ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

NCT01675128 | Completed Phase 1 Results DMC

• 2 other identifiers: 12018712-C-0187
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Tumors

Keywords

Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein; Refractory; Oncogene; Maximum Tolerated Dose; Safety

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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).

  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.

  2 weeks

Secondary Outcomes (8)

• Number of Participants With Adverse Events

  21 months

• Objective Response

  up to 2 cycles

• Number of Participants With Progression Free Survival

  ≤ 6 months

• Overall Survival

  ≥ 12 months

• AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)

  up to 24 hours post end of infusion

Study Arms (3)

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.

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.

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.

Drug: ISIS 183750; Drug: Irinotecan

Interventions

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• 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.

  PMID: 27194579 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

LY 2275796; Irinotecan

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Dr.Tim Greten
• Organization: National Cancer Institute

gretentf@mail.nih.gov

301-451-4723

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 25, 2012
• First Posted: August 29, 2012
• Study Start: August 1, 2012
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2015
• Last Updated: April 25, 2016
• Results First Posted: April 25, 2016

Record last verified: 2016-03

Locations

US (1)