Clinical trial NCT02608229: BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
Official title: Phase Ib Study of BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Pancreatic Cancer
Cancer of Pancreas
Cancer of the Pancreas
Pancreas Cancer
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: BioMed Valley Discoveries, Inc
name: National Cancer Institute (NCI)
First posted: 2015-11-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In light of the central role of extracellular signal-regulated kinases (ERK) in pancreatic cancer, the investigators propose a phase I study to evaluate the ERK inhibitor BVD-523 at the recommended phase 2 dose in combination with nab-paclitaxel plus gemcitabine in patients with newly diagnosed metastatic pancreatic cancer. The primary endpoint will be maximum tolerated dose (MTD) or RP2D and safety. The secondary endpoints include safety, response rate, biochemical response, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints include the assessing the impact of BVD-523 on the MEK/ERK pathway and other major pathway pertain to pancreatic cancer.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed newly diagnosed treatment-naïve metastatic adenocarcinoma of the pancreas with metastatic disease diagnosed no more than 6 weeks prior to enrollment. Patients with advanced pancreatic cancer progressed on 5-FU (or capecitabine) based regimen will be allowed in the expansion cohort.
* Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
* At least 18 years of age.
* Life expectancy \> 3 months.
* ECOG performance status ≤ 1
* Normal bone marrow and organ function as defined below:

  * Absolute neutrophil count ≥ 1,500/mcL
  * Platelets ≥ 100,000/mcL
  * Hemoglobin ≥ 9.0 g/dL
  * Total bilirubin ≤ IULN
  * AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
  * Creatinine ≤ 1.5 x IULN OR GFR of ≥ 50 mL/min
  * Cardiac function ≥ ILLN, e.g., LVEF of \> 50% as assessed by MUGA or ECHO, QTc \< 470 ms
* Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for three months following study discontinuation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

* Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment.
* A history of other malignancy with the exception of those treated with curative intent with no evidence of disease for 2 years.
* Currently receiving any other investigational agents.
* Known brain metastases or CNS involvement.
* Significant ascites that require therapeutic paracentesis.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to BVD-523, gemcitabine, nab-paclitaxel, or other agents used in the study.
* Neuropathy ≥ grade 2.
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
* History of interstitial lung disease or pneumonitis.
* Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4 (see Appendix B).
* Gastrointestinal condition which could impair absorption of BVD-523 or inability to ingest BVD-523.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.
* Known HIV-positivity.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of BVD-523
timeFrame: Completion of cycle 1 for all dose de-escalation patients (1.8 years), the first cycle is 28 days for each individual patient
Secondary outcomes:
measure: Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events
timeFrame: 30 days after completion of treatment (median time was 67.5 days)
measure: Response Rate
timeFrame: Through completion of treatment (median time was 37.5 days)
measure: Biochemical Response of Treatment Regimen
timeFrame: Through completion of treatment (median time was 37.5 days)
measure: Time to Tumor Progression (TTP)
timeFrame: Up to 2 years
measure: Progression-free Survival (PFS)
timeFrame: Up to 2 years
measure: Overall Survival (OS)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Kian-Huat Lim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.