First Line Gemcitabine, Cisplatin and MEK162 in Advanced Biliary Tract Carcinoma
Study Details
Study Description
Brief Summary
The purpose of this study is to test an investigational combination of drugs for bile duct or gallbladder cancers. Gemcitabine and cisplatin are two forms of chemotherapy commonly used in combination to treat bile duct and gallbladder cancers. The investigators are looking to improve treatment results. They will attempt to do so by adding the drug MEK162 to the treatment plan. MEK162 acts by blocking a protein called MEK 1/2 which helps cancer cells grow and divide. This study will help answer the question of whether MEK162 is a helpful drug in patients with bile duct or gallbladder cancers when given with gemcitabine and cisplatin.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Gemcitabine, Cisplatin and MEK162 Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
Drug: Gemcitabine
Drug: Cisplatin
Drug: MEK162
|
Outcome Measures
Primary Outcome Measures
- MTD of MEK162 - Phase I [1 year]
In the phase I portion, up to 18 patients will be enrolled in classic 3+3 cohort dose escalation design to identify the MTD of MEK162 when administered with gemcitabine and cisplatin given weeks 2 and 3 of a 3 week cycle .
- Six-month Progression Free Survival [6 months]
An exact binomial single stage design will be used to discriminate between true 6-month PFS rates of 59% vs. 82%, and between true response rates of 26% and 50%. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
- Objective Response Rate (ORR) [1 year]
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 Outcome Measures
- Median PFS [1 year]
progression free survival will be calculated from study entry to documented disease progression or death from any cause, whatever occurs first.
- Median Overall Survival [1 year]
(survival) will be calculated from study entry to death or last follow up
- Participants Evaluated for Toxicity [2 years]
All toxicities will be rated as per the NCI Common Toxicity Criteria, version 4.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma. Combined cholangiocarcinoma and hepatocellular carcinoma is allowed.
-
Patients must have measurable disease by RECIST 1.1
-
KPS ≥ 80%
-
Age ≥ 18 years
-
Adequate bone marrow function defined as: Hb ≥ 8 g/dl, ANC ≥ 1.5 K/mcL, Platelets ≥ 100 K/mcL
-
Adequate renal function defined as serum creatinine < 1.6 mg/dl and/or measured creatinine clearance from 24-hour urine collection of ≥ 60 ml/min
-
Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, ALT/AST ≤ 5 x ULN.
-
Patients with biliary obstruction can join if bilirubin corrects to required limit after adequate biliary drainage.
Adequate cardiac function defined as ejection fraction ≥ 45% as determined by transthoracic echocardiogram or MUGA
-
Patients who have received prior local therapy, including but not limited to embolization, chemoembolization, radiofrequency ablation, radiation therapy, are eligible provided that measurable disease falls outside the treatment field or within the field but has shown an increase of ≥ 20% in the size. Prior local therapy must be completed at least 4 weeks prior to the baseline scan
-
Women of childbearing potential must have a negative pregnancy test within 7 days prior to study treatment
-
Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.
-
Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
-
Any previous chemotherapy, biologic therapy, or investigational agent, except for adjuvant therapy as single agents and/or as radio-sensitizing agents limited to 5-fluorouracil and gemcitabine. Patient must have completed adjuvant therapy no less than six months prior to accrual.
-
Evidence of another active cancer that may influence patient outcome as determined by the Principal Investigator (PI) or co-Principal Investigator (co-PI), except for nonmelanoma skin carcinoma, melanoma in-situ, in-situ carcinoma of the cervix curatively treated, treated superficial bladder cancer, and adenocarcinoma of the prostate that has been surgically treated with a post-treatment PSA that is non-detectable.
-
Known brain metastases or primary central nervous system tumors with seizures that are not well controlled with standard medical therapy.
-
Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements.
-
Known HIV positive patient
-
Significant cardiovascular disease including congestive heart failure (New York Heart Association Class II or higher) or active angina pectoris.
-
History of a myocardial infarction within 6 months.
-
History of a stroke or transient ischemic attack within 6 months.
-
Clinically significant peripheral vascular disease.
-
Major surgical procedure within 4 weeks.
-
Uncontrolled infection.
-
Known or suspected allergy to gemcitabine or cisplatin
-
Pregnant (positive pregnancy test)
-
Breast-feeding should be discontinued if a nursing mother is to be treated on clinical trial.
-
Any condition that impairs patient's ability to swallow whole pills
-
Malabsorption problem that may limit or inhibit the absorption of MEK 162
-
Patients with a history or current known evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy at baseline that would be considered a risk factor for CSR or RVO.
