Colorectal Cancer, Metastatic Colorectal Cancer, RAS Wild Type Colorectal Cancer, Refractory Colorectal Cancer
Conditions
Brief summary
This phase I/II trial studies the best dose and side effects of glutaminase inhibitor CB-839 and how well it works with panitumumab and irinotecan hydrochloride (phase I only) in treating patients with RAS wildtype colorectal cancer that has spread to other places in the body and does not respond to treatment. Glutaminase inhibitor CB-839 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving glutaminase inhibitor CB-839 with panitumumab and irinotecan hydrochloride may work better in treating patients with colorectal cancer.
Detailed description
Objectives: Primary Objective of Phase I: • Determine the safety and tolerability of CB-839 in combination with panitumumab and irinotecan. Exploratory Objective of Phase I (Optional Imaging Sub-study): • Correlate radiological features of pre- and post-treatment 11C-Glutamine PET/CT and 18F-FSPG PET/CT with clinical outcome. Primary Objective of Phase II: • Determine the efficacy of CB-839 in combination with panitumumab as measured by the response rate (RR). Secondary Objectives of Phase II: * Determine the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). * Perform the following correlative studies (in the phase 2 component): * Correlate radiological features of pre- and post-treatment 18F-FSPG PET/CT with clinical outcome and biological correlates (tissue gene signature, exosomes). * Collect blood samples during each radiotracer injection to assess pharmacokinetics. * Collect pre-treatment biopsy tissue and prospectively correlate clinical outcome with a glutamine metabolism gene signature. * Quantify exosomal content in the plasma. Exploratory Objective of Phase II: • Development of patient-derived organoids from pre-treatment tissue biopsy OUTLINE: Phase I is a dose-escalation study of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab and irinotecan hydrochloride. Phase II will study efficacy of glutaminase inhibitor CB-839 in combination with standard doses of panitumumab. Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28, panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 28 days and then every 3 months for up to 1 year.
Interventions
Given by mouth
BIOLOGICALPanitumumab
Given by vein
DRUGIrinotecan Hydrochloride (phase I only)
Given by vein
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
DEVICEImaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans
During phase II at baseline and day 28 of cycle 1
Sponsors
National Cancer Institute (NCI)
Calithera Biosciences, Inc
Vanderbilt-Ingram Cancer Center
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
* Signed and dated written informed consent * Histologically or cytologically-confirmed diagnosis of metastatic KRAS wildtype colorectal cancer (CRC) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * In dose escalation, patients must have had at least one prior line of chemotherapy for advanced disease or progressed within 6 months of adjuvant therapy (prior chemotherapy and/or anti-EGFR therapy is permitted) * In dose expansion, patients must have received prior anti-EGFR therapy and achieved at least stable disease on at least one scan as their best response * In dose expansion, patients must be willing to undergo a pre-treatment biopsy, and four research PET imaging techniques (11C-Glutamine and 18F-FSPG), two pre-treatment and two after one cycle of treatment * In dose expansion, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 which can be followed by CT or magnetic resonance imaging (MRI) * Absolute neutrophil count (ANC) \>= 1,500/uL * Platelets \>= 100,000/uL * Serum albumin \>= 3.0 g/dL * Serum creatinine =\< 2 mg/dL, or calculated creatinine clearance \> 50 mL/min (per the Cockcroft-Gault formula) * Total bilirubin =\< 1.5 times upper limit of normal (ULN) * Aspartate transaminase (AST) and alanine aminotransferase (ALT) =\< 5.0 x ULN * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of protocol-indicated treatment; and additionally agree to use at least 2 methods of acceptable contraception or abstain from heterosexual intercourse from the time of signing consent, and until 2 months after patient's last dose of protocol-indicated treatment; WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women * Men able to father children who are sexually active with WOCBP must agree to use at least 2 methods of acceptable contraception from the time of signing consent and until 2 months after patient's last dose of protocol-indicated treatment; men able to father children are defined as those who are not surgically sterile (i.e. patient has not had a vasectomy)
Exclusion criteria
* Within 28 days before first dose of protocol-indicated treatment: * Anti-cancer treatment including chemotherapy, radiation, hormonal therapy, targeted therapy, immunotherapy, or biological therapy * Major surgery requiring general anesthesia; (Note: within this time frame, placement of a central line or portacath is acceptable and does not exclude) * Receipt of an investigational agent * Within 14 days before first dose of protocol-indicated treatment: \* Active uncontrolled infection; patients with infection under active treatment and controlled with antibiotics initiated at least 14 days prior to initiation of protocol-indicated treatment are not excluded (e.g. urinary tract infection controlled with antibiotics) * Dose escalation only: known grade 4 toxicity probably or definitely attributed to past irinotecan treatment * Active inflammatory bowel disease, other bowel disease causing chronic diarrhea (defined as \> 4 loose stools per day), or bowel obstruction * History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest CT scan * Unable to receive oral medication * Central nervous system (CNS) metastasis, unless asymptomatic or previously treated and stable; and no evidence of CNS progression for at least 30 days prior to initiating protocol-indicated treatment; anticonvulsant and/or corticosteroid therapy will be allowed if patient is on a stable or decreasing dose of such treatment for at least 30 days prior to initiating protocol-indicated treatment * Patients with known Gilbert's disease * Patient is pregnant or breastfeeding * Current or previous malignant disease (other than colorectal cancer) within the last 5 years; with the exception of the following if considered curatively treated: non-melanoma skin cancer(s), carcinoma in situ of the cervix, and ductal carcinoma in situ; subjects with another active malignancy requiring concurrent anti-cancer intervention are excluded; (Note the following does not exclude: effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured AND no additional anti-cancer therapy is ongoing and required during the study period) * Known positive test for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis A, hepatitis B, hepatitis C, or cytomegalovirus (CMV) * Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride | Up to 12 months | The maximum tolerated dose of CB-839 will be determined in Phase I with dose-escalation following Bayesian continual reassessment method. Patients were treated in cohort of 3. The CB839 dose leves were 400, 600 and 800mg. |
