Colorectal NeoplasmsPhase 1/2NCT01675128
ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer
A Phase 1/2 study testing ISIS 183750 and Irinotecan in people with Colorectal Neoplasms and Colorectal Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the deoxyribonucleic acid (DNA) of growing cancer cells. It is most often used with other chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Neoplasms, Colorectal Carcinoma, Colorectal Tumors
- What is being tested?
- ISIS 183750 and Irinotecan
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2012to Dec 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Phase I: Patients must have histopathological confirmation of carcinoma by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study.
- Phase II: Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the NCI prior to entering this study. For this portion of the study patients must also have irinotecan-refractory colorectal cancer and have also received prior treatment for advanced/metastatic disease with an oxaliplatin-, bevacizumab-, or epidermal growth factor receptor (EGFR) inhibitor-containing (only for subjects with wild type Kras) regimen. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it.
- Patients must have disease that is not amenable to potentially curative resection or ablative techniques and have received at least one prior standard chemotherapeutic regimen for metastatic disease.
- All patients enrolled will be required to have measurable disease. For the phase II portion of the study patients must have disease that is amenable to biopsy and be willing to undergo this.
- Age greater than18 years
- Life expectancy of greater than 3 months
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- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Patients must have acceptable organ and marrow function as defined below:
- leukocytes > 3,000/mcL
- absolute neutrophil count > 1,500/mcL
- platelets > 100,000/mcL
- total bilirubin Within normal institutional limits
- Serum albumin greater than or equal to 2.5 g/dL
- Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) measuring 3 x upper limit of normal (ULN) if no liver metastasis or up to 5 x ULN with liver metastasis.
- creatinine < 1.5X institution upper limit of normal
- OR
- creatinine clearance > 45 mL/min/1.73 m^2, as calculated below, for patients with creatinine levels above institutional normal
- Estimated creatinine clearance (mL/min)
- Females see calculations
- Males see calculations - May use a 24 hr. urine collection to determine creatinine clearance.
- Measured creatinine clearance (mL/min)
- Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be < grade 1 or returned to baseline.
- Patients must not have other invasive malignancies within the past 3 years (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix and noninvasive bladder cancer that has had successful curative treatment).
- The effects of ISIS 183750 on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months after dosing with study medication ceases. However, adequate contraception for male patients should be used for 16 weeks post- last dose due to sperm life cycle. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women of child-bearing potential must have a negative pregnancy test prior to entry.
- Patient must be able to understand and willing to sign a written informed consent document.
- Men and women of all races and ethnic groups are eligible for this trial.
- Ejection fraction > 55% on echocardiogram.
Who cannot join
- Patients who have had chemotherapy (or so-called targeted systemic therapy), large field radiotherapy, or major surgery must wait 4 weeks after completing treatment prior to entering the study.
- Patients may not be receiving any antineoplastics or other drugs intended to treat cancer within 4 weeks prior to starting ISIS 183750.
- Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with clinically significant ascites, pleural effusion, and/or peripheral edema, unless the ascites or pleural effusion occurred as a result of malignancy.
- Patients with known hypersensitivity to irinotecan.
- Patients with known homozygous mutations in the UTG1A1 UUDP-glucuronosyltransferase 1-1) allele, or with unknown UTG1A1 status but who could not tolerate irinotecan even after dose reduction.
- Patients with bleeding diathesis and subjects who are receiving anticoagulation treatment with International Normalized Ratio (INR) > 2.5 are excluded.
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- Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) > 160, diastolic BP > 100), ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.
- Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and the investigational agent.
- Known hepatitis B or hepatitis C infection.
- Pregnancy and breast feeding are exclusion factors. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer
Background:
- Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the deoxyribonucleic acid (DNA) of growing cancer cells. It is most often used with other chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. They want to see if the drugs are a safe and effective treatment for advanced solid tumors or colorectal cancer that has not responded to other treatments.
Read more
Objectives:
- To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid tumors or colorectal cancer.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or colorectal cancer that has not responded to other treatments.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. Tumor tissue samples may be collected as well before and after treatment. Imaging studies will also be performed.
- Participants will take ISIS 183750 once a week for 28-day cycles of treatment. On the first cycle, they will also have ISIS 183750 on days 3 and 5.
- Participants will take irinotecan every second week, beginning on day 15 of the first cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Treatment will continue as long as the cancer does not grow and the side effects are not severe.
Read the detailed description
Background:
The eukaryotic translation initiation factor - eIF4E - is a potent oncogene that is found to be dysregulated in approximately 30% of human cancers. Upregulation of eIF4E is an early event in colorectal cancer (CRC) and correlates with CRC progression. ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the human eukaryotic translation initiation factor 4E (eIF4E) protein.
Objectives:
Primary:
To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS 183750 and irinotecan in advanced solid tumors.
Secondary:
- To evaluate Response Rate, Progression Free Survival (PFS), Overall Survival (OS) for the combination of ISIS 183750 and irinotecan in advanced irinotecan-refractory colorectal cancer.