-
History of any organ or bone marrow transplant.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- Array BioPharma
Investigators
- Principal Investigator: Ghassan Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 13-004
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 |
|---|---|---|---|---|
| Arm/Group Description | Cohort 1 Phase I, Dose Level 1 - MEK162 25 mg | Cohort 2 Phase I, Dose Level 2 - MEK162 45mg | Cohort 3 Phase I, Dose Level 3 / Phase II - MTD mg | Cohort 4 Phase II only, MTD mg |
| Period Title: Overall Study | ||||
| STARTED | 3 | 6 | 3 | 30 |
| COMPLETED | 3 | 6 | 3 | 29 |
| NOT COMPLETED | 0 | 0 | 0 | 1 |
Baseline Characteristics
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Cohort 1 Phase I, Dose Level 1 - MEK162 25 mg | Cohort 2 Phase I, Dose Level 2 - MEK162 45mg | Cohort 3 Phase I, Dose Level 3 / Phase II - MTD mg | Cohort 4 Phase II only, MTD mg | Total of all reporting groups |
| Overall Participants | 3 | 6 | 3 | 29 | 41 |
| Age (years) [Median (Full Range) ] | |||||
| Median (Full Range) [years] |
64.3
|
54.3
|
71.3
|
69
|
66
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
2
66.7%
|
3
50%
|
2
66.7%
|
13
44.8%
|
20
48.8%
|
| Male |
1
33.3%
|
3
50%
|
1
33.3%
|
16
55.2%
|
21
51.2%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
2
66.7%
|
5
83.3%
|
3
100%
|
27
93.1%
|
37
90.2%
|
| Unknown or Not Reported |
1
33.3%
|
1
16.7%
|
0
0%
|
2
6.9%
|
4
9.8%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
1
2.4%
|
| White |
2
66.7%
|
5
83.3%
|
2
66.7%
|
27
93.1%
|
36
87.8%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
33.3%
|
1
16.7%
|
0
0%
|
2
6.9%
|
4
9.8%
|
| Region of Enrollment (Count of Participants) | |||||
| United States |
3
100%
|
6
100%
|
3
100%
|
29
100%
|
41
100%
|
Outcome Measures
| Title | MTD of MEK162 - Phase I |
|---|---|
| Description | In the phase I portion, up to 18 patients will be enrolled in classic 3+3 cohort dose escalation design to identify the MTD of MEK162 when administered with gemcitabine and cisplatin given weeks 2 and 3 of a 3 week cycle . |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 12 |
| Number [mg] |
45
|
| Title | Six-month Progression Free Survival |
|---|---|
| Description | An exact binomial single stage design will be used to discriminate between true 6-month PFS rates of 59% vs. 82%, and between true response rates of 26% and 50%. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 42 |
| Progression free |
19
633.3%
|
| Progressed |
23
766.7%
|
| Title | Objective Response Rate (ORR) |
|---|---|
| Description | 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 | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant withdrew consent before starting treatment |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 41 |
| Number [percentage of participants with ORR] |
12
400%
|
| Title | Median PFS |
|---|---|
| Description | progression free survival will be calculated from study entry to documented disease progression or death from any cause, whatever occurs first. |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participants withdrew consent before received treatment |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 41 |
| Median (95% Confidence Interval) [months] |
6
|
| Title | Median Overall Survival |
|---|---|
| Description | (survival) will be calculated from study entry to death or last follow up |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participant withdrew consent before starting treatment |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 41 |
| Mean (95% Confidence Interval) [months] |
13.3
|
| Title | Participants Evaluated for Toxicity |
|---|---|
| Description | All toxicities will be rated as per the NCI Common Toxicity Criteria, version 4. |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1 participants withdrew consent before receiving treatment |
| Arm/Group Title | Gemcitabine, Cisplatin and MEK162 |
|---|---|
| Arm/Group Description | Phase I component of the study, a classic 3+3 cohort dose escalation scheme will be used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m2 and cisplatin given at dose 20 mg/m2 week 2 & 3 of a 3 week cycle. The final cohort will receive gemcitabine 1000mg/m2 and cisplatin 20mg/m2 week 2 and 3 of a 3 week cycle in combination with MEK162 at the MTD as determined above. In the phase II part of the study, patients will receive MEK162 at the MTD dose plus gemcitabine and cisplatin at the dose level determined acceptable in the phase I portion. In the phase II part of the study, patients will receive MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and cisplatin (20 mg/m2) as determined by the phase I portion. |
| Measure Participants | 42 |
| Evaluated for toxicity |
41
1366.7%
|
| Not evaluable/withdrew consent before treatment |
1
33.3%
|
Adverse Events
| Time Frame | 2 years | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | SAE's collected. Non-SAE/AE data were not collected. | |||||||
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | ||||
| Arm/Group Description | Cohort 1 Phase I, Dose Level 1 - MEK162 25 mg | Cohort 2 Phase I, Dose Level 2 - MEK162 45mg | Cohort 3 Phase I, Dose Level 3 / Phase II - MTD mg | Cohort 4 Phase II only, MTD mg | ||||
All Cause Mortality |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/3 (66.7%) | 4/6 (66.7%) | 1/3 (33.3%) | 16/29 (55.2%) | ||||
Serious Adverse Events |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/3 (33.3%) | 1/6 (16.7%) | 3/3 (100%) | 29/29 (100%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anemia | 0/3 (0%) | 0/6 (0%) | 2/3 (66.7%) | 16/29 (55.2%) | ||||
| Leukopenia | 0/3 (0%) | 0/6 (0%) | 1/3 (33.3%) | 17/29 (58.6%) | ||||
| Investigations | ||||||||
| Blood bilirubin increased | 0/3 (0%) | 0/6 (0%) | 0/3 (0%) | 7/29 (24.1%) | ||||
| Neutropenia | 1/3 (33.3%) | 1/6 (16.7%) | 2/3 (66.7%) | 20/29 (69%) | ||||
| Hyperlipasemia | 0/3 (0%) | 0/6 (0%) | 0/3 (0%) | 7/29 (24.1%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Hyponatremia | 0/3 (0%) | 0/6 (0%) | 0/3 (0%) | 7/29 (24.1%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | 0/0 (NaN) | 0/0 (NaN) | 0/0 (NaN) | ||||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Ghassan Abou-Alfa, MD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 646-888-4184 |
| abou-alg@mskcc.org |
- 13-004