Metastatic Malignant Neoplasm in the Brain, Metastatic Solid Neoplasm, Recurrent Colorectal Carcinoma, Recurrent Pancreatic Carcinoma, Recurrent Solid Neoplasm, Stage IVA Colorectal Cancer, Stage IVA Pancreatic Cancer, Stage IVB Colorectal Cancer, Stage IVB Pancreatic Cancer, Stage IV Colorectal Cancer, Stage IV Pancreatic Cancer, Unresectable Solid Neoplasm
Conditions
Brief summary
This phase I trial studies the side effects and best dose of APN401 in treating patients with pancreatic cancer, colorectal cancer, or other solid tumors that have spread to other places in the body or have come back. APN401 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the toxicities and establish the safety of multiple infusions of small interfering ribonucleic acid (siRNA)-transfected peripheral blood mononuclear cells APN401 (APN401). SECONDARY OBJECTIVES: I. To determine the immunologic effects of multiple infusions of APN401. II. To document clinical response and survival. OUTLINE: Patients receive siRNA-transfected peripheral blood mononuclear cells APN401 intravenously (IV) over 30 minutes on days 1, 29, and 57 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 5 years.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALsiRNA-transfected Peripheral Blood Mononuclear Cells (PBMC) APN401
Given IV
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with histologically confirmed inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have either: * Failed to respond to standard therapy or * For whom no standard therapy is available or * Refuse to receive standard therapies * The study is intended to enroll patients with pancreatic and colorectal cancer; patients with other types of solid tumors will require approval by the principal investigator * Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) * Patients with treated, stable, and asymptomatic brain metastases are eligible * Patients on every 3 or every 4 week systemic therapy programs must be at least 4 weeks since treatment and recovered from any clinically significant toxicity experienced; patients on weekly or daily systemic therapy programs and patients receiving radiation must be at least 1 week since treatment and recovered from any clinically significant toxicity experienced; must be at least 4 weeks and have recovered from major surgery * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * White blood cells \>= 3000/uL * Platelets \>= 100,000/uL * Hematocrit \>= 28% * Creatinine =\< 1.6 mg/dL * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 x upper limit of normal * Bilirubin =\< 1.6 mg/dL (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) * Albumin \>= 3.0 g/dL * International normalized ratio (INR) =\< 1.5
Exclusion criteria
* Women must not be pregnant or breastfeeding; all women of childbearing potential must have a blood test within 72 hours to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception; women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential * Untreated, progressing, or symptomatic brain metastases * Autoimmune disease, as follows: patients with a history of inflammatory bowel disease are excluded as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\]); patients with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis) are excluded; patients with a history of autoimmune thyroiditis are eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy * Any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix * Other ongoing systemic therapy for cancer, including any other experimental treatment; these include concomitant therapy with any of the following: IL-2, interferon, ipilimumab, pembrolizumab, nivolumab, or other immunotherapy; cytotoxic chemotherapy; and targeted therapies * Ongoing requirement for an immunosuppressive treatment, including the use of glucocorticoids or cyclosporine, or with a history of chronic use of any such medication within the last 4 weeks before enrollment; patients are excluded if they have any concurrent medical condition that requires the use of systemic steroids (the use of inhaled or topical steroids is permitted) * Infection with human immunodeficiency virus (HIV) * Active infection with hepatitis B; active or chronic infection with hepatitis C * Clinically significant pulmonary dysfunction, as determined by medical history and physical examination; patients with a history of pulmonary dysfunction must have pulmonary function tests with a forced expiratory volume in 1 second (FEV1) \>= 60% of predicted and a diffusing capacity of the lung for carbon monoxide (DLCO) \>= 55% (corrected for hemoglobin) * Clinically significant cardiovascular abnormalities (e.g., congestive heart failure or symptoms of coronary artery disease), as determined by medical history and physical examination; patients with a history of cardiac disease must have a normal cardiac stress test (treadmill, echocardiogram, or myocardial perfusion scan) within the past 6 months of study entry * Active infections or oral temperature \> 38.2 degrees Celsius (C) within 48 hours of study entry * Systemic infection requiring chronic maintenance or suppressive therapy * Patients are excluded for any underlying medical or psychiatric condition, which in the opinion of the investigator, will make treatment hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent rashes or diarrhea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Up to 1 year | Will be categorized by organ system and severity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Related treatment emergent adverse events by maximum severity. Unexpected grade 4 and all grade 5 events are considered severe adverse events. CTCAE grades 3-5 allergic reactions related to study cell infusion CTCAE grades 3 and greater autoimmune reactions other than that vitiligo CTCAE grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study product infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Immune Cells | Days 15 and 28 | Immune response as measured by frequency of immune cells |
| Immune Response as Measured by Interferon Production | Days 15 and 28 | Immune response as measured by interferon production |
| Clinical Response as Assessed by RECIST | Up to approximately 4 years | Will be summarized as frequency counts and percentages. RECIST criteria: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started |
| Overall Survival (OS) | From the initial infusion to confirmation of death, assessed up to approximately 4 years | Exploratory survival plots will be estimated using the Kaplan Meier approach and median overall survival will be estimated if enough events occur. |
| Progression-free Survival (PFS) | From the initial infusion to confirmation of progression or death, assessed up to approximately 4 years | Exploratory survival plots will be estimated using the Kaplan Meier approach and median PFS will be estimated if enough events occur. |
| Neutrophil to Lymphocyte Ratio | Days 15 and 28 | Immune response as measured by neutrophil to lymphocyte ratio |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (APN401) Patients receive siRNA-transfected peripheral blood mononuclear cells APN401 IV over 30 minutes on days 1, 29, and 57 in the absence of disease progression or unacceptable toxicity.
