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

Sponsor
Mohammed Najeeb Al Hallak (Other)
Overall Status
Suspended
CT.gov ID
NCT02178436
Collaborator
National Cancer Institute (NCI) (NIH)
56
Enrollment
2
Locations
3
Arms
122
Anticipated Duration (Months)
28
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: gemcitabine hydrochloride
  • Drug: Selinexor
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
  • Drug: Nab paclitaxel
 Phase 1/Phase 2

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
56 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Phase I is completed, due to Dose Limiting Toxicities (DLT).Phase I is completed, due to Dose Limiting Toxicities (DLT).
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase Ib Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330), Gemcitabine and Nab-Paclitaxel and Phase II Study of Gemcitabine and Selinexor in Patients With Metastatic Pancreatic Cancer
Actual Study Start Date :
Oct 31, 2014
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Group I: Phase Ib (gemcitabine, nab-paclitaxel, 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.

Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • Gemcitabine HCI
  • Gemzar

    • Drug: Selinexor
    Given IV
    Other Names:
  • KPT-330
  • Xpovio
  • CRM1 nuclear export inhibitor KPT-330
  • selective inhibitor of nuclear export KPT-330
  • SINE KPT-330

    • Other: Pharmacological Study
    Correlative studies

    Other: Laboratory Biomarker Analysis
    Correlative studies

    Drug: Nab paclitaxel
    Given IV
    Other Names:
  • ABI 007
  • Abraxane
  • Protein-bound Paclitaxel
  • Nanoparticle Paclitaxel,

    		•
    Experimental: Group II: Phase II Group I (gemcitabine, 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

    Drug: gemcitabine hydrochloride
    Given IV
    Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • Gemcitabine HCI
  • Gemzar

    • Drug: Selinexor
    Given IV
    Other Names:
  • KPT-330
  • Xpovio
  • CRM1 nuclear export inhibitor KPT-330
  • selective inhibitor of nuclear export KPT-330
  • SINE KPT-330

    • Other: Pharmacological Study
    Correlative studies

    Other: Laboratory Biomarker Analysis
    Correlative studies
    Experimental: GroupIII: Phase II Group II (gemcitabine, 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.

    Drug: gemcitabine hydrochloride
    Given IV
    Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • Gemcitabine HCI
  • Gemzar

    • Drug: Selinexor
    Given IV
    Other Names:
  • KPT-330
  • Xpovio
  • CRM1 nuclear export inhibitor KPT-330
  • selective inhibitor of nuclear export KPT-330
  • SINE KPT-330

    • Other: Pharmacological Study
    Correlative studies

    Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. Incidence of toxicity graded according to NCI CTCAE version 4.03 (Phase II) [Up to 2 years]

      Point and 90% Wilson's confidence intervals will be estimated to describe toxicity rate.

    3. Overall 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.

    Secondary Outcome Measures

    1. 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

    2. Response rate [Up to 2 years]

      Point and 90% Wilson's confidence intervals will be estimated to describe response rate.

    3. 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.

    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) [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    19 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Barbara Ann Karmanos Cancer Institute Detroit Michigan United States 48201
    2 Stony Brook University Cancer Center Stony Brook New York United States 11794

    Sponsors and Collaborators

    • Mohammed Najeeb Al Hallak
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Mohammed N Al Hallak, M.D., Barbara Ann Karmanos Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Mohammed Najeeb Al Hallak, Principal Investigator, Barbara Ann Karmanos Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT02178436
    Other Study ID Numbers:
    • 2013-133
    • NCI-2014-01249
    • P30CA022453
    First Posted:
    Jun 30, 2014
    Last Update Posted:
    Feb 17, 2022
    Last Verified:
    Feb 1, 2022
    Additional relevant MeSH terms:
    Adenocarcinoma
    Pancreatic Neoplasms
    Carcinoma, Acinar Cell
    Gemcitabine
    Paclitaxel
    Albumin-Bound Paclitaxel

    Study Results

    No Results Posted as of Feb 17, 2022