Metastatic Colorectal Cancer
Conditions
Keywords
wild-type KRAS, panitumumab, biomarker, mechanisms of acquired resistance, metastatic colorectal cancer
Brief summary
This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus oncogene (KRAS) tumor status at the time of initial diagnosis.
Detailed description
In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2. In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.
Interventions
BIOLOGICALPanitumumab
Panitumumab 6 mg/kg administered via IV infusion over 60 minutes
BIOLOGICALGanitumab
AMG 479 12 mg/kg adminstered by IV infusion over 60 minutes
DRUGIrinotecan
Irinotecan starting dose of 180 mg/m² adminstered via IV infusion
Sponsors
NantBioScience, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum; * Subjects with wild-type KRAS tumor status confirmed by an Amgen approved central laboratory assessment or an experienced local laboratory assessment of archival tumor tissue (preferably from the primary tumor); * Radiographic evidence of disease progression while on or ≤ 6 months after completion of treatment with irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC; * Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of treatment with investigational product); * At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm by spiral CT scan per modified RECIST v1.0. Lesion must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to enrollment. All sites of disease must be evaluated; * At least 1 tumor (preferably a metastasis or unresected primary tumour) that is amenable to core biopsy, as determined by the clinician who will perform the biopsy; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; * A life expectancy estimate of ≥ 3 months; * Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected primary); * other criteria may apply
Exclusion criteria
* History of other primary cancer, unless: * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician, * Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease, * Adequately treated cervical carcinoma in situ without evidence of disease, * Prostatic intraepithelial neoplasia without evidence of prostate cancer; * History of prior or concurrent central nervous system (CNS) metastases; * Prior treatment with anti-EGFR (eg, panitumumab, cetuximab or small molecule inhibitors (eg, erlotinib, gefitinib); * Prior treatment with monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) or small molecule inhibitors directed against IGF-1R; * Use of systemic chemotherapy or radiotherapy ≤ 21 days before enrollment. Subjects must have recovered from acute toxicities related to radiotherapy; * Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrolment; * Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules ≤ 30 days before enrolment; * Known allergy or hypersensitivity to any component of panitumumab, irinotecan, or AMG 479; * Known uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms predisposing to increased irinotecan toxicity; * History of irinotecan intolerance that may interfere with planned treatment; * History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan; * Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment; * Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea (defined as ≥ grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 3.0); * Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection; * Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. Core biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or paracentesis is not considered a major or minor surgical procedure; - Other investigational procedures or drugs (ie, participation in another clinical study) ≤ 30 days before enrolment; * other criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Hazard Ratio | From baseline up to 152 weeks (from baseline to the time of the second biopsy prior to entering part 2) . | KRAS mutation status changed from wild-type at baseline to mutant at time of second biopsy in part 1, as measured by the PFS hazard ratio. Hazard ratio is presented as wild-type: mutant |
| Objective Response Rate in Part 2 | From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival for Part 2 | 119 weeks from the start of part 2, up to a maximum duration of 152 week | Time from the start of Part 2 to the first date of disease progression per the modified RECIST v1.0 or death by any cause, initiating a new line of antitumor therapy, or receiving study treatment in Part 2, whichever is earlier. Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study per RECIST v1.0. |
| Overall Survival for Part 1 | from first dose of investigational product up to 152 weeks | Time from the first dose of investigational product to death from any cause in Part 1. |
| Overall Survival for Part 2 | from the start of Part 2 up to 119 weeks | Time from the start of Part 2 to death from any cause. |
| Objective Response Rate for Part 1 | from first dose of investigational product up to 152 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. |
| Duration of Response for Part 1 | from first dose of investigational product up to 152 weeks | Time from first confirmed objective response to disease progression per modified RECIST v1.0 in Part 1. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR; Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study. |
| Part 2 Time to Response and Duration of Response | From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks) | Time to response was defined as the time from study day 1 to the first observation of an objective response (confirmed complete response or partial response using modified Response Evaluation Criteria in Solid Tumors \[RECIST\]). Duration of response was the time from the first observation of an objective response to the subsequent time of disease progression (per modified RECIST or clinical progression, whichever came first) or death due to any cause. Objective response = a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\]. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Time to Response for Part 1 | from first dose of investigational product up to 152 weeks | Time from the first dose of investigational product to the date of first confirmed objective response in Part 1. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. |
| Progression-Free Survival for Part 1 | from first dose of investigational product up to 152 weeks | Time from the first dose of investigational product to the first date of disease progression per the modified RECIST v1.0 or death by any cause, initiating a new line of antitumor therapy, or receiving study treatment in Part 2, whichever is earlier in Part 1. Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study per RECIST v1.0 |
Participant flow
Pre-assignment details
Upon radiographically confirmed disease progression per modified RECIST version 1.0, eligible subjects from part 1 proceeded to part 2 of the study to receive panitumumab plus ganitumab.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W. | 74 |
| Part 2 Participants received panitumumab (6 mg/kg starting dose) with irinotecan (starting dose of 180 mg/m²) every 2 weeks (Q2W) during Part 1. Upon radiographically confirmed disease progression, participants proceeded to Part 2 of the study and received treatment with panitumumab (6 mg/kg starting dose) and ganitumab (12 mg/kg starting dose) Q2W. | 36 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part 1 Panitumumab + Irinotecan | Death | 66 |
| Part 1 Panitumumab + Irinotecan | Full Consent Withdrawn | 2 |
| Part 1 Panitumumab + Irinotecan | Lost to Follow-up | 1 |
| Part 2 Panitumumab + AMG479 | Death | 30 |
| Part 2 Panitumumab + AMG479 | Full Consent Withdrawn | 1 |
Baseline characteristics
| Characteristic | Part 1 | Total | Part 2 |
|---|---|---|---|
| Age, Continuous Part 1 | 62.2 years STANDARD_DEVIATION 9.8 | 62.2 years STANDARD_DEVIATION 9.8 | — |
| Age, Continuous Part 2 | — | 62.9 years STANDARD_DEVIATION 10.1 | 62.9 years STANDARD_DEVIATION 10.1 |
| Race (NIH/OMB) Part 1 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Part 1 White | 73 Participants | 73 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2 Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Part 2 White | 0 Participants | 35 Participants | 35 Participants |
| Sex: Female, Male Part 1 Female | 27 Participants | 27 Participants | 0 Participants |
| Sex: Female, Male Part 1 Male | 47 Participants | 47 Participants | 0 Participants |
| Sex: Female, Male Part 2 Female | 0 Participants | 11 Participants | 11 Participants |
| Sex: Female, Male Part 2 Male | 0 Participants | 25 Participants | 25 Participants |
| Subjects With Metastatic Colorectal Carcinoma Expressing Wild-type KRAS and Refractory to Oxaliplati Part 1 | 74 Participants | 74 Participants | 0 Participants |
| Subjects With Metastatic Colorectal Carcinoma Expressing Wild-type KRAS and Refractory to Oxaliplati Part 2 | 0 Participants | 36 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 66 / 74 | 30 / 36 |
| other Total, other adverse events | 74 / 74 | 35 / 36 |
| serious Total, serious adverse events | 26 / 74 | 8 / 36 |
Outcome results
Primary
Objective Response Rate in Part 2
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 | Objective Response Rate in Part 2 | 0.00 percentage of participants |
Primary
PFS Hazard Ratio
KRAS mutation status changed from wild-type at baseline to mutant at time of second biopsy in part 1, as measured by the PFS hazard ratio. Hazard ratio is presented as wild-type: mutant
Time frame: From baseline up to 152 weeks (from baseline to the time of the second biopsy prior to entering part 2) .
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 | PFS Hazard Ratio | 0.365 months |
p-value: 0.013Regression, Cox
Secondary
Duration of Response for Part 1
Time from first confirmed objective response to disease progression per modified RECIST v1.0 in Part 1. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR; Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study.
Time frame: from first dose of investigational product up to 152 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 | Duration of Response for Part 1 | 7.7 months |
Secondary
Objective Response Rate for Part 1
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR.
Time frame: from first dose of investigational product up to 152 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 | Objective Response Rate for Part 1 | 21.62 percentage of participants |
Secondary
Overall Survival for Part 1
Time from the first dose of investigational product to death from any cause in Part 1.
Time frame: from first dose of investigational product up to 152 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 | Overall Survival for Part 1 | 11.6 months |
Secondary
Overall Survival for Part 2
Time from the start of Part 2 to death from any cause.
Time frame: from the start of Part 2 up to 119 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 | Overall Survival for Part 2 | 7.6 months |
Secondary
Part 2 Time to Response and Duration of Response
Time to response was defined as the time from study day 1 to the first observation of an objective response (confirmed complete response or partial response using modified Response Evaluation Criteria in Solid Tumors \[RECIST\]). Duration of response was the time from the first observation of an objective response to the subsequent time of disease progression (per modified RECIST or clinical progression, whichever came first) or death due to any cause. Objective response = a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\]. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks)
Population: Due to no subjects having complete or partial responses, these Secondary Outcomes were not summarized.
Secondary
Progression-Free Survival for Part 1
Time from the first dose of investigational product to the first date of disease progression per the modified RECIST v1.0 or death by any cause, initiating a new line of antitumor therapy, or receiving study treatment in Part 2, whichever is earlier in Part 1. Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study per RECIST v1.0
Time frame: from first dose of investigational product up to 152 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 | Progression-Free Survival for Part 1 | 4.6 months |
Secondary
Progression-Free Survival for Part 2
Time from the start of Part 2 to the first date of disease progression per the modified RECIST v1.0 or death by any cause, initiating a new line of antitumor therapy, or receiving study treatment in Part 2, whichever is earlier. Disease progression is a \>= 20% increase in the sum of the longest diameter of the target lesions as compared to the smallest sum while on study per RECIST v1.0.
Time frame: 119 weeks from the start of part 2, up to a maximum duration of 152 week
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 | Progression-Free Survival for Part 2 | 1.7 months |
Secondary
Time to Response for Part 1
Time from the first dose of investigational product to the date of first confirmed objective response in Part 1. An objective response is defined as a confirmed complete response or partial response per modified RECIST v1.0 criteria during the treatment period. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR.
Time frame: from first dose of investigational product up to 152 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 | Time to Response for Part 1 | 2.0 months | Standard Deviation 0.4 |