Gemcitabine, Nab-paclitaxel and KPT-330 in Advanced Pancreatic Cancer

Phase 1

Completed

Conditions: Acinar Cell Adenocarcinoma of the Pancreas
Duct Cell Adenocarcinoma of the Pancreas
Stage IV Pancreatic Cancer

Interventions: Drug: gemcitabine hydrochloride
Drug: Selinexor
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Drug: Nab paclitaxel

Registration Number: NCT02178436

Lead Sponsor: Mohammed Najeeb Al Hallak

Brief Summary: 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.

Detailed Description: Primary Objectives:

1. Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nabpaclitaxel and selinexor for untreated metastatic pancreatic cancer \[COMPLETED\]

2. Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel and selinexor \[COMPLETED\]

3. Phase II: 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 patient receiving gemcitabine only based on historical data.

Secondary Objectives:

1. To determine objective response rate to the combination of gemcitabine and selinexor using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

2. To assess safety of selinexor in combination with gemcitabine in phase II portion of the study

3. To determine progression free survival (PFS) in patients treated with gemcitabine and selinexor

4. To determine the influence of selinexor and gemcitabine on the nuclear expression and localization of tumor suppressor gene proteins.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I: Phase Ib (gemcitabine, nab-paclitaxel, selinexor)	gemcitabine hydrochloride	Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group I: Phase Ib (gemcitabine, nab-paclitaxel, selinexor)	Selinexor	Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group I: Phase Ib (gemcitabine, nab-paclitaxel, selinexor)	Pharmacological Study	Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group I: Phase Ib (gemcitabine, nab-paclitaxel, selinexor)	Laboratory Biomarker Analysis	Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group I: Phase Ib (gemcitabine, nab-paclitaxel, selinexor)	Nab paclitaxel	Patients receive gemcitabine hydrochloride IV, nab-paclitaxel IV, and selinexor PO on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group II: Phase II Group I (gemcitabine, selinexor)	gemcitabine hydrochloride	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: Phase II Group I (gemcitabine, selinexor)	Pharmacological Study	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: Phase II Group I (gemcitabine, selinexor)	Laboratory Biomarker Analysis	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
GroupIII: Phase II Group II (gemcitabine, selinexor)	gemcitabine hydrochloride	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.
GroupIII: Phase II Group II (gemcitabine, selinexor)	Pharmacological Study	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.
GroupIII: Phase II Group II (gemcitabine, selinexor)	Laboratory Biomarker Analysis	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.
Group II: Phase II Group I (gemcitabine, selinexor)	Selinexor	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
GroupIII: Phase II Group II (gemcitabine, selinexor)	Selinexor	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.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-stabilized Nanoparticle Formulation Combination (Phase Ib)	28 days	MTD is defined as the lowest dose for which less than a third of patients experience a dose limiting toxicity graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Overall Survival (Phase II)	Up to 7 months post treatment initiation	Estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed at least one 4-week treatment cycle) using the Kaplan-Meier method.
Proportion of Patients With a Toxic Event, Graded According to NCI CTCAE Version 4.03	Up to 2 years	The reported output is the proportion of patients that had a toxic event along with the associated 90% Wilson's confidence interval.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (Phase II)	Up to 2 years	Estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed at least one 4-week treatment cycle) using the Kaplan-Meier method. Both progression and death are considered events for this analysis.
Proportion of Patients With a Response	Up to 2 years	Point and 90% Wilson's confidence intervals will be estimated to describe response rate. If the best observed clinical response was complete response or partial response, we consider that the patient responded.
Effects the Study Drug Combination Has on Participants	Day 1 of course 1 (before selinexor administration, 1, 2, 4 and 8 hours after selinexor administration) and days 2, 3 and 8	Pharmacodynamics of selinexor in combination with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation

Trial Locations

Locations (2): Stony Brook University Cancer Center
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Stony Brook, New York, United States
Barbara Ann Karmanos Cancer Institute
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Detroit, Michigan, United States