Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Stage IV Pancreatic Cancer
Conditions
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.
Interventions
DRUGgemcitabine hydrochloride
Given IV
DRUGSelinexor
Given IV
OTHERPharmacological Study
Correlative studies
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGNab paclitaxel
Given IV
Sponsors
Mohammed Najeeb Al Hallak
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I is completed, due to Dose Limiting Toxicities (DLT).
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Accrual time period: 10/31/14 - 02/09/22
Pre-assignment details
2 patients enrolled but did not receive any treatment
Participants by arm
| Arm | Count |
|---|---|
| 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.
gemcitabine hydrochloride: Given IV
Selinexor: Given IV
Pharmacological Study: Correlative studies
Laboratory Biomarker Analysis: Correlative studies
Nab paclitaxel: Given IV | 9 |
| 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
gemcitabine hydrochloride: Given IV
Selinexor: Given IV
Pharmacological Study: Correlative studies
Laboratory Biomarker Analysis: Correlative studies | 0 |
| 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.
gemcitabine hydrochloride: Given IV
Selinexor: Given IV
Pharmacological Study: Correlative studies
Laboratory Biomarker Analysis: Correlative studies | 4 |
| Total | 13 |
Baseline characteristics
| Characteristic | Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Total | GroupIII: Phase II Group II (Gemcitabine, Selinexor) |
|---|---|---|---|
| Age, Continuous | 68 years | 61 years | 56 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 11 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 2 Participants |
| Region of Enrollment United States | 9 participants | 13 participants | 4 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 9 | 0 / 0 | 0 / 4 |
| other Total, other adverse events | 9 / 9 | 0 / 0 | 4 / 4 |
| serious Total, serious adverse events | 6 / 9 | 0 / 0 | 0 / 4 |
Outcome results
Primary
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.
Time frame: 28 days
Population: Maximum tolerated dose is only estimated using the Phase 1b samples
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Maximum Tolerated Dose (MTD) of Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-stabilized Nanoparticle Formulation Combination (Phase Ib) | 80 milligrams |
Primary
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.
Time frame: Up to 7 months post treatment initiation
Population: Group II enrolled no patients because patients refused to undergo the required biopsy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Overall Survival (Phase II) | 5.45 months |
| GroupIII: Phase II Group II (Gemcitabine, Selinexor) | Overall Survival (Phase II) | NA months |
Primary
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.
Time frame: Up to 2 years
Population: Group II enrolled no patients because patients refused to undergo the required biopsy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Proportion of Patients With a Toxic Event, Graded According to NCI CTCAE Version 4.03 | 1.00 proportion of patients |
| GroupIII: Phase II Group II (Gemcitabine, Selinexor) | Proportion of Patients With a Toxic Event, Graded According to NCI CTCAE Version 4.03 | 0.75 proportion of patients |
Secondary
Effects the Study Drug Combination Has on Participants
Pharmacodynamics of selinexor in combination with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation
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
Population: Pharmacodynamics data was not measured.
Secondary
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.
Time frame: Up to 2 years
Population: Group II enrolled no patients because patients refused to undergo the required biopsy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Progression Free Survival (Phase II) | 4.60 months |
| GroupIII: Phase II Group II (Gemcitabine, Selinexor) | Progression Free Survival (Phase II) | 1.74 months |
Secondary
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.
Time frame: Up to 2 years
Population: Group II enrolled no patients because patients refused to undergo the required biopsy. Four patients in Group I were not evaluated for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Phase Ib (Gemcitabine, Nab-paclitaxel, Selinexor) | Proportion of Patients With a Response | 0.40 proportion of patients |
| GroupIII: Phase II Group II (Gemcitabine, Selinexor) | Proportion of Patients With a Response | 0 proportion of patients |
Other Pre-specified
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.
Time frame: Baseline to up to 2 years
Population: Gene expression data was not measured.