Metastatic Colorectal Cancer
Conditions
Keywords
Pivotal, Colorectal, Survival, Phase 3
Brief summary
The purpose of this study is to determine if the True Human Monoclonal antibody Xilonix (MABp1) can prolong the life of colorectal carcinoma patients that are refractory to standard therapy.
Detailed description
In the setting of refractory, metastatic disease a complete resolution of tumor burden is not a reasonable expectation. Instead, the primary goal of anti-tumor therapy at this stage is to eliminate or reduce the symptomatic effects of the tumor, while trying to prolong survival for as long as possible. Due to treatment related morbidity however, few treatment modalities are ideal for this objective. Even with the most recent targeted agents (such as multi-kinase inhibitors), drug related toxicities frequently lead to relatively short treatment durations. With discontinuation of therapy, disease progression is uncontrolled and prognosis is poor. New agents that control disease progression-while improving tumor-related symptoms, rather than causing significant therapy related morbidity-are vitally needed to treat patients with advanced cancer, including those with colorectal cancer. An approach has been taken to develop such an agent using a monoclonal antibody to block the chronic inflammation involved in both malignant disease progression and constitutional symptoms. Xilonix™ is expected to inhibit tumor growth and metastasis by interrupting crucial signals that drive angiogenesis and invasiveness. The antibody therapy may also block tumor microenvironment infiltration by leukocytes (such as myeloid suppressor cells) that suppress antitumor immunity, enabling better host immune control of the disease. In addition to local effects on the tumor, Xilonix™ is expected to work systemically to correct the metabolic dysregulation, fatigue and anxiety mediated by chronic inflammatory signaling to the central nervous system.
Interventions
DRUGXilonix
Xilonix is a True Human Monoclonal Antibody targeting Interleukin 1 alpha, and is administered intravenously every 2 weeks with best supportive care until clinical or radiographic progression.
DRUGPlacebo
Placebo plus best supportive care will be administered intravenously every 2 weeks until clinical or radiographic progression.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects with pathologically confirmed colorectal carcinoma that is metastatic or unresectable and which is refractory to standard therapy. To be considered refractory, a subject must have experienced progression (or intolerance) after treatment with standard approved regimens including, oxaliplatin, irinotecan flouropyrimidine, bevacizumab, and cetuximab or panitumumab if KRAS wildtype. 2. Subjects will not be treated with any radiation, chemotherapy, or investigational agents while enrolled in this protocol. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2. 4. At least 2 weeks since the last previous cancer treatment including: chemotherapy, radiation therapy, immunotherapy, surgery, hormonal therapy, or targeted biologics. 5. Age ≥ 18 years, male or female subjects. 6. Serum potassium and magnesium levels within institutional normal limits. Total serum calcium or ionized calcium level must be greater than or equal to the lower limit of normal. 7. Adequate renal function, defined by serum creatinine ≤ 1.5 x ULN. 8. Adequate hepatic function 9. Adequate bone marrow function 10. For women of childbearing potential (WOCBP), a negative serum pregnancy test result at Screening. 11. Signed and dated institutional review board (IRB)-approved informed consent before any protocol-specific screening procedures are performed. 12. Patients enrolled must, in the Investigator's judgment, be healthy enough to stay on the clinical trial for three months.
Exclusion criteria
1. Mechanical obstruction that would prevent adequate oral nutritional intake. 2. Serious uncontrolled medical disorder, or active infection, that would impair the ability of the patient to receive protocol therapy. 3. Uncontrolled or significant cardiovascular disease, including: 4. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent. 5. Subjects who have not recovered from the adverse effects of prior therapy at the time of enrollment to ≤ grade 1; excluding alopecia and grade 2 neuropathy. 6. Immunocompromised subjects, including subjects known to be infected with human immunodeficiency virus (HIV). 7. Known hepatitis B surface antigen and/or positive hepatitis C antibody and presence of hepatitis C RNA. 8. History of tuberculosis (latent or active) or positive Interferon-gamma release assay (IGRA). 9. Receipt of a live (attenuated) vaccine within 1 month prior to Screening 10. Subjects with history of hypersensitivity to compounds of similar chemical or biologic composition of XILONIX™. 11. Women who are pregnant or breastfeeding. 12. WOCBP or men whose sexual partners are WOCBP who are unwilling or unable to use an acceptable method of contraception for at least 1 month prior to study entry, for the duration of the study, and for at least 3 months after the last dose of study medication. 13. Weight loss \>20% in the previous 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 18 months | Overall survival time was defined as the duration from the date of randomization until death or last follow-up. OS was summarized by Kaplan-Meier method and compared between the treatment groups using un-adjusted log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Baseline and Week 8 | The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. Each item, except Global Health Status, is answered on a four-point scale (1-4): 1-not at all, 2-a little, 3-quite a bit, 4-very much. Response to Global Health Status is measured on a 1 to 7 scale. 1 being very poor and 7 being excellent. Each scale (symptom scale \[pain, fatigue, and appetite loss\] and Global Health Status/Quality of Life \[QoL\] scale) was linearly transformed to be in range from 0-100 where a higher score represents good health status, while lower scores indicate poor health status. As planned, the data for symptom scales (pain, fatigue, appetite loss) and a Global Health Status/QoL scale was evaluated and reported. |
| Change From Baseline in Platelet Counts | Baseline and Week 8 | Change from baseline in platelet counts up to Week 8 was evaluated. |
| Change From Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans | Baseline and Week 8 | Change from baseline in LBM as measured by Dexa scans was reported. DEXA is an X-ray imaging modality used to determine the mass of one material in the presence of another material, using the knowledge of their unique X-ray attenuation at different energies. |
| Percentage of Participants With Objective Response (OR) | Up to 18 months | The percentage of OR was estimated by dividing the total number of confirmed complete response (CR) and partial response (PR) by the total number of participants randomized where CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented and PR was decrease in tumor burden \>= 50 % relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. |
| Percentage of Participants With Disease Control | Up to 18 months | Percentage of participants who achieved disease control was estimated by dividing the total number of confirmed CRs, PRs and stable disease (SD) by the total number of participants randomized where CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented, PR was decrease in tumor burden \>= 50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation and SD defined as not meeting criteria for CR and PR, in absence of Progressive Disease (increase in tumor burden \>= 25 % relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented). |
| Progression Free Survival (PFS) | Up to 18 Months | PFS was defined as time from randomization to tumor progression or death. Progressive Disease defined as increase in tumor burden greater than or equals to (\>=) 25 (%) percent relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented. Participants surviving without disease progression at end of study were censored. PFS was compared by Kaplan-Meier method using log-rank test. |
Countries
Australia, Austria, Belgium, Czechia, Hungary, Israel, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Total 643 participants were screened and enrolled in the study. Out of them, only 611 participants have received the study drug and participated in the study while 32 participants never received any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Xilonix Participants received 7.5 milligram per kilogram (mg/kg) Xilonix (MABp1) via intravenous (IV) injection once every 2 weeks until evidence of radiographic or clinical progression along with best supportive care (BSC) (up to 18 months). | 411 |
| Placebo Participants received placebo via IV injection once every 2 weeks until evidence of radiographic or clinical progression plus BSC (up to 18 months). | 200 |
| Total | 611 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 27 | 7 |
| Overall Study | Death | 28 | 13 |
| Overall Study | Lack of Efficacy | 299 | 151 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 17 | 10 |
| Overall Study | Protocol Terminated | 1 | 0 |
| Overall Study | Randomized But Never Treated | 19 | 13 |
| Overall Study | Withdrawal by Subject | 38 | 18 |
Baseline characteristics
| Characteristic | Total | Xilonix | Placebo |
|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 10.11 | 62.9 years STANDARD_DEVIATION 10.14 | 61.1 years STANDARD_DEVIATION 9.98 |
| Age (years) < 65 years | 351 Participants | 229 Participants | 122 Participants |
| Age (years) > 75 years | 55 Participants | 41 Participants | 14 Participants |
| Age (years) Between 65 and 75 years | 205 Participants | 141 Participants | 64 Participants |
| Age (years) Missing | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 17 Participants | 15 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 20 Participants | 8 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 25 Participants | 21 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 541 Participants | 355 Participants | 186 Participants |
| Region of Enrollment Australia | 25 Participants | 18 Participants | 7 Participants |
| Region of Enrollment Austria | 15 Participants | 12 Participants | 3 Participants |
| Region of Enrollment Belgium | 76 Participants | 49 Participants | 27 Participants |
| Region of Enrollment Czech Republic | 11 Participants | 8 Participants | 3 Participants |
| Region of Enrollment England | 10 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Hungary | 11 Participants | 8 Participants | 3 Participants |
| Region of Enrollment Israel | 7 Participants | 4 Participants | 3 Participants |
| Region of Enrollment Italy | 18 Participants | 11 Participants | 7 Participants |
| Region of Enrollment Netherlands | 12 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Poland | 48 Participants | 30 Participants | 18 Participants |
| Region of Enrollment Spain | 173 Participants | 118 Participants | 55 Participants |
| Region of Enrollment Switzerland | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment USA | 199 Participants | 135 Participants | 64 Participants |
| Sex: Female, Male Female | 253 Participants | 159 Participants | 94 Participants |
| Sex: Female, Male Male | 358 Participants | 252 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 28 / 411 | 13 / 200 |
| other Total, other adverse events | 324 / 411 | 167 / 200 |
| serious Total, serious adverse events | 169 / 411 | 84 / 200 |
Outcome results
Primary
Overall Survival (OS)
Overall survival time was defined as the duration from the date of randomization until death or last follow-up. OS was summarized by Kaplan-Meier method and compared between the treatment groups using un-adjusted log-rank test.
Time frame: Up to 18 months
Population: The modified intent-to-treat (mITT) population included all participants who were randomized and received at least one infusion of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Xilonix | Overall Survival (OS) | 5.6 Months |
| Placebo | Overall Survival (OS) | 5.4 Months |
p-value: 0.613Log Rank
Secondary
Change From Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans
Change from baseline in LBM as measured by Dexa scans was reported. DEXA is an X-ray imaging modality used to determine the mass of one material in the presence of another material, using the knowledge of their unique X-ray attenuation at different energies.
