ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer

Colorectal Neoplasms Clinical Trial

Official title:

A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01675128
• Other study ID #: 120187
• Secondary ID: 12-C-0187
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: August 25, 2012
• Last updated: October 22, 2014
• Start date: August 2012
• Est. completion date: December 2014

Study information

• Verified date: April 2014
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Background:

• Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the 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.

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, PFS, 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.

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/m2 as an intravenous infusion every second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be to establish 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 colorectoal 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 mRNA and protein (IHC) analysis will be performed in the phase II portion of the study; Immune subsets; PET responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of irinotecan and ISIS183750 in 10-12 patients.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

• Phase I: Patients must have histopathological confirmation of carcinoma by the Laboratory of Pathology of the 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 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

• 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 ALT or AST measuring 3 x ULN if no liver metastasis or up to5 x ULN with liver metastasis.

• creatinine < 1.5X institution upper limit of normal

• OR

• creatinine clearance > 45 mL/min/1.73 m2, 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 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 INR > 2.5 are excluded.

• Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic 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.

• 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.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Carcinoma
• Colorectal Neoplasms
• Colorectal Tumors

Intervention

Drug:
• ISIS 183750

• Irinotecan

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. — View Citation

Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, Sportelli P, Gardner L, Richards DA. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2011 Nov 20;29(33):4394-400. doi: 10.1200/JCO.2011.36.1980. Epub 2011 Oct 3. — View Citation

Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, Kim TY, Pover GM, Morris CD, Douillard JY. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs. 2011 Oct;29(5):1021-8. doi: 10.1007/s10637-010-9392-8. Epub 2010 Feb 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose		2 years	Yes
Primary	Change of eIF4e and protein (HC) in pre- and post- tumor biopies		2 years	No
Secondary	Evaluate the effect of eIF4E on relevant regulated proteins and immune cells		2 years	No
Secondary	Evaluate Response Rate, PFS, and OS		2 years	No
Secondary	Pharmacokinetic parameters		2 years	No

External Links

•   NIH Clinical Center Detailed Web Page