (6.3) | – | – | – | 1 (6.3) |
| Dysgeusia | 1 (6.3) | – | – | – | 1 (6.3) |
| Peripheral sensory neuropathy | 1 (6.3) | 1 (6.3) | – | – | 2 (12.5) |
| Psychiatric disorders | |||||
| Insomnia | 1 (6.3) | – | – | – | 1 (6.3) |
| Respiratory, thoracic and mediastinal disorders | |||||
| Dyspnea | 3 (18.8) | – | – | – | 3 (18.8) |
| Skin and subcutaneous tissue disorders | |||||
| Alopecia | 3 (18.8) | 1 (6.3) | – | – | 4 (25.0) |
| Erythema multiforme | 1 (6.3) | – | – | – | 1 (6.3) |
| Hyperhidrosis | 4 (25.0) | – | – | – | 4 (25.0) |
| Pruritus | 1 (6.3) | – | – | – | 1 (6.3) |
| Rash maculo-papular | 2 (12.5) | – | – | – | 2 (12.5) |
Grade 3 or 4 related AEs included neutropenia (6), thrombocytopenia (1), hyperglycemia (2), hyponatremia (1) and hypophosphatemia (1). No treatment related deaths were observed.
Pharmacodynamic
The median baseline levels of IGF-1, IGFBP-1 and IGFBP-3 were 96.5 mg/mL (Range: 45.7–226.8 mg/mL), 4.5 ng/mL (Range: 1–107.6 ng/mL) and 2776 ng/mL (Range: 1263.5–4181.5 ng/mL) respectively. There was statistical significant reduction in the levels of IGF-1 and IGFBP-3 after treatment with pasireotide with the median decrease of 67.3 and 687.5 ng/mL respectively (Table 3). There was no significant difference in the levels of IGFBP-1. There was no correlation with baseline levels or change in these biomarkers with responses likely due to small numbers.
Table 3.
Biomarker levels
| Baseline |
Change (last cycle – first Cycle) |
P Value | |||||
|---|---|---|---|---|---|---|---|
| Mean | Median | SD | Mean | Median | SD | ||
| IGF-1, ng/mL | 114.7 | 96.5 | 55 | −67.3 | −55 | 35 | 0.0053 |
| IGFBP-1, ng/mL | 14.4 | 4.5 | 28 | 16 | 5.3 | 28.9 | 0.2336 |
| IGFBP-3, ng/mL | 2835.4 | 2776 | 847.1 | −903.3 | −687.5 | 780.6 | 0.0365 |
SD standard deviation
Discussion
In this trial, no DLTs were observed with addition of pasireotide up to 120 mg administered intramuscularly with standard FOLFIRI regimen in patients with gastrointestinal malignancies. The treatment related AEs were predictable and primarily grade 1 or 2. Hyperglycemia was commonly observed and related to treatment with pasireotide. Patients were pre-medicated with dexamethasone prior to FOLFIRI regimen which could have contributed to hyperglycemia as well. Cardiac bradycardia and prolongation of QTc interval has been reported with pasireotide [12, 13]. QTc interval was closely monitored throughout the trial. No prolongation in QTc interval was observed in this trial. Hematological toxicities related to chemotherapy were noted and were the most common cause of dose reduction and delays. Overall, the treatment regimen was generally well tolerated with few grade 3 or 4 related AEs. It is difficult to interpret the efficacy outcomes in a dose escalation study that involves multiple tumor types. FOLFIRI is an active treatment regimen for gastrointestinal malignancies, therefore it is difficult to evaluate if addition of pasireotide provides additional benefit.
In this trial, significant decrease in the levels of IGF-1 and IGFBP-3 was observed after treatment with pasireotide. However, we did not find any correlation between levels of these biomarkers and efficacy outcomes. Reduction of IGF-1 by pasireotide is the pivotal antitumor mechanism. IGF1R, activated by IGF-1, is a receptor tyrosine kinase involved in normal growth and development. IGF1R consists of two extracellular binding α subunits and two β subunits comprising the transmembrane and tyrosine kinase domains [14]. Binding of the ligand induces the conformational change in the receptor and activation of kinase. The kinase activity of the receptor leads to phosphorylation of members of the insulin receptor substrate family of proteins and this in turns results in activation of phosphatidylinositol-3-kinase (PI3-kinase)/Akt and mitogen-activated protein kinase pathway [15]. Insulin or IGF1 can stimulate the proliferation of tumor cells through binding to IGF1R. IGF1R can cause neoplastic transformation in vitro and is required for the transforming ability of several oncogenes [16]. In vivo models utilizing mutations associated with low IGF-1 levels or genetic manipulations to decrease ligand levels demonstrates that reduced IGF levels decreases tumor growth [17–19]. IGF1R overexpression is associated with worse prognosis in various tumor types. Further, epidemiological studies suggest that increase insulin and IGF1 levels are associated not only with higher risk of developing several malignancies including prostate, breast and colorectal cancers but also worse prognosis in oncology patients [20, 21]. The antitumor activity of pasireotide is likely secondary to its action on IGF-1. Blocking of IGF-1R and irinotecan has demonstrated synergistic activity in colorectal cancer xenograft models [7].
Pasireotide can also inhibit the cell growth through binding to somatostatin receptors 1, 2, 3 and 5. It has much higher binding affinity than octreotide. In the pancreatic and other gastrointestinal endocrine tumors somatostatin receptors are present, especially sst2. Binding of somatostatin receptors by pasireotide is an important mechanism for decreasing hormone secretion and inhibiting tumor growth in patients with neuroendocrine tumors. However, the role of somatostatin receptor inhibition in carcinoma remains unclear. Somatostatin receptor, have been demonstrated to be expressed in other tumor types including small cell lung cancer, breast cancer, meningiomas, neuroblastomas and astrocytomas [22]. It is plausible that somatostatin receptor inhibition may also be involved in tumor inhibitory activity of pasireotide. In this trial, we did not evaluate the expression of somatostatin receptors which could potentially be utilized as a biomarker.
The combination of FOLFIRI regimen with pasireotide was reasonably well tolerated with expected toxicities. To our knowledge, this is the first trial to combine pasireotide at high doses (120 mg) with chemotherapy. Due to small sample size it is not possible to make firm conclusions regarding effectiveness of the combination as compared to chemotherapy alone. Pasireotide does decrease the levels of IGF-1 and IGFBP-3 and their role as predictive biomarkers needs to be evaluated. Somatostatin receptor expression needs to be tested as a biomarker as well. A larger randomized trial is needed to determine if addition of pasireotide to FOLFIRI improves outcomes in patients with gastrointestinal malignancies, especially in tumor types which highly express somatostatin receptors such as gastroesophageal cancers.
Acknowledgments
Funding source This trial was funded by Novartis Pharmaceuticals Corporation.
References
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