- To perform correlative studies to evaluate the effect of eIF4E inhibition on relevant regulated proteins and immune cells.
- To characterize the plasma pharmacokinetic (PK) parameters for ISIS 183750 in the absence and presence of irinotecan
- To characterize the plasma PK parameters for irinotecan in the presence of ISIS 183750
Eligibility:
-Adult patients with irinotecan-resistant colorectal cancer (or advanced solid tumor in phase I part).
Design:
- This is a single-arm phase I/II study whereby all patients will receive the combination of ISIS 183750 and irinotecan. All cycles are 28 days.
- Cycle 1 only: ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22.
- Cycle 2 and beyond: ISIS 183750 will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.
- Irinotecan will be administered at a dose of 160mg/m^2 as an intravenous infusion every second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be to establish maximum tolerated dose (MTD) for the combination of ISIS 183750 and irinotecan in advanced solid tumors. The phase II portion of the study will be confined to irinotecan-refractory colorectal cancer. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it.
- Correlative studies will comprise: Mandatory pre- and post- dose biopsies for eIF4e messenger ribonucleic acid (mRNA) and protein (IHC) analysis will be performed in the phase II portion of the study; Immune subsets; positron emission tomography (PET) responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of irinotecan and ISIS183750 in 10-12 patients.
- Being tested
- ISIS 183750, Irinotecan
- Keywords
- Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein, Refractory, Oncogene, Maximum Tolerated Dose, Safety
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ISIS 183750Drug
IrinotecanDrug
| Study group | Role | What they receive |
|---|---|---|
| Phase I Dose Level I | Experimental | Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks. Receives: Drug: ISIS 183750; Drug: Irinotecan |
| Phase I Dose Level II | Experimental | Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks. Receives: Drug: ISIS 183750; Drug: Irinotecan |
| Phase II Dose Level I | Experimental | Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks. Receives: Drug: ISIS 183750; Drug: Irinotecan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
Measured: 2 years
Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
Measured: 2 years
Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies
A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).
Measured: 2 weeks
Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies
A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.
Measured: 2 weeks
Secondary outcomes (8)
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Measured: 21 months
Objective Response
Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more lesions is also considered progression).
Measured: up to 2 cycles
Number of Participants With Progression Free Survival
Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.
Measured: ≤ 6 months
Overall Survival
Overall survival is defined as the time from the on study date until the date of death or date last known alive.
Measured: ≥ 12 months
AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)
AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).
Measured: up to 24 hours post end of infusion
Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue
Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.
Measured: 2 weeks
Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins
Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.
Measured: 2 weeks
Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood
Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2012 (estimated)
- Study startAug 2012
- Primary completionDec 2014
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Colorectal NeoplasmsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Tim Greten, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Tim F Greten, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01675128
- Sponsor's protocol ID
- 120187
- Other IDs
- 12-C-0187
- Status last verified
- Mar 2016
- First submitted
- 25 Aug 2012
- Last updated
- 25 Apr 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Duffy AG, Makarova-Rusher OV, Ulahannan SV, Rahma OE, Fioravanti S, Walker M, Abdullah S, Raffeld M, Anderson V, Abi-Jaoudeh N, Levy E, Wood BJ, Lee S, Tomita Y, Trepel JB, Steinberg SM, Revenko AS, MacLeod AR, Peer CJ, Figg WD, Greten TF. Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int J Cancer. 2016 Oct 1;139(7):1648-57. doi: 10.1002/ijc.30199. Epub 2016 Jun 27.
PubMed 27194579
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer
- ClinicalTrials.gov ID
- NCT01675128
- Acronym / sponsor ID
- 120187
- Keywords
- Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein, Refractory, Oncogene, Maximum Tolerated Dose, Safety
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Aug 2012
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 29 Aug 2012 (estimated)
- Results
- Posted 25 Apr 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the deoxyribonucleic acid (DNA) of growing cancer cells. It is most often used with other chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. They want to see if the drugs are a safe and effective treatment for advanced solid tumors or colorectal cancer that has not responded to other treatments.
Objectives:
- To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid tumors or colorectal cancer.
Eligibility:
- Individuals at least 18 years of age who have solid tumors or colorectal cancer that has not responded to other treatments.
Design:
- Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. Tumor tissue samples may be collected as well before and after treatment. Imaging studies will also be performed.
- Participants will take ISIS 183750 once a week for 28-day cycles of treatment. On the first cycle, they will also have ISIS 183750 on days 3 and 5.
- Participants will take irinotecan every second week, beginning on day 15 of the first cycle.
- Treatment will be monitored with frequent blood tests and imaging studies.
- Treatment will continue as long as the cancer does not grow and the side effects are not severe.
Detailed description
Background:
The eukaryotic translation initiation factor - eIF4E - is a potent oncogene that is found to be dysregulated in approximately 30% of human cancers. Upregulation of eIF4E is an early event in colorectal cancer (CRC) and correlates with CRC progression. ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the human eukaryotic translation initiation factor 4E (eIF4E) protein.
Objectives:
Primary:
To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS 183750 and irinotecan in advanced solid tumors.
