Colon Cancer
Conditions
Brief summary
To investigate the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer.
Detailed description
The investigators will conduct a single-arm, open-label Phase II clinical trial investigating the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). There will be an initial safety lead-in cohort to ensure the combination is well-tolerated. The primary objective of this study is to estimate the overall response rate in these subjects at 12 weeks . Secondary objectives include the following: estimating the overall response rate in these subjects at 12 weeks by immune-related RECIST criteria (irRECIST), estimating the best response rate by both RECIST 1.1 and irRECIST criteria, estimating progression-free survival (PFS) and duration of response using both RECIST 1.1 and irRECIST criteria, estimating overall survival (OS), and characterizing the safety issues associated with this regimen. Exploratory objectives involve investigating various biomarkers and peripheral blood and tumor assays.
Interventions
DRUGPanitumumab
6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab
DRUGNivolumab
240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab
DRUGIpilimumab
1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Sponsors
Amgen
Bristol-Myers Squibb
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This will be a single-arm, open-label, multicenter Phase II clinical trial investigating the clinical efficacy of nivolumab, ipilimumab, and panitumumab in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type microsatellite stable metastatic colorectal cancer after an initial safety lead-in cohort to ensure the three drug combination is well-tolerated.
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable metastatic or locally advanced disease documented on diagnostic imaging studies. 2. Previously received 1-2 prior lines of therapy. Subjects who relapse within 6 months of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior line of therapy. 3. Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; and BRAF codon 600, by standard of care testing of tumor specimen. Tissue used for testing may have been collected from primary or metastatic site. 4. Microsatellite stable as detected by PCR-based assay or CLIA-certified sequencing methodology such as Foundation One; or mismatch repair proficient as detected by immunohistochemistry showing intact nuclear staining of MLH1, MSH2, MSH6, and PMS2 5. Radiographically measurable disease present per RECIST 1.1 6. Age ≥ 18 years at the time of consent. 7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 8. Blood counts performed within 3 weeks prior to starting study therapy must have absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin ≥ 9 g/dL. \*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy. 9. Liver function tests performed within 3 weeks prior to starting study therapy must have total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 3 x ULN, and albumin ≥ 2.5 g/dL. 10. Serum creatinine performed within 3 weeks prior to starting study therapy must be ≤ 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula provided in Appendix 11.3) of ≥ 50 mL/minute. 11. Females of childbearing potential must have a negative serum pregnancy test within 24 hours prior to receiving the first dose of study medication. Females of childbearing potential must agree to use 2 methods of effective contraception or abstain from heterosexual sex throughout the treatment period and for 5 months after the last dose of study treatment. Females of childbearing potential are women who have not been surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or have not been free of menses for \>1 year. 12. Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 7 months after the last dose of study treatment. 13. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 14. An adequate amount of archival tumor tissue must be available at baseline to be eligible for enrollment in the study. If archival tissue is not available or is inadequate, then the subject must consent to undergo a mandatory biopsy at baseline in order to participate in the study.
Exclusion criteria
1. Past treatment with an antibody targeting EGFR including cetuximab or panitumumab. 2. Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1, PD-L1, PD-L2, or CD137. 3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trial. 4. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 5. Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease free for at least five years. 6. Treatment within 21 days of the first dose of study drug with any other chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment for the treatment of malignancy, or failure to recover from adverse effects of prior therapies administered over 4 weeks prior to Study Day 1. All toxicities from prior therapies must be ≤ Grade 1 (or ≤ Grade 2 for alopecia or peripheral neuropathy). Prior systemic treatment in the adjuvant setting is allowed. See note above under inclusion 3.1.8 7. Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent, or compliance to the study procedures. 8. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment. (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 9. History of organ allograft or other history of immunodeficiency, or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of investigational treatment. 10. Inability or unwillingness to comply with study and/or follow-up requirements. 11. Any major surgery, extensive radiotherapy, chemotherapy with clinically significant delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization. 12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug. 13. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted. 14. Active autoimmune disease requiring systemic treatment in the past 3 months (for example with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, local steroid injections, or inhaled or topical steroids would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study. 15. Active infection requiring intravenous systemic therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 12 weeks | Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Per irRECIST | 12 weeks | Overall Response Rate (ORR) = irCR + irPR Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes \< 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later |
| Median Progression Free Survival | Up to 3 years | Median Progression Free Survival is the time at which 50% of the study population has experienced disease progression as defined by RECIST, irRECIST, or death from any cause. |
| Median Overall Survival | Up to 3 years | Time from the first day of treatment until death from any cause. |
| Median Duration of Response | Up to 3 years | Duration of response is the time from documentation of tumor response to disease progression. |
| Toxicity of Treatment | Up to 36 month | The number of treatment-emergent grade 3 and 4 toxicities as defined by the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) was reported. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from 5 medical institutions between March 2018 and June 2020.
