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Trial record 1 of 1 for:    NCT02178436
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Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Metastatic Pancreatic Cancer

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ClinicalTrials.gov Identifier: NCT02178436
Recruitment Status : Active, not recruiting
First Posted : June 30, 2014
Last Update Posted : April 17, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Philip Philip, Barbara Ann Karmanos Cancer Institute

Brief 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.

Condition or disease Intervention/treatment Phase
Acinar Cell Adenocarcinoma of the Pancreas Duct Cell Adenocarcinoma of the Pancreas Stage IV Pancreatic Cancer Drug: gemcitabine hydrochloride Drug: paclitaxel albumin-stabilized nanoparticle formulation Drug: selinexor Other: pharmacological study Other: laboratory biomarker analysis Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330, Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer
Study Start Date : October 2014
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Group I (selinexor, gemcitabine, nab-paclitaxel)
Patients receive gemcitabine hydrochloride IV and paclitaxel albumin-stabilized nanoparticle formulation IV once weekly (Mondays) for 3 weeks. 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.
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar

Drug: paclitaxel albumin-stabilized nanoparticle formulation
Given IV
Other Names:
  • ABI-007
  • nab paclitaxel
  • nab-paclitaxel
  • nanoparticle albumin-bound paclitaxel

Drug: selinexor
Given PO
Other Names:
  • CRM1 nuclear export inhibitor KPT-330
  • KPT-330
  • selective inhibitor of nuclear export KPT-330
  • SINE KPT-330

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Other: laboratory biomarker analysis
Correlative studies

Experimental: Group II (selinexor, gemcitabine, nab-paclitaxel)
Patients receive gemcitabine hydrochloride IV and paclitaxel albumin-stabilized nanoparticle formulation IV once weekly (Mondays) for 3 weeks. 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.
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar

Drug: paclitaxel albumin-stabilized nanoparticle formulation
Given IV
Other Names:
  • ABI-007
  • nab paclitaxel
  • nab-paclitaxel
  • nanoparticle albumin-bound paclitaxel

Drug: selinexor
Given PO
Other Names:
  • CRM1 nuclear export inhibitor KPT-330
  • KPT-330
  • selective inhibitor of nuclear export KPT-330
  • SINE KPT-330

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Other: laboratory biomarker analysis
Correlative studies




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of selinexor, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation combination (Phase Ib) [ Time Frame: 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.

  2. Incidence of toxicity graded according to NCI CTCAE version 4.03 (Phase II) [ Time Frame: Up to 2 years ]
    Point and 90% Wilson's confidence intervals will be estimated to describe toxicity rate.

  3. Overall survival (Phase II) [ Time Frame: 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.


Secondary Outcome Measures :
  1. Effects the study drug combination has on participants [ Time Frame: 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

  2. Response rate [ Time Frame: Up to 2 years ]
    Point and 90% Wilson's confidence intervals will be estimated to describe response rate.

  3. Progression free survival (Phase II) [ Time Frame: 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.


Other Outcome Measures:
  1. Change in gene expression (including forkhead box protein O, I-kappaB, cyclin-dependent kinase inhibitor 1B, Par4 and phosphorylated signal transducer and activator of transcription 3) (Phase II) [ Time Frame: Baseline to up to 2 years ]
    Seven patients in each group will yield a two-sided 90% confidence interval with a distance from the mean change to the limits of 0.75 standard deviation units. A two-sided p-value of 0.10 will be used for all analyses.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02178436


Locations
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Philip Philip Barbara Ann Karmanos Cancer Institute

Responsible Party: Philip Philip, Principal Investigator, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT02178436     History of Changes
Other Study ID Numbers: 2013-133
NCI-2014-01249 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1403012942
2013-133 ( Other Identifier: Barbara Ann Karmanos Cancer Institute )
P30CA022453 ( U.S. NIH Grant/Contract )
First Posted: June 30, 2014    Key Record Dates
Last Update Posted: April 17, 2018
Last Verified: April 2018

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma, Acinar Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs