Esophageal Cancer, Gastric Cancer
Conditions
Keywords
HER2 positive
Brief summary
The purpose of this study is to determine the safety and effectiveness of a combination of chemotherapy, capecitabine and oxaliplatin, plus the antibodies bevacizumab and trastuzumab. Trastuzumab (also called Herceptin) is an antibody that attacks HER2 protein in tumor cells. Bevacizumab (also called Avastin) works by slowing or stopping the growth of cells in cancer tumors by decreasing the blood supply of the tumors. If blood supply is decreased, oxygen and nutrients that are needed for tumor growth are decreased. The chemotherapy used in this trial is called CAPOX, which is an abbreviation of capecitabine and oxaliplatin.
Detailed description
* We recommend that the participants have a vascular access device, more commonly known as a PORT, inserted prior to starting chemotherapy. A port is a small device that is inserted under the skin (usually near the collar bone) by a minor surgical procedure and is then connected to one of the large veins inside the chest. The port will be used to give the intravenous medications. * During the first cycle, the participant will receive trastuzumab intravenously on Day 1. Cycle 2 will then start one week later. On this day, bevacizumab will be given intravenously first followed by trastuzumab and then oxaliplatin. The participant will then start taking capecitabine tablets orally twice a day for 14 days. Each treatment cycle is 21 days long. * Participants will have the following tests and procedures at specific time points during study treatment; physical exam, blood tests, CT scan, MUGA scan or echocardiogram, and urine test.
Interventions
DRUGbevacizumab
Given intravenously on day 1 of each cycle beginning cycle 2
DRUGtrastuzumab
Given intravenously on day 1 of each treatment cycle
DRUGoxaliplatin
Given intravenously on day one of each cycle beginning cycle 2
DRUGcapecitabine
Taken orally on days 1-14 of each cycle beginning cycle 2
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
Genentech, Inc.
Dana-Farber Cancer Institute
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
* Confirmed HER2-positive esophageal, GE junction or gastric adenocarcinoma that is metastatic or unresectable. * All patients must have available tumor sample (either paraffin block or 15 freshly cut, unstained slides) prior to study entry. Part II: Patient must have primary esophagogastric tumor in place or other tumor that is accessible for mandatory biopsy. * Measurable disease, defined in RECIST 1.1 * 18 years of age or older * Life expectancy of greater than 12 weeks * ECOG performance status of 0 or 1 * Organ and marrow function as outlined in the protocol * Women of child-bearing potential and men must agree to use adequate contraception during study participation and for 30 days from the date of the last study drug administration. * Part II only: Participant agrees to undergo mandatory pre and post loading dose of trastuzumab biopsy for correlative science.
Exclusion criteria
* Prior therapy with any of the following; capecitabine, oxaliplatin, bevacizumab or trastuzumab is not allowed. May have received and completed adjuvant therapy at least 6 months prior to study entry or one prior therapy for metastatic disease as long as it did not include any of the above agents. * Chemotherapy or radiotherapy to greater then 25% of bone marrow within 4 weeks prior to entering the study. * Palliative radiation therapy to isolated bone metastasis within 2 weeks of initiating therapy. * Major surgery, open biopsy, significant traumatic injury within 4 weeks prior to study entry,. * Minor surgery, including placement of vascular access device within 7 days prior to the first dose of bevacizumab. * Residual toxicity from prior chemotherapy and/or radiation therapy of Grade 2 or greater. * Participants may not be receiving any concurrent investigational agents * Active brain or other CNS metastasis by history or clinical examination. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to capecitabine, bevacizumab or trastuzumab. No known allergy or hypersensitivity to Chinese hamster ovary, or any of the study agents. No known DPD deficiency. * Warfarin is prohibited; anticoagulation using low molecular weight heparin is allowed. * Uncontrolled, intercurrent illness * Patients with a history of other malignancy are not eligible except for the following circumstances: disease-free for at least 3 years and are deemed to be at low risk for recurrence of that malignancy; cervical cancer in situ, basal cell or squamous cell carcinoma of the skin that was treated with curative intent within the past 5 years. * Known HIV seropositivity, hepatitis C, acute or chronic hepatitis B or other serious active infection * LVEF less than 50% as determined by MUGA scan or echocardiogram within 28 days prior to initiation of therapy * Inadequately controlled hypertension * History of prior hypertensive crisis or hypertensive encephalopathy * History of any arterial thrombosis, CVA, TIA, MI or unstable angina in past 6 months. * Evidence of bleeding diathesis or coagulopathy * Serious, unhealed wounds, bone fractures or skin ulcers * Pregnant or breast feeding * Greater than grade 1 peripheral neuropathy at baseline * Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Patients received a median of 19 cycles of therapy (Interquartile range (IQR): 8 - 34.5 cycles). Median duration of follow-up of 23.2 months (IQR: 11.0 - 46.9 months ). | ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | 23.2 months (IQR: 11.0 - 46.9 months ). | Overall survival based on the Kaplan-Meier method is defined as the time from randomization to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant. |
| Median Duration of Response (DOR) | 23.2 months (IQR: 11.0 - 46.9 months ). | DOR is defined as the time from date of first documented confirmed objective response to date of first documented progressive disease (PD). Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
| Median Progression Free Survival (PFS) | Patients received a median of 19 cycles of therapy (Interquartile range (IQR): 8 - 34.5 cycles). Median duration of follow up of 23.2 months (IQR: 11.0 - 46.9 months ). | PFS is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
Countries
United States
Participant flow
Recruitment details
Of 61 participants assessed for eligibility, 37 met the inclusion criteria and enrolled for treatment. One patient withdrew consent prior to starting therapy. 36 were evaluable for efficacy and safety.
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine for patients with HER2-positive metastatic esophagogastric cancer. Each cycle is 21 days.
Cycle 1, Day 1 Trastuzumab (loading dose) 4mg/kg IV
Cycle 2, Day 1 and all Subsequent Cycles Bevacizumab (7.5mg/kg) IV Trastuzumab (6mg/kg) IV Oxaliplatin (130mg/m2) IV Capecitabine (1200mg/m2) PO (taken Days 1-14 of each cycle)
Patients remained on treatment until disease progression, intercurrent illness that prevented further administration of treatment, unacceptable adverse events, participant decision to withdraw consent or general or specific changes in the participant's condition that rendered the participant unacceptable for further treatment. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Break from chemotherapy | 2 |
| Overall Study | Death | 1 |
| Overall Study | Not completed but analyzed | 25 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Pursue chemoradiation | 2 |
| Overall Study | Subject never received treatment and wasn't analyzed. | 1 |
| Overall Study | Surveillance | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine |
|---|---|
| Age, Continuous | 55.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 0 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 31 / 36 |
| other Total, other adverse events | 36 / 36 |
| serious Total, serious adverse events | 13 / 36 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Patients received a median of 19 cycles of therapy (Interquartile range (IQR): 8 - 34.5 cycles). Median duration of follow-up of 23.2 months (IQR: 11.0 - 46.9 months ).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine | Objective Response Rate (ORR) | 81 percentage of patients |
Secondary
Median Duration of Response (DOR)
DOR is defined as the time from date of first documented confirmed objective response to date of first documented progressive disease (PD). Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: 23.2 months (IQR: 11.0 - 46.9 months ).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine | Median Duration of Response (DOR) | 14.9 months |
Secondary
Median Overall Survival
Overall survival based on the Kaplan-Meier method is defined as the time from randomization to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant.
Time frame: 23.2 months (IQR: 11.0 - 46.9 months ).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine | Median Overall Survival | 23.2 months |
Secondary
Median Progression Free Survival (PFS)
PFS is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: Patients received a median of 19 cycles of therapy (Interquartile range (IQR): 8 - 34.5 cycles). Median duration of follow up of 23.2 months (IQR: 11.0 - 46.9 months ).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab, Bevacizumab, Oxaliplatin and Capecitabine | Median Progression Free Survival (PFS) | 14.0 months |