Metastatic Disease
Conditions
Keywords
metastatic biliary tract cancer
Brief summary
An open-label, uncontrolled, multicenter phase I/Ib trial to investigate safety and efficacy of BIBW 2992 added to the standard therapy of Gemcitabine/Cisplatin in chemo-naïve patients with advanced and/or metastatic adenocarcinoma of the biliary tract
Detailed description
The primary objective is safety and toxicity, including maximum tolerated dose, of BIBW 2992 when given as add-on therapy to Gem/Cis.
Interventions
DRUGBIBW 2992
once daily per os
Sponsors
Johannes Gutenberg University Mainz
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
For Part A of the study a standard 3+3 design was used. The recruitment was carried out in cohorts. Subjects were not allowed to participate in both cohorts. If the maximum tolerated dose was found there should be additional patients recruited to confirm the maximum tolerated dose (part B)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged ≥ 18 years * Signed and dated written informed consent, * Histologically confirmed adenocarcinoma of the gallbladder or intrahepatic bile ducts or extrahepatic bile ducts (metastasized) or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer or a Klatskin tumour (hilar cholangiocarcinoma) * with pain and biliary obstruction controlled * adequate biliary drainage, no uncontrolled infection * ECOG Performance Status of 0-1 * LFTs: bilirubin (total) ≤ 1.5 x ULN, ALT/ AST/ alkaline phosphatase ≤ 3 2.5 x ULN (≤ 5 x ULN if liver metastases are present) * No prior systemic treatment i) previous adjuvant chemotherapy is allowed (completed ≥ 6 months if containing Gemcitabine or platinum salts); ii) previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed, provided that there is still at least one unidimensionally measurable target lesion in an untreated area * Resolution of all side effects of prior surgical procedures to CTCAE grade ≤ 1 (except for the laboratory values specified below) * At least 4 weeks from any major surgery (at first dose of study drug) * Life expectancy of at least 12 weeks. * Cardiac left ventricular function with resting ejection fraction (LVEF) ≥ 50% * Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of therapy: * Haemoglobin \> 10.0 g/dl (=6.2 mmol/l), blood transfusion is allowed * Absolute neutrophil count (ANC) \> 1,500/mm3 (=1.5x 109/L) * Platelet count ≥ 100,000/μl (=100x 109/L) * Total bilirubin ≤ 1.5 times the upper limit of normal * ALT and AST ≤ 2.5 x institutional upper limit of normal (in case of liver metastases: ALT and AST ≤ 5 x institutional upper limit of normal) * Prothrombin rate \> 60% or INR \< 1.5 Main
Exclusion criteria
* Large surgery (except diagnostic biopsy) or smaller surgical procedures, external radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment. * Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. * History of acute cardiac disease: congestive heart failure \> NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); * Patients on immunosuppressant therapy or with known HIV infection * Active clinically serious infections (\> grade 2 NCI-CTC version 3.0) * History of organ allograft * Pregnant or breast-feeding patients. * Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation * Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study * Gastrointestinal (GI) tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease * History of pre-existing interstitial lung disease (ILD) * Patients with untreated or symptomatic brain metastases. * Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. | In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation. Safety and toxicity will be evaluated as described and considered primary for part B of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progress (TTP) | Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. | Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death. |
| Overall Survival (OS) | Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks | Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates. |
| Objective Response Rate | Treatment period: up to eight cycles (maximum 8 months). | Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment |
| Tumor Control Rate | Treatment period: up to eight cycles (maximum 8 months). | Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.) | 3 |
| Dose Level -1 30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.) | 6 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 5 |
Baseline characteristics
| Characteristic | Dose Level 1 | Total | Dose Level -1 |
|---|---|---|---|
| Age, Continuous | 62.00 years STANDARD_DEVIATION 21.63 | 60.78 years STANDARD_DEVIATION 12.3 | 60.17 years STANDARD_DEVIATION 7.31 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 9 Participants | 6 Participants |
| Region of Enrollment Germany | 3 participants | 9 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 5 / 6 |
| other Total, other adverse events | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 3 | 5 / 6 |
Outcome results
Primary
Number of Adverse Events
In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation. Safety and toxicity will be evaluated as described and considered primary for part B of the study.
Time frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Adverse Events | 2 Participants |
| Dose Level -1 | Number of Adverse Events | 1 Participants |
Secondary
Objective Response Rate
Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment
Time frame: Treatment period: up to eight cycles (maximum 8 months).
Population: For one patient, there was no CT assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Objective Response Rate | 0 Participants |
| Dose Level -1 | Objective Response Rate | 0 Participants |
Secondary
Overall Survival (OS)
Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.
Time frame: Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Overall Survival (OS) | 163 days |
| Dose Level -1 | Overall Survival (OS) | 260 days |
Secondary
Time to Progress (TTP)
Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death.
Time frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Time to Progress (TTP) | 159 days |
| Dose Level -1 | Time to Progress (TTP) | NA days |
Secondary
Tumor Control Rate
Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1.
Time frame: Treatment period: up to eight cycles (maximum 8 months).
Population: For one patient there was no CT assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Tumor Control Rate | 0 Participants |
| Dose Level -1 | Tumor Control Rate | 4 Participants |