Metastatic Pancreatic Cancer
Conditions
Keywords
Pancreatic Cancer, Stage IV Pancreatic Cancer, Stage IV metastatic pancreatic ductal adenocarcinoma
Brief summary
The goal of this study is to identify the maximum tolerated dose and dose-limiting side effects of LCL161 in combination with gemcitabine and nab-paclitaxel and to provide safety data in patients with measurable metastatic pancreatic cancer.
Detailed description
Improved therapeutic options for advanced pancreatic adenocarcinoma treatment need to continue to be investigated. Since 1997, gemcitabine has been the agent of choice for first-line therapy in advanced pancreatic cancer, with a median survival of 5.7 months, and a 20% 1-year survival (Eli Lilly 1996). Combination therapies using gemcitabine as a backbone have been investigated, but none are superior to gemcitabine monotherapy, except for a modest increase in overall survival (OS) with erlotinib and gemcitabine (Moore et al 2007). In a study of FOLFIRINOX compared with gemcitabine as first-line therapy in 342 metastatic pancreatic cancer patients, median OS was 11.1 months in the FOLFIRINOX group and 6.8 months in the gemcitabine group; however, the FOLFIRINOX group experienced more adverse events particularly febrile neutropenia (Conroy et al 2011). LCL161 is a biostable, cell-permeable, small molecular weight Smac-mimetic compound. It is an orally bioavailable pan-IAP inhibitor that demonstrates anti-tumor efficacy as a single agent in a small subset of cell lines, and in many more cell lines and xenograft models when given in combination with paclitaxel. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a formulation that is readily soluble in saline, eliminating the need for lipid-based solvents (ie, Cremophor EL) and corticosteroid and antihistamine premedications for hypersensitivity reactions required for traditional unbound paclitaxel. nab-paclitaxel has also been shown to actively bind to secreted protein acidic and rich in cysteine (SPARC) in the tumor stroma, which is highly expressed in pancreatic cancer and actively binds to the albumin in nab-paclitaxel and further concentrates the drug into the tumor. SPARC expression in the stroma of tumor cells has been associated with poor survival. In a Phase I/II trial (Von Hoff et al 2011) involving 67 patients with metastatic pancreatic adenocarcinoma, the regimen of nab-paclitaxel plus gemcitabine had tolerable adverse effects with substantial antitumor activity, warranting Phase III evaluation. The Phase III study (MPACT) was a large, international study that determined that survival with nab-paclitaxel plus gemcitabine is superior to gemcitabine alone. nab-paclitaxel plus gemcitabine is a new standard for treatment of patients with metastatic pancreatic cancer (Von Hoff et al 2013). However, although this study shows promise for substantially improving OS in patients with pancreatic adenocarcinoma, insensitivity to these agents is likely to occur due to resistance to apoptosis, which has been observed in laboratory studies to occur for most of the cytotoxic agents used to treat pancreatic cancer in the past (Westphal and Kaltoff 2003). Exploitation of the apoptosis pathway may ultimately provide more effective, less toxic anticancer therapy that selectively circumvents treatment-resistant pathways. Based on the above, there is a high likelihood that LCL161 in combination with nab-paclitaxel and gemcitabine will be determined to be safe and well tolerated, and will show substantial antitumor activity, warranting Phase II evaluation. Up to 24 patients will be enrolled in Part A - Phase I Safety study. If the combination therapy is determined to be safe and well tolerated and shows substantial antitumor activity, a safety expansion cohort of 12 additional patients will be enrolled in Part B - Efficacy study to further confirm the tolerability and efficacy of LCL161 with an endpoint of complete response (CR).
Interventions
DRUGLCL161
LCL161 (tablets): 300, 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days
DRUGGemcitabine
Gemcitabine IV: 1,000 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days
DRUGnab-Paclitaxel
nab-paclitaxel IV: 125 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days
Sponsors
Novartis Pharmaceuticals
Delta Clinical Research, LLC
US Oncology Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must provide written informed consent prior to any screening procedures. 2. A signed Patient Authorization Form (HIPPA) has been obtained prior to registration. 3. Age 18 years or older. 4. Willing and able to comply with scheduled visits, treatment plan and laboratory tests 5. Patient is able to swallow and retain oral medication. 6. Histologically or cytologically documented measureable metastatic (Stage IV) pancreatic cancer with disease by computed tomography scan as defined by RECIST Version 1.1. 7. ECOG performance status 0-1. 8. Required baseline laboratory status: * Hemoglobin (Hgb) ≥ 90 g/L (9 g/dL) * Platelets ≥ 100 x 109/L (100,000/mm3) * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/mm3) * Serum total bilirubin ≤ 1.5 x ULN (upper limit of normal) * AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN, except for patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN * Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 40 mL/min 9. Patient did not receive previous treatment for Stage IV pancreatic cancer. Note: However, prior adjuvant treatment with fluorouracil or gemcitabine administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed. If patient received adjuvant therapy, tumor recurrence must have occurred ≥ 6 months after the last treatment.
Exclusion criteria
1. Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities. 2. Patient has impaired cardiac function or clinically significant cardiac diseases, including any of the following: * History or presence of ventricular tachyarrhythmia * Presence of unstable atrial fibrillation (ventricular response \> 100 bpm); Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose of LCL161 | 1.6 years | The maximum dose of LCL161 (tablets: 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days) that is tolerated by the patients. |
| Percentage of patients with Dose-Limiting Toxicities | 1.6 years | The percentage of patients that have side effects that require dosage of LCL161 to be stopped or reduced. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 1.6 years | Number of patients with Complete Response or Partial Response |
Countries
United States
Outcome results
None listed