Clinical trial NCT01675128: ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer
Official title: A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Colorectal Neoplasms
Colorectal Carcinoma
Colorectal Tumors
Keywords: Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein
Refractory
Oncogene
Maximum Tolerated Dose
Safety
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-08-29
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: * INCLUSION CRITERIA:
* 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
* 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.

EXCLUSION CRITERIA:

* 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.
* 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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
timeFrame: 2 years
measure: Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors
timeFrame: 2 years
measure: 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
timeFrame: 2 weeks
measure: Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies
timeFrame: 2 weeks
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 21 months
measure: Objective Response
timeFrame: up to 2 cycles
measure: Number of Participants With Progression Free Survival
timeFrame: ≤ 6 months
measure: Overall Survival
timeFrame: ≥ 12 months
measure: AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)
timeFrame: up to 24 hours post end of infusion
measure: Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue
timeFrame: 2 weeks
measure: Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins
timeFrame: 2 weeks
measure: Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Tim F Greten, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.