Pre-assignment details
A total of 61 subjects were consented to the trial, but 5 were deemed to be ineligible during screening and therefore were not enrolled on the trial.
Participants by arm
| Arm | Count |
|---|---|
| Open-label, Single Arm, Phase II Nivolumab and ipilimumab with panitumumab
Panitumumab: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab
Nivolumab: 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab
Ipilimumab: 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab | 56 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Subject was ineligible after enrollment | 1 |
Baseline characteristics
| Characteristic | Open-label, Single Arm, Phase II |
|---|---|
| Age, Customized Age 30-39 | 1 Participants |
| Age, Customized Age 40-49 | 9 Participants |
| Age, Customized Age 50-59 | 25 Participants |
| Age, Customized Age 60-69 | 17 Participants |
| Age, Customized Age 70-79 | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 44 Participants |
| Region of Enrollment United States | 56 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 27 / 56 |
| other Total, other adverse events | 56 / 56 |
| serious Total, serious adverse events | 21 / 56 |
Outcome results
Primary
Overall Response Rate
Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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
Time frame: 12 weeks
Population: Seven participants were unevaluable for the primary endpoint at 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label, Single Arm, Phase II | Overall Response Rate | 32 percentage of participants |
Secondary
Median Duration of Response
Duration of response is the time from documentation of tumor response to disease progression.
Time frame: Up to 3 years
Population: Participants initiated the study and were assessed for response and disease progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-label, Single Arm, Phase II | Median Duration of Response | 5 months |
Secondary
Median Overall Survival
Time from the first day of treatment until death from any cause.
Time frame: Up to 3 years
Population: Participants initiated the study and were assessed for survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-label, Single Arm, Phase II | Median Overall Survival | 17.4 months |
Secondary
Median Progression Free Survival
Median Progression Free Survival is the time at which 50% of the study population has experienced disease progression as defined by RECIST, irRECIST, or death from any cause.
Time frame: Up to 3 years
Population: Participants initiated the study and were assessed for disease progression or survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-label, Single Arm, Phase II | Median Progression Free Survival | 6 months |
Secondary
Overall Response Rate Per irRECIST
Overall Response Rate (ORR) = irCR + irPR Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes \< 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later
Time frame: 12 weeks
Population: Seven participants were unevaluable for the primary endpoint at 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-label, Single Arm, Phase II | Overall Response Rate Per irRECIST | 34 percentage of participants |
Secondary
Toxicity of Treatment
The number of treatment-emergent grade 3 and 4 toxicities as defined by the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) was reported.
Time frame: Up to 36 month
Population: Participants started to study the treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Headache | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Delirium | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Psychiatric disorders - Other, specify | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Rash acneiform | 6 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Rash maculo-papular | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Skin and subcutaneous tissue disorders - Other, specify | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Colonic obstruction | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Constipation | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Diarrhea | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Acute kidney injury | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Urinary retention | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Dyspnea | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypoxia | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Pneumonitis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Stevens-Johnson syndrome | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Surgical and medical procedures - Other, specify | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypertension | 6 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypotension | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Thromboembolic event | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Blood and lymphatic system disorders - Other, specify | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hemolysis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Myocarditis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Adrenal insufficiency | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Endocrine disorders - Other, specify | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Abdominal pain | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Colitis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Gastrointestinal disorders - Other, specify | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Nausea | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Pancreatitis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Rectal pain | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Small intestinal obstruction | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Vomiting | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Fatigue | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Cholecystitis | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Allergic reaction | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Autoimmune disorder | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Infections and infestations - Other, specify | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Papulopustular rash | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Paronychia | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Rash pustular | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Sepsis | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Soft tissue infection | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Alanine aminotransferase increased | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Aspartate aminotransferase increased | 3 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Lipase increased | 5 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Lymphocyte count decreased | 4 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Neutrophil count decreased | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Platelet count decreased | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Serum amylase increased | 4 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | White blood cell decreased | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Anorexia | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Dehydration | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hyperglycemia | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypocalcemia | 2 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypokalemia | 4 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypomagnesemia | 8 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hyponatremia | 1 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Hypophosphatemia | 4 Participants |
| Open-label, Single Arm, Phase II | Toxicity of Treatment | Pain in extremity | 1 Participants |