Phase 2 Completed N=24 Treatment

ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

Colorectal Cancer · Colorectal Tumors

Source: ClinicalTrials.gov NCT01675128 ↗

Enrolled (actual)

Serious AEs

41.7%

Results posted

Apr 2016

Primary outcomePrimary: Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors — 1000 mg

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.

Outcome Measures

Outcome	Result	p-value
PRIMARY Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors	1000	—
PRIMARY Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors	160	—
PRIMARY 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	5	—
PRIMARY Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies	5	—
SECONDARY Number of Participants With Adverse Events	4; 10; 10	—
SECONDARY Objective Response	0; 0; 0; 0; 3; 4	—
SECONDARY Number of Participants With Progression Free Survival	3; 6	—
SECONDARY Overall Survival	1; 1	—
SECONDARY AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)	9016; 119; 1340	—
SECONDARY Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue	10	—
SECONDARY Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins	10	—
SECONDARY Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood	10	—

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 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 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 pharmacokin

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Data sourced from ClinicalTrials.gov (NCT01675128). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.