Clinical trial NCT00841191: A Safety, Efficacy and Pharmacokinetic Study of Siltuximab (CNTO 328) in Participants With Solid Tumors
Official title: A Phase 1/2, Multiple-Dose, Dose-Escalation Study to Assess the Safety, Efficacy, and Pharmacokinetics of Intravenous CNTO 328, an Anti-Interleukin 6 (IL-6) Monoclonal Antibody, in Subjects With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ovarian Neoplasms
Pancreatic Neoplasms
Colorectal Neoplasms
Head and Neck Neoplasms
Lung Neoplasms
Keywords: Resistant to anti-EGFR
Interleukin-6
Neoplasms by Histologic Type
Immunologic Factors
Mol Physiological Effects of Drugs
KRAS protein, human
CNTO 328
Lead sponsor: Centocor, Inc.
Sponsor class: INDUSTRY
First posted: 2009-02-11
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the recommended dose of siltuximab monotherapy, in participants with solid malignant (cancerous) tumors (a mass in a specific area) and to estimate the clinical benefit of siltuximab monotherapy in participants with ovarian cancer and with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant tumors.

Detailed description: This is a 2-part, Phase 1/2, open-label (all people know the identity of the intervention), multiple-dose and dose-escalation study of intravenous (directly into a vein) siltuximab in participants with malignant solid tumors. The study tests the safety and effectiveness of the experimental drug, siltuximab, in participants with advanced cancer (abnormal tissue that grows and spreads in the body). This study also tests how siltuximab is cleared from the body and how the body reacts to it. For this reason blood tests will be performed and some characteristics of the tumor will be analyzed. Siltuximab will be given by intravenous infusion (a fluid or a medicine delivered into a vein by way of a needle) over 1 hour. In Phase 1 (Cohort 1-4) doses will be administered in a range of 2.8-15 milligram per kilogram (mg/kg). Cohort 5 of Phase 1 will receive the recommended dose and schedule as determined from Cohort 1-4. Participants in Phase 1 (Cohort 1-4) will receive 4 administrations of siltuximab over a 10-13 week period, while participants in Cohort 5 and Phase 2 will receive 12 administrations over a 33 week period. Follow-up visits up to 12 weeks after last dose will be scheduled. Participants may then be contacted for up to 1 year after the last dose for follow-up survival and disease status information. Efficacy will primarily be evaluated as per response evaluation criteria in solid tumors (RECIST) criteria. Participants' safety will be monitored at every visit.

Eligibility criteria: Inclusion Criteria:

* Histologic (pertaining to body tissues) or cytologic (pertaining to cells) documentation of malignancy (cancer or other progressively enlarging and spreading tumor) as follows: malignant solid tumors (Cohort 1-4 only); Cohorts 5 and Phase 2: epithelial (tissue covering outer layers of most body organs and parts) ovarian cancers (abnormal tissue growth) that have progressed on or after standard therapy, or for which there is no effective therapy or platinum resistant and taxane resistant, defined as progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy, or participants with known KRAS mutant tumors or pancreatic cancer, or non-small cell lung cancer (NSCLC), colorectal cancer (CRC) or head and neck (H\&N) cancer that are refractory or resistant to anti-epidermal growth factor receptor (EGFR) therapy and all participants must have received at least 1 line of standard chemotherapy
* Eastern cooperative oncology group (ECOG) performance status score less than or equal to 2
* Participants must have recovered from reversible toxicity (any harmful effect of a drug or poison) of previous treatment to less than or equal to grade 1 or an acceptable baseline
* Women of child bearing potential must have a negative pregnancy test at screening
* Cohort 5 and Phase 2 cohorts must have evaluable or measurable disease (defined by response evaluation criteria in solid tumors \[RECIST\], as applicable)

Exclusion Criteria:

