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

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

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.

Study Overview

• Status: Completed
• Conditions: Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Stage IV Pancreatic Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: gemcitabine hydrochloride; Drug: Nab paclitaxel; Drug: Selinexor

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 Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; dFdC; Gemcitabine HCI; difluorodeoxycytidine hydrochloride; Drug: Nab paclitaxel; Given IV; Other Names: Abraxane; ABI 007; Protein-bound Paclitaxel; Nanoparticle Paclitaxel,; Drug: Selinexor; Given IV; Other Names: KPT-330; SINE KPT-330; Xpovio; CRM1 nuclear export inhibitor KPT-330; selective inhibitor of nuclear export KPT-330
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	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; dFdC; Gemcitabine HCI; difluorodeoxycytidine hydrochloride; Drug: Selinexor; Given IV; Other Names: KPT-330; SINE KPT-330; Xpovio; CRM1 nuclear export inhibitor KPT-330; selective inhibitor of nuclear export KPT-330
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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: gemcitabine hydrochloride; Given IV; Other Names: Gemzar; dFdC; Gemcitabine HCI; difluorodeoxycytidine hydrochloride; Drug: Selinexor; Given IV; Other Names: KPT-330; SINE KPT-330; Xpovio; CRM1 nuclear export inhibitor KPT-330; selective inhibitor of nuclear export KPT-330

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-stabilized Nanoparticle Formulation Combination (Phase Ib)	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.	28 days
Proportion of Patients With a Toxic Event, Graded According to NCI CTCAE Version 4.03	The reported output is the proportion of patients that had a toxic event along with the associated 90% Wilson's confidence interval.	Up to 2 years
Overall Survival (Phase II)	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.	Up to 7 months post treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects the Study Drug Combination Has on Participants	Pharmacodynamics of selinexor in combination with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation	Day 1 of course 1 (before selinexor administration, 1, 2, 4 and 8 hours after selinexor administration) and days 2, 3 and 8
Proportion of Patients With a Response	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.	Up to 2 years
Progression Free Survival (Phase II)	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.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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.	Baseline to up to 2 years

Collaborators and Investigators

• Sponsor: Mohammed Najeeb Al Hallak
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mohammed N Al Hallak, M.D., Barbara Ann Karmanos Cancer Institute

Publications and helpful links

General Publications

• Azmi AS, Khan HY, Muqbil I, Aboukameel A, Neggers JE, Daelemans D, Mahipal A, Dyson G, Kamgar M, Al-Hallak MN, Tesfaye A, Kim S, Shidham V, M Mohammad R, Philip PA. Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2020 Mar 15;26(6):1338-1348. doi: 10.1158/1078-0432.CCR-19-1728. Epub 2019 Dec 12.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2014
• Primary Completion (Actual): November 27, 2021
• Study Completion (Actual): April 5, 2023

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 26, 2014
• First Posted (Estimated): June 30, 2014

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 5, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Carcinoma, Acinar Cell; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Albumin-Bound Paclitaxel; Gemcitabine
• Other Study ID Numbers: 2013-133; NCI-2014-01249 (Other Identifier: CTRP (Clinical Trial Reporting Program))