| Response Rate (Phase II) | Up to 12 months | The percent of patients with best response as complete response (CR) and partial response(PR) among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I) | Up to 12 months. | The recommended phase 2 dose will be determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (Phase II) | Up to 12 months | It is defined as the time from on treatment to disease progression or death (whichever comes first). For those alive without progression, they were censored at last follow up date. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval. |
| Disease Control Rate | Up to 12 months | The disease control rate will be evaluated. It is defined as the percent of patients with response as CR, PR, or SD among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Overall Survival | Up to 12 months | It is defined as the days from on treatment date to death due to any cause. Those alive were censored at the last date of follow up. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval. |
| Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II) | Up to 8 weeks | Evaluate the relationship between 18F-FSPG uptake change from baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The coefficient of determination (R2) describes the strength of the relationship between the change in 18F-FSPG and the change in tumor size. The squared root of R2 is the correation coefficient between the change in 18F-FSPG and the change in tumor size. R2 is reported. |
| Plasma Exosomal Content (Phase II) | Up to 12 months | Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants who were treated with CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 | 3 |
| CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 | 8 |
| CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 | 18 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 3 | 5 | 16 |
| Overall Study | Follow-Up Period Completed | 0 | 2 | 0 |
| Overall Study | Participant unable to return | 0 | 0 | 1 |
| Overall Study | Study Closed | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) | CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) | CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 7 Participants | 2 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 16 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 13 Participants | 20 Participants |
| Region of Enrollment United States | 3 participants | 8 participants | 18 participants | 29 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 13 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 8 / 8 | 17 / 18 |
| other Total, other adverse events | 3 / 3 | 8 / 8 | 18 / 18 |
| serious Total, serious adverse events | 1 / 3 | 3 / 8 | 4 / 18 |
Outcome results
Primary
Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride
The maximum tolerated dose of CB-839 will be determined in Phase I with dose-escalation following Bayesian continual reassessment method. Patients were treated in cohort of 3. The CB839 dose leves were 400, 600 and 800mg.
Time frame: Up to 12 months
Population: Patients got CB-839 combined with 6 mg/kg panitumumab, and 180 mg/m2 irinotecan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride | 800 mg |
Primary
Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I)
The recommended phase 2 dose will be determined.
Time frame: Up to 12 months.
Population: Patient received CB-839 in combination with panitumumab and irinotecan hydrochloride (Phase I)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I) | 800 mg |
Primary
Response Rate (Phase II)
The percent of patients with best response as complete response (CR) and partial response(PR) among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Up to 12 months
Population: Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Response Rate (Phase II) | 11.8 percentage of participants |
Secondary
Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II)
Evaluate the relationship between 18F-FSPG uptake change from baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The coefficient of determination (R2) describes the strength of the relationship between the change in 18F-FSPG and the change in tumor size. The squared root of R2 is the correation coefficient between the change in 18F-FSPG and the change in tumor size. R2 is reported.
Time frame: Up to 8 weeks
Population: Patients received the phase II dose and had both SUVmax and tumor size data available
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II) | 0.0983 Coefficient of determination |
Secondary
Disease Control Rate
The disease control rate will be evaluated. It is defined as the percent of patients with response as CR, PR, or SD among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Up to 12 months
Population: Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Disease Control Rate | 41.2 percentage of participants |
Secondary
Overall Survival
It is defined as the days from on treatment date to death due to any cause. Those alive were censored at the last date of follow up. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.
Time frame: Up to 12 months
Population: Patients received CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Overall Survival | 265 days |
Secondary
Plasma Exosomal Content (Phase II)
Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.
Time frame: Up to 12 months
Population: Patients who were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 and had plasma exosomal measurement available at pre-treatment, after cycle 1, and/or at progression.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Plasma Exosomal Content (Phase II) | 3.9 mg |
| CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 | Plasma Exosomal Content (Phase II) | 3.2 mg |
| CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression | Plasma Exosomal Content (Phase II) | 4.1 mg |
Secondary
Progression Free Survival (Phase II)
It is defined as the time from on treatment to disease progression or death (whichever comes first). For those alive without progression, they were censored at last follow up date. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.
Time frame: Up to 12 months
Population: Patients received CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panitumumab/Irinotecan/CB-839 | Progression Free Survival (Phase II) | 56 days |