Colorectal Cancer, Metastatic Cancer
Conditions
Keywords
Pembrolizumab, Binimetinib, Bevacizumab, Combination Therapy
Brief summary
This is an open-label, single-center, single-arm phase II clinical trial evaluating the combination of pembrolizumab, binimetinib, and bevacizumab in patients with metastatic colorectal adenocarcinoma who have not responded to prior therapy.
Detailed description
This study will be done in two stages. In stage 1, ten patients will be treated with standard doses of pembrolizumab, binimetinib, and bevacizumab to ensure that the doses are safe and tolerable. In stage 2, patients will be enrolled into either cohort A, where they will be treated with a 7-day run-in of binimetinib, followed by pembrolizumab, bevacizumab, and binimetinib combination treatment in 21 day cycles, or they will be enrolled to cohort B, which does not include the 7-day run-in of binimetinib. Treatment in cohort B will include combination therapy of pembrolizumab, binimetinib, and bevacizumab from first day of treatment.
Interventions
DRUGPembrolizumab
An intravenous, potent and highly selective humanized monoclonal antibody of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
DRUGBevacizumab
The pharmacokinetics of bevacizumab are characterized by a slow CL, long half-life, and a volume of distribution consistent with limited extravascular distribution.
DRUGBinimetinib
Binimetinib (MEK162/ARRY-438162) is an orally bioavailable, small molecule selective and potent mitogen-activated protein kinase (MEK) 1 and MEK 2 inhibitor.
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Provision to sign and date the consent form. 2. Age ≥ 18 years. 3. Able to comply with the study protocol, in the investigator's judgment. 4. Patient must state willingness to undergo pre- and post-treatment biopsies. According to the investigator's judgement, the planned biopsies should not expose the patient to substantially increased risk of complications. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or one. 6. Histologically confirmed unresectable metastatic colorectal adenocarcinoma. 7. Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma. o Administration of bevacizumab previously does not impact study inclusion. 8. Measurable disease, according to RECIST v1.1. Note that lesions intended to be biopsied should not be target lesions. 9. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment: * WBC ≥ 2.5 and ≤ 15.0 × 109/L * ANC ≥ 1.5 × 109/L * Platelet count ≥ 100 × 109/L * Hemoglobin ≥ 9 g/dL without transfusion in the previous week * Albumin ≥ 2.5 g/dL * Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN * INR and PTT ≤ 1.5 × ULN; amylase and lipase ≤ 1.5 × ULN * AST, ALT, and alkaline phosphatase (ALP) ≤ 3 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 ×ULN * Patients with documented liver or bone metastases: ALP ≤ 5×ULN * Creatinine clearance ≥ 50 mL/min 10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. 11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion criteria
1\. Cancer-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response | Study beginning to study end; 12 months | Each study subject will be considered as a responder if their best CT imaging result is either CR (complete response) or PR (partial response) based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) evaluation criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Study start date to first sign of disease progression or death, whichever comes first. | The median progression-free survival was calculated using the Kaplan-Meier product-limit method. |
| Overall Survival (OS) | Time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact. | OS is defined as the time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact. |
| Adverse Events | Study beginning to study end, 12 months | Grade 1, 2, 3, 4, or 5 adverse events (AE) as defined by CTCAE v4 were summarized. All adverse events summarized were non-baseline AEs (i.e. each AE was not present at baseline). AEs were summarized by generating counts of AEs by AE description and severity, but no formal statistical test was performed on the AEs. For the purpose of this section, the outcome measure will be defined as the number of subjects who had at least 1 AE. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Safety run-in Ten patients will be accrued to stage 1 and treated with standard doses of pembrolizumab, binimetinib and bevacizumab. If the standard doses are not tolerable and 2 or more patients experience a DLT, then patients would be enrolled in dose level -1 which would comprise of standard doses of pembrolizumab and bevacizumab but binimetinib would be at a dose lower of 30 mg PO BID. If 2 or more patients experience a DLT at dose level-1, then patients will be enrolled in dose level -2 which will comprise of standard doses of pembrolizumab and bevacizumab but a lower dose of binimetinib at 15 mg BID. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to stage 2. | 11 |
| Cohort A Patients will start with 7-day run-in of binimetinib on day -7 of cycle 1 only. Pembrolizumab and bevacizumab will then be added to binimetinib on cycle 1 day +1. Cycle 1 will end on day 21. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles. | 21 |
| Cohort B Patients will be treated with pembrolizumab, bevacizumab, and binimetinib together on day 1 of all cycles including cycle 1. Patients will start treatment with pembrolizumab, binimetinib, and bevacizumab on day 1 of all subsequent cycles. | 21 |
| Total | 53 |
Baseline characteristics
| Characteristic | Safety run-in | Cohort A | Cohort B | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 1 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 16 Participants | 20 Participants | 43 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 11.4 | 52 years STANDARD_DEVIATION 13.1 | 53 years STANDARD_DEVIATION 9.8 | 53.9 years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 19 Participants | 21 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 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 | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 7 Participants | 18 Participants | 18 Participants | 43 Participants |
| Region of Enrollment United States | 11 participants | 21 participants | 21 participants | 53 participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 4 / 21 | 1 / 21 |
| other Total, other adverse events | 11 / 11 | 21 / 21 | 21 / 21 |
| serious Total, serious adverse events | 3 / 11 | 11 / 21 | 8 / 21 |
Outcome results
Primary
Objective Response
Each study subject will be considered as a responder if their best CT imaging result is either CR (complete response) or PR (partial response) based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) evaluation criteria.
Time frame: Study beginning to study end; 12 months
Population: All eligible subjects with response data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In | Objective Response | 1 Participants |
| Cohort A | Objective Response | 3 Participants |
| Cohort B | Objective Response | 2 Participants |
Secondary
Adverse Events
Grade 1, 2, 3, 4, or 5 adverse events (AE) as defined by CTCAE v4 were summarized. All adverse events summarized were non-baseline AEs (i.e. each AE was not present at baseline). AEs were summarized by generating counts of AEs by AE description and severity, but no formal statistical test was performed on the AEs. For the purpose of this section, the outcome measure will be defined as the number of subjects who had at least 1 AE.
Time frame: Study beginning to study end, 12 months
Population: Adverse events from all subjects were evaluated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In | Adverse Events | 10 Participants |
| Cohort A | Adverse Events | 20 Participants |
| Cohort B | Adverse Events | 20 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact.
Time frame: Time (measured in months) from each subject starting treatment until either death (from any cause) or being censored at their last contact.
Population: All 50 subjects enrolled onto the trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In | Overall Survival (OS) | 12.6 Months-to-Death |
| Cohort A | Overall Survival (OS) | 9.3 Months-to-Death |
| Cohort B | Overall Survival (OS) | 8.5 Months-to-Death |
Secondary
Progression-Free Survival (PFS)
The median progression-free survival was calculated using the Kaplan-Meier product-limit method.
Time frame: Study start date to first sign of disease progression or death, whichever comes first.
Population: All patients who had follow-up data. Among the 50 total subjects, subjects 11, 19, 32, 33, and 53 did not have follow-up data. This resulted in 45 subjects being included in the PFS analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In | Progression-Free Survival (PFS) | 8.7 Months |
| Cohort A | Progression-Free Survival (PFS) | 7.6 Months |
| Cohort B | Progression-Free Survival (PFS) | 5.8 Months |