* Received any prior systemic therapy or had major surgery for the cancer under study within 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) prior to first siltuximab administration
* Prior anti-interleukin 6 (IL-6) targeted therapy
* Serious concurrent illness or history of uncontrolled heart disease such as: unstable angina (chest pain due to decreased oxygen being supplied to the heart), congestive heart failure (failure of the heart resulting in fluid build-up in the lungs, other body tissues, or both), myocardial infarction (heart attack) within preceding 12 months, clinically significant rhythm or conduction abnormality
* Participants with known allergies (over sensitivity to a substance) or clinically significant reactions to murine, chimeric, or human proteins
* Any uncontrolled medical condition, including the presence of laboratory abnormalities, that places the participant at unacceptable risk by participating in the study or confounds the ability to interpret data from the study

Primary outcomes:
measure: Percentage of Participants With Clinical Benefit Response (CBR)
timeFrame: Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration
Secondary outcomes:
measure: Percentage of Participants With Overall Response
timeFrame: Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration
measure: Number of Participants With Tumor Marker Response
timeFrame: Baseline until disease progression or withdrawal of consent, assessed every 9 weeks up to Week 4 after last dose administration
measure: Percentage of Participants With Hemoglobin (Hb) Response
timeFrame: Baseline up to Week 4 after last dose administration
measure: Progression Free Survival (PFS)
timeFrame: Baseline until disease progression or death, assessed every 9 weeks up to Week 4 after last dose administration
measure: Overall Survival (OS)
timeFrame: From first dose administration until death, assessed every 3 months up to 12 months after last dose administration
measure: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
timeFrame: Baseline up to 4 weeks after last dose administration
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-OV28) Score at Week 4 After Last Dose Administration
timeFrame: Baseline and Week 4 after last dose administration
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf])
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC[0-t])
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Minimum Observed Serum Concentration at Steady-State (Cmin,ss)
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Maximum Observed Serum Concentration (Cmax)
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Terminal Elimination Half Life (t1/2)
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Total Systemic Clearance (CL)
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Volume of Distribution at Steady State (Vss)
timeFrame: Cohort1-4:0,1,4,6,24h post-dose on D1,8,15,22; D1 of extended treatment; Cohort1,2:0,1h post-dose on D28,42,56; Cohort3,4:D28,49,70; Cohort5-7:0,1,2h post-dose on D1,8,15; 0,1h post-dose on D21,42,63,84,105,168,231; up to Wk12 after last dose (Cohort1-7)
measure: Percent Change From Baseline in C-Reactive Protein (CRP) Level
timeFrame: Baseline; Day (D) 1,8,15 (post-dose) for cohort 1 to 7; Day 22 (post-dose), 28 (pre-dose) for cohort 1 to 4; Day 42,56 (pre-dose) for cohort 1, 2; Day 49,70 (pre-dose) for cohort 3, 4; Day 21,42,63,84,105,126,147,168,189,210 (pre-dose) for cohort 5 to 7
measure: Percent Change From Baseline in Inflammatory Cytokines Level
timeFrame: Baseline; Day 8 and 15 (post-dose) for cohort (C) 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7
measure: Percent Change From Baseline in the Angiogenesis Related Factors Level
timeFrame: Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7
measure: Percent Change From Baseline in Interleukin 6 Receptor (IL-6R) Subunits Level
timeFrame: Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7
measure: Number of Participants Assessed Positive for Antibodies to Siltuximab
timeFrame: Day 1 (pre-dose) up to Week 12 after last dose administration
measure: Percent Change From Baseline in Hepcidin Level
timeFrame: Baseline; Day 8 and 15 (post-dose) for cohort 1 to 7; Day 22 (post-dose) and 28 (pre-dose) for cohort 1 to 4; Day 42 and 56 (pre-dose) for cohort 1 and 2; Day 49 and 70 (pre-dose) for cohort 3 and 4; Day 21, 42 and 63 (pre-dose) for cohort 5 to 7
Other outcomes:
Locations:
city: Philadelphia
country: United States
state: Pennsylvania
city: Houston
country: United States
state: Texas
city: Brussel
country: Belgium
city: Wilrijk
country: Belgium
city: Caen
country: France
city: Lyon
country: France
city: Villejuif
country: France
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Birmingham
country: United Kingdom
city: Edinburgh
country: United Kingdom
city: Southampton
country: United Kingdom
Study officials:
affiliation: Centocor, Inc.
name: Centocor, Inc. Clinical Trial
role: STUDY_DIRECTOR
References: