Selinexor, Gemcitabine, and Nab-Paclitaxel in Treating Patients with Metastatic Pancreatic Cancer
This partially randomized phase Ib/II trial studies the side effects and best dose of selinexor when given together with gemcitabine and nab-paclitaxel, and to see how well they work in treating patients with pancreatic cancer that has spread to other parts of the body (metastatic). Drugs used in chemotherapy, such as selinexor, gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Inclusion Criteria
- Written informed consent in accordance with federal, local, and institutional guidelines
- Age > 18 years
- Patients with metastatic pancreatic adenocarcinoma who have failed one non-gemcitabine based regimen for metastatic disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Platelet count >= 100,000/mm^3
- Bilirubin < 2 times the upper limit of normal (ULN) (except patients with Gilbert’s syndrome who must have a total bilirubin of < 3 times ULN)
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2.5 times ULN
- Serum creatinine =< 1.5 mg/dL
- Serum albumin >= 3.0 g/dL
- Effective contraception: female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential; acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal; for both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose
- Patients with history of previously treated malignancies who do not have any evidence of disease for the last three years are allowed
Exclusion Criteria
- Patients who are pregnant or breast feeding
- Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 3 weeks prior to cycle 1 day 1; treatment with mitomycin C or radio-immunotherapy must be completed within 6 weeks prior to cycle 1 day 1
- Major surgery within three weeks before cycle 1 day 1
- Prior therapy with gemcitabine based regimen for metastatic disease or gemcitabine based adjuvant therapy completed less than twelve months from enrollment
- Unstable cardiovascular function: * Symptomatic ischemia, or * Uncontrolled clinically significant conduction abnormalities (e.g.: ventricular tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or * Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or * Myocardial infarction (MI) within 3 months of cycle 1 day 1 dose
- Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose
- Known to be human immunodeficiency virus (HIV) seropositive who are on anti-HIV drugs because of the unknown interactions between these drugs and the study agents
- Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)
- Patients with active central nervous system (CNS) malignancy; asymptomatic small lesions are not considered active; treated lesions may be considered inactive if they are stable for at least 3 months
- Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea
- History of seizures, movement disorders or cerebrovascular accident within the past 5 years prior to cycle 1 day 1
- Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity based on physician’s assessment
- Serious psychiatric illness (e.g., depression, psychosis) or medical conditions that could interfere with treatment
- Participation in an investigational anti-cancer study within 3 weeks prior to cycle 1 day 1
- Concurrent therapy with approved or investigational anticancer therapeutic other than what is stipulated by the protocol
- Clinically significant ascites
- Major surgery within 3 weeks of cycle 1 day 1 (C1D1)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02178436.
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose (RP2D) of gemcitabine hydrochloride (gemcitabine), nab-paclitaxel and selinexor for untreated metastatic pancreatic cancer [COMPLETED]. (Phase I)
II. To determine the safety profile of gemcitabine, nab-paclitaxel, and selinexor [COMPLETED]. (Phase I)
III. To test whether the combination of gemcitabine and selinexor improves the median overall survival of patients with metastatic pancreatic cancer who have failed frontline non-gemcitabine containing regimens, beyond 5.6 months (median overall survival of patients receiving gemcitabine only based on historical data. (Phase II)
SECONDARY OBJECTIVES:
I. To determine objective response rate to the combination of gemcitabine and selinexor using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
II. To assess safety of selinexor in combination with gemcitabine in phase II portion of the study.
III. To determine progression free survival (PFS) in patients treated with gemcitabine and selinexor.
IV. To determine the influence of selinexor and gemcitabine on the nuclear expression and localization of tumor suppressor gene proteins.
OUTLINE: This is a phase Ib, dose-escalation study of selinexor followed by a phase II study.
PHASE IB: Patients receive gemcitabine hydrochloride intravenously (IV), nab-paclitaxel IV, and selinexor orally (PO) on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
PHASE II: The first 14 patients with liver metastases are randomized to 1 of 2 treatment groups. Remaining patients are assigned to Group II.
GROUP I: Patients receive gemcitabine hydrochloride IV on days 1, 8, and 15. Patients also receive selinexor PO on days 3, 8, and 15 of cycle 1 and on days 1, 8, and 15 for the subsequent cycles. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
GROUP II: Patients receive gemcitabine hydrochloride IV and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 2 months for 1 year.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationWayne State University/Karmanos Cancer Institute
Principal InvestigatorMohammed Najeeb Al Hallak
- Primary ID2013-133
- Secondary IDsNCI-2014-01249, 1403012942
- ClinicalTrials.gov IDNCT02178436