Laboratory Biomarker Analysis: Correlative studies
siRNA-transfected Peripheral Blood Mononuclear Cells APN401: Given IV | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease progression before starting treatment, removed from study | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment (APN401) |
|---|---|
| Age, Continuous | 56 years |
| CD14+ | 6.0 percentage of cells STANDARD_DEVIATION 6.6 |
| CD19+ | 2.6 percentage of cells STANDARD_DEVIATION 4.9 |
| CD3+ | 27.4 percentage of cells STANDARD_DEVIATION 16.4 |
| CD3-CD56+ | 4.2 percentage of cells STANDARD_DEVIATION 2.8 |
| CD4+ | 24.2 percentage of cells STANDARD_DEVIATION 26.8 |
| CD4+CD45RO+ | 26.2 percentage of cells STANDARD_DEVIATION 19.2 |
| CD4+FOXP3+ | 12.0 percentage of cells STANDARD_DEVIATION 14.7 |
| CD4+ICOS+ | 13.2 percentage of cells STANDARD_DEVIATION 20 |
| CD56+ | 4.9 percentage of cells STANDARD_DEVIATION 4.2 |
| CD8+ | 19.3 percentage of cells STANDARD_DEVIATION 23.7 |
| CD8+ICOS+ | 11.3 percentage of cells STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| IFN | 65.1 pg/ml STANDARD_DEVIATION 17.7 |
| IL-2 | 195.1 pg/ml STANDARD_DEVIATION 231.5 |
| Neutrophil to Lymphocyte Ratio | 3.32 ratio STANDARD_DEVIATION 1.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 2 / 9 |
Outcome results
Primary
Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0
Will be categorized by organ system and severity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Related treatment emergent adverse events by maximum severity. Unexpected grade 4 and all grade 5 events are considered severe adverse events. CTCAE grades 3-5 allergic reactions related to study cell infusion CTCAE grades 3 and greater autoimmune reactions other than that vitiligo CTCAE grades 3 and greater organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, pulmonary, renal/genitourinary or neurologic) not pre-existing or due to the underlying malignancy and occurring within 30 days of study product infusion
Time frame: Up to 1 year
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | General disorders and administration site conditions | Grade 3 | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | General disorders and administration site conditions | Unobserved | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | General disorders and administration site conditions | Grade 1 | 1 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | General disorders and administration site conditions | Grade 2 | 8 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Nervous System Disorders | Unobserved | 5 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Nervous System Disorders | Grade 1 | 4 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Nervous System Disorders | Grade 2 | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Nervous System Disorders | Grade 3 | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Gastrointestinal Disorders | Unobserved | 6 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Gastrointestinal Disorders | Grade 1 | 2 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Gastrointestinal Disorders | Grade 2 | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Gastrointestinal Disorders | Grade 3 | 1 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Musculoskeletal and connective tissue disorders | Unobserved | 7 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Musculoskeletal and connective tissue disorders | Grade 1 | 0 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Musculoskeletal and connective tissue disorders | Grade 2 | 2 Participants |
| Treatment (APN401) | Number of Adverse Events Common Terminology Criteria for Adverse Events Version 4.0 | Musculoskeletal and connective tissue disorders | Grade 3 | 0 Participants |
Secondary
Clinical Response as Assessed by RECIST
Will be summarized as frequency counts and percentages. RECIST criteria: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Time frame: Up to approximately 4 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (APN401) | Clinical Response as Assessed by RECIST | Complete Response | 0 Participants |
| Treatment (APN401) | Clinical Response as Assessed by RECIST | Partial Response | 0 Participants |
| Treatment (APN401) | Clinical Response as Assessed by RECIST | Stable Disease | 3 Participants |
| Treatment (APN401) | Clinical Response as Assessed by RECIST | Progressive Disease | 6 Participants |
Secondary
Frequency of Immune Cells
Immune response as measured by frequency of immune cells
Time frame: Days 15 and 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (APN401) | Frequency of Immune Cells | CD3+ (day 15) | 37.1 percentage of cells | Standard Deviation 17.3 |
