Patient case: 48-year-old male with Pancreatic cancer. Genetic variant: CDK6 Amplification. Other conditions: None.

Clinical trial: Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Metastatic Pancreatic Cancer

Summary: This partially randomized phase Ib/II trial studies the side effects and best dose of selinexor when given together with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation and to see how well they work in treating patients with pancreatic cancer that has spread to other parts of the body. Drugs used in chemotherapy, such as selinexor, gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation, 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.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine the recommended phase 2 dose (RP2D) of gemcitabine (gemcitabine hydrochloride), nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) and KPT-330 (selinexor) for untreated metastatic pancreatic cancer.
  II. To determine the safety profile of gemcitabine, nab-paclitaxel and KPT-330. III. To test whether gemcitabine, nab-paclitaxel and KPT-330 improves overall survival as compared to historical controls comprising of patients with metastatic pancreatic cancer.
  SECONDARY OBJECTIVES:
  I. To determine objective response rate to combination of gemcitabine, nab-paclitaxel and KPT-330 using Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
  II. To confirm safety of KPT-330 at the RP2D in combination with gemcitabine and nab-paclitaxel in phase II arm of the study.
  III. To determine progression free survival (PFS) in phase II cohort treated with gemcitabine, nab-paclitaxel and KPT-330.
  IV. To determine the influence of KP-330, gemcitabine and nab-paclitaxel on the nuclear expression and localization of tumor suppressor gene proteins.
  OUTLINE: This is a phase Ib, dose-escalation study of selinexor followed by phase II.
  PHASE IB:
  Patients receive gemcitabine hydrochloride intravenously (IV) and paclitaxel albumin-stabilized nanoparticle formulation IV once weekly (Mondays) for 3 weeks. Patients also receive selinexor orally (PO) twice weekly (Mondays and Wednesdays) for 4 weeks. Courses 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 and paclitaxel albumin-stabilized nanoparticle formulation IV as in Phase Ib. Beginning day 3 of course 1, patients also receive selinexor PO twice weekly (Mondays and Wednesdays) for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  GROUP II: Patients receive gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, and selinexor as in Phase Ib.
  After completion of study treatment, patients are followed up for 2 years.

Eligibility: Inclusion Criteria:
  -  Written informed consent in accordance with federal, local, and institutional guidelines
  -  Patients with metastatic pancreatic adenocarcinoma not treated with chemotherapy for metastatic disease
  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  -  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) < 2.5 times ULN
  -  Serum creatinine =< 1.5 mg/dL
  -  Serum albumin >= 3.0 g/dL
  -  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 have no evidence of disease for last five years are allowed to participate
  Exclusion Criteria:
  -  Patients who are pregnant or lactating
  -  Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 3 weeks prior to cycle 1 day 1; mitomycin C or radio-immunotherapy 6 weeks prior to cycle 1 day 1
  -  Major surgery within four weeks before cycle 1 day 1
  -  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 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
  -  Grade >= 2 peripheral neuropathy within 14 days prior to cycle 1 day 1
  -  History of seizures, movement disorders or cerebrovascular accident within the past 5 years prior to cycle 1 day 1
  -  Patients with muscular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity based on physician's assessment
  -  Serious psychiatric 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
  -  Presence of clinically significant ascites

Relevance to patient case: not relevant