Secondary:
- To evaluate Response Rate, Progression Free Survival (PFS), Overall Survival (OS) for the combination of ISIS 183750 and irinotecan in advanced irinotecan-refractory colorectal cancer.
- To perform correlative studies to evaluate the effect of eIF4E inhibition on relevant regulated proteins and immune cells.
- To characterize the plasma pharmacokinetic (PK) parameters for ISIS 183750 in the absence and presence of irinotecan
- To characterize the plasma PK parameters for irinotecan in the presence of ISIS 183750
Eligibility:
-Adult patients with irinotecan-resistant colorectal cancer (or advanced solid tumor in phase I part).
Design:
- This is a single-arm phase I/II study whereby all patients will receive the combination of ISIS 183750 and irinotecan. All cycles are 28 days.
- Cycle 1 only: ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22.
- Cycle 2 and beyond: ISIS 183750 will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.
- Irinotecan will be administered at a dose of 160mg/m^2 as an intravenous infusion every second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be to establish maximum tolerated dose (MTD) for the combination of ISIS 183750 and irinotecan in advanced solid tumors. The phase II portion of the study will be confined to irinotecan-refractory colorectal cancer. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it.
- Correlative studies will comprise: Mandatory pre- and post- dose biopsies for eIF4e messenger ribonucleic acid (mRNA) and protein (IHC) analysis will be performed in the phase II portion of the study; Immune subsets; positron emission tomography (PET) responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of irinotecan and ISIS183750 in 10-12 patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Phase I Dose Level I | Experimental | Drug: ISIS 183750, Drug: IrinotecanIrinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks. |
| Phase I Dose Level II | Experimental | Drug: ISIS 183750, Drug: IrinotecanIrinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks. |
| Phase II Dose Level I | Experimental | Drug: ISIS 183750, Drug: IrinotecanIrinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- Phase I: Patients must have histopathological confirmation of carcinoma by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study.
- Phase II: Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the NCI prior to entering this study. For this portion of the study patients must also have irinotecan-refractory colorectal cancer and have also received prior treatment for advanced/metastatic disease with an oxaliplatin-, bevacizumab-, or epidermal growth factor receptor (EGFR) inhibitor-containing (only for subjects with wild type Kras) regimen. Irinotecan-refractory will be defined as patients who have radiological evidence of disease progression whilst receiving irinotecan or within 3 months after completing it.
- Patients must have disease that is not amenable to potentially curative resection or ablative techniques and have received at least one prior standard chemotherapeutic regimen for metastatic disease.
- All patients enrolled will be required to have measurable disease. For the phase II portion of the study patients must have disease that is amenable to biopsy and be willing to undergo this.
- Age greater than18 years
Key exclusion criteria (10 listed)
- Patients who have had chemotherapy (or so-called targeted systemic therapy), large field radiotherapy, or major surgery must wait 4 weeks after completing treatment prior to entering the study.
- Patients may not be receiving any antineoplastics or other drugs intended to treat cancer within 4 weeks prior to starting ISIS 183750.
- Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with clinically significant ascites, pleural effusion, and/or peripheral edema, unless the ascites or pleural effusion occurred as a result of malignancy.
- Patients with known hypersensitivity to irinotecan.
- Patients with known homozygous mutations in the UTG1A1 UUDP-glucuronosyltransferase 1-1) allele, or with unknown UTG1A1 status but who could not tolerate irinotecan even after dose reduction.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ISIS 183750 | Drug | Phase I Dose Level I, Phase I Dose Level II, Phase II Dose Level I |
| Irinotecan | Drug | Phase I Dose Level I, Phase I Dose Level II, Phase II Dose Level I |
Primary outcome
Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
Time frame: 2 years
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors
Time frame: 2 years
MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies
Time frame: 2 weeks
A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).
Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies
Time frame: 2 weeks
A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.
8 secondary outcomes
Number of Participants With Adverse Events
Time frame: 21 months
Objective Response
Time frame: up to 2 cycles
Number of Participants With Progression Free Survival
Time frame: ≤ 6 months
Overall Survival
Time frame: ≥ 12 months
AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)
Time frame: up to 24 hours post end of infusion
Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue
Time frame: 2 weeks
Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins
Time frame: 2 weeks
Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood
Time frame: 2 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 27194579Duffy AG, Makarova-Rusher OV, Ulahannan SV, Rahma OE, Fioravanti S, Walker M, Abdullah S, Raffeld M, Anderson V, Abi-Jaoudeh N, Levy E, Wood BJ, Lee S, Tomita Y, Trepel JB, Steinberg SM, Revenko AS, MacLeod AR, Peer CJ, Figg WD, Greten TF. Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int J Cancer. 2016 Oct 1;139(7):1648-57. doi: 10.1002/ijc.30199. Epub 2016 Jun 27.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tim F Greten, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing ISIS 183750 and Irinotecan in people with Colorectal Neoplasms and Colorectal Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Apr 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors (time frame: 2 years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01675128, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Apr 2016.