| Treatment (APN401) | Frequency of Immune Cells | CD14+ (day 15) | 5.1 percentage of cells | Standard Deviation 2.8 |
| Treatment (APN401) | Frequency of Immune Cells | CD3+ (day 28) | 40.3 percentage of cells | Standard Deviation 15.1 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+ (day 15) | 19.0 percentage of cells | Standard Deviation 20 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+ (day 28) | 26.4 percentage of cells | Standard Deviation 4 |
| Treatment (APN401) | Frequency of Immune Cells | CD8+ (day 15) | 15.5 percentage of cells | Standard Deviation 16.1 |
| Treatment (APN401) | Frequency of Immune Cells | CD8+ (day 28) | 22.7 percentage of cells | Standard Deviation 14.1 |
| Treatment (APN401) | Frequency of Immune Cells | CD14+ (day 28) | 7.3 percentage of cells | Standard Deviation 7.3 |
| Treatment (APN401) | Frequency of Immune Cells | CD19+ (day 15) | 1.2 percentage of cells | Standard Deviation 1.6 |
| Treatment (APN401) | Frequency of Immune Cells | CD19+ (day 28) | 2.6 percentage of cells | Standard Deviation 3.2 |
| Treatment (APN401) | Frequency of Immune Cells | CD45RO+ (day 15) | 14.8 percentage of cells | Standard Deviation 8.2 |
| Treatment (APN401) | Frequency of Immune Cells | CD45RO+ (day 28) | 37.3 percentage of cells | Standard Deviation 2 |
| Treatment (APN401) | Frequency of Immune Cells | CD56+ (day 15) | 4.8 percentage of cells | Standard Deviation 3.4 |
| Treatment (APN401) | Frequency of Immune Cells | CD56+ (day 28) | 8.3 percentage of cells | Standard Deviation 8.5 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+ICOS+ (day 15) | 12.8 percentage of cells | Standard Deviation 19.7 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+ICOS+ (day 28) | 16.8 percentage of cells | Standard Deviation 15.7 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+CD45RO+ (day 15) | 14.8 percentage of cells | Standard Deviation 8.2 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+CD45RO+ (day 28) | 37.3 percentage of cells | Standard Deviation 2 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+FOXP3+ (day 15) | 13.9 percentage of cells | Standard Deviation 16.4 |
| Treatment (APN401) | Frequency of Immune Cells | CD4+FOXP3+ (day 28) | 29.5 percentage of cells | Standard Deviation 18.3 |
| Treatment (APN401) | Frequency of Immune Cells | CD8+ICOS+ (day 15) | 12.3 percentage of cells | Standard Deviation 14.5 |
| Treatment (APN401) | Frequency of Immune Cells | CD8+ICOS+ (day 28) | 25.2 percentage of cells | Standard Deviation 7.8 |
| Treatment (APN401) | Frequency of Immune Cells | CD3-CD56+ (day 15) | 4.2 percentage of cells | Standard Deviation 1.7 |
| Treatment (APN401) | Frequency of Immune Cells | CD3-CD56+ (day 28) | 5.4 percentage of cells | Standard Deviation 1.1 |
Secondary
Immune Response as Measured by Interferon Production
Immune response as measured by interferon production
Time frame: Days 15 and 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (APN401) | Immune Response as Measured by Interferon Production | IFN (day 15) | 75.1 pg/ml | Standard Deviation 17.6 |
| Treatment (APN401) | Immune Response as Measured by Interferon Production | IFN (day 28) | 90.7 pg/ml | Standard Deviation 37.8 |
| Treatment (APN401) | Immune Response as Measured by Interferon Production | IL-2 (day 15) | 226 pg/ml | Standard Deviation 51.1 |
| Treatment (APN401) | Immune Response as Measured by Interferon Production | IL-2 (day 28) | 674.4 pg/ml | Standard Deviation 978.6 |
Secondary
Neutrophil to Lymphocyte Ratio
Immune response as measured by neutrophil to lymphocyte ratio
Time frame: Days 15 and 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (APN401) | Neutrophil to Lymphocyte Ratio | Day 15 | 2.72 ratio | Standard Deviation 1.21 |
| Treatment (APN401) | Neutrophil to Lymphocyte Ratio | Day 28 | 4.98 ratio | Standard Deviation 5.81 |
Secondary
Overall Survival (OS)
Exploratory survival plots will be estimated using the Kaplan Meier approach and median overall survival will be estimated if enough events occur.
Time frame: From the initial infusion to confirmation of death, assessed up to approximately 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (APN401) | Overall Survival (OS) | 181 days |
Secondary
Progression-free Survival (PFS)
Exploratory survival plots will be estimated using the Kaplan Meier approach and median PFS will be estimated if enough events occur.
Time frame: From the initial infusion to confirmation of progression or death, assessed up to approximately 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (APN401) | Progression-free Survival (PFS) | 70 days |