Time frame: Baseline and Week 8
Population: The per protocol (PP) population was defined as participants that had baseline and follow up values for both the DEXA assessment and the European Organization for Research and Treatment of Cancer (EORTC) questionnaire.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Xilonix | Change From Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans | 0.51 kilogram (kg) | Standard Error 0.158 |
| Placebo | Change From Baseline in Lean Body Mass (LBM) Measured by Dual-energy X-ray Absorptiometry (DEXA) Scans | -0.21 kilogram (kg) | Standard Error 0.231 |
p-value: 0.011ANCOVA
Secondary
Change From Baseline in Platelet Counts
Change from baseline in platelet counts up to Week 8 was evaluated.
Time frame: Baseline and Week 8
Population: The PP population was defined as participants that had baseline and follow up values for both the DEXA assessment and the EORTC questionnaire.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Xilonix | Change From Baseline in Platelet Counts | 5.50 1000 cells/cubic millimeter | Standard Error 4.721 |
| Placebo | Change From Baseline in Platelet Counts | 16.19 1000 cells/cubic millimeter | Standard Error 7.082 |
p-value: 0.21ANCOVA
Secondary
Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)
The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. Each item, except Global Health Status, is answered on a four-point scale (1-4): 1-not at all, 2-a little, 3-quite a bit, 4-very much. Response to Global Health Status is measured on a 1 to 7 scale. 1 being very poor and 7 being excellent. Each scale (symptom scale \[pain, fatigue, and appetite loss\] and Global Health Status/Quality of Life \[QoL\] scale) was linearly transformed to be in range from 0-100 where a higher score represents good health status, while lower scores indicate poor health status. As planned, the data for symptom scales (pain, fatigue, appetite loss) and a Global Health Status/QoL scale was evaluated and reported.
Time frame: Baseline and Week 8
Population: The PP population was defined as participants that had baseline and follow up values for both the DEXA assessment and the EORTC questionnaire.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Xilonix | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Global Health Status/Qol | -6.64 Units on a scale | Standard Error 1.392 |
| Xilonix | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Pain | 8.50 Units on a scale | Standard Error 1.707 |
| Xilonix | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Fatigue | 7.42 Units on a scale | Standard Error 1.516 |
| Xilonix | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Appetite Loss | 9.34 Units on a scale | Standard Error 2.01 |
| Placebo | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Appetite Loss | 11.84 Units on a scale | Standard Error 2.947 |
| Placebo | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Global Health Status/Qol | -8.16 Units on a scale | Standard Error 2.041 |
| Placebo | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Fatigue | 8.82 Units on a scale | Standard Error 2.223 |
| Placebo | Change From Baseline in Symptom Scale and Global Health Status/Quality of Life (QoL) Assessed Through the Cancer-specific European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Pain | 10.27 Units on a scale | Standard Error 2.503 |
Comparison: Statistical Analysis for Global Health Status/Qolp-value: 0.541ANCOVA
Comparison: Statistical Analysis for Painp-value: 0.56ANCOVA
Comparison: Statistical Analysis for Fatiguep-value: 0.603ANCOVA
Comparison: Statistical Analysis for Appetite Lossp-value: 0.485ANCOVA
Secondary
Percentage of Participants With Disease Control
Percentage of participants who achieved disease control was estimated by dividing the total number of confirmed CRs, PRs and stable disease (SD) by the total number of participants randomized where CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented, PR was decrease in tumor burden \>= 50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation and SD defined as not meeting criteria for CR and PR, in absence of Progressive Disease (increase in tumor burden \>= 25 % relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented).
Time frame: Up to 18 months
Population: The participants with baseline and follow up radiographic assessments were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xilonix | Percentage of Participants With Disease Control | 25 Percentage of Participants |
| Placebo | Percentage of Participants With Disease Control | 27.3 Percentage of Participants |
Secondary
Percentage of Participants With Objective Response (OR)
The percentage of OR was estimated by dividing the total number of confirmed complete response (CR) and partial response (PR) by the total number of participants randomized where CR was complete disappearance of all lesions (whether measurable or not, and no new lesions); confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented and PR was decrease in tumor burden \>= 50 % relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
Time frame: Up to 18 months
Population: The mITT population included all participants who were randomized and received at least one infusion of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Xilonix | Percentage of Participants With Objective Response (OR) | 0 Percentage of Participants |
| Placebo | Percentage of Participants With Objective Response (OR) | 0 Percentage of Participants |
Secondary
Progression Free Survival (PFS)
PFS was defined as time from randomization to tumor progression or death. Progressive Disease defined as increase in tumor burden greater than or equals to (\>=) 25 (%) percent relative to nadir (minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented. Participants surviving without disease progression at end of study were censored. PFS was compared by Kaplan-Meier method using log-rank test.
Time frame: Up to 18 Months
Population: The intent-to-treat (ITT) population consisted of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Xilonix | Progression Free Survival (PFS) | 2.1 Months |
| Placebo | Progression Free Survival (PFS) | 2.1 Months |
p-value: 0.768Log Rank