Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
Phase I study. To determine the MTD (Maximum Tolerated Dose) of nintedanib + weekly Docetaxel in patients with locally advanced or metastatic lung adenocarcinoma after failure of platinum-based first line chemotherapy.
Interventions
DRUGDocetaxel
DRUGNintedanib
Low Dose
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Patients with histologically/ cytologically confirmed locally advanced (Stage IIIB) or metastatic (Stage IV) lung adeno carcinoma after failure of first line platinum - based chemotherapy (patients with non-target lesion only are eligible). First line chemotherapy may include continuation or switch maintenance therapy. One prior adjuvant and/or neoadjuvant chemotherapy line is accepted. Prior immunotherapy is allowed. * ECOG inferior or equal to 1 at screening. * Further inclusion criteria apply
Exclusion criteria
* Patients who have received more than one prior line of chemotherapy (i.e. second or third line chemotherapy) for advanced or metastatic NSCLC. * Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) mutation or patients known to be positive for ALK translocation * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel | First treatment cycle, the first 28 days following the start of trial medication. | Maximum tolerated dose (MTD) of nintedanib administered in combination with docetaxel. The MTD was defined as the highest dose combination studied for which the incidence of DLTs was no more than 1 out of 6 subjects experiencing a DLT during the first treatment cycle i.e. the incidence of DLTs was no more than 17%. In case dose escalation reached dose level 3 (200 mg bid nintedanib administered without interruption on days of docetaxel infusion) and no more than 1 out of 6 subjects experienced a DLT during the first 28-day cycle at this dose level, dose level 3 was considered the MTD. |
| Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | First treatment cycle, the first 28 days following the start of trial medication. | Number of participants with DLT occurring during the first treatment cycle. DLT was defined as any of the following adverse events related to nintedanib: * Non-haematological drug-related Common Terminology Criteria for AEs (CTCAE) grade 3 or greater * diarrhoea CTCAE grade 2 for \>7 days despite supportive care * nausea CTCAE grade 3 or greater despite supportive care * vomiting CTCAE grade 2 or greater despite supportive care * increase in Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) to CTCAE grade 3 or greater * A increase in ALT and/or AST to CTCAE grade 2 or greater in conjunction with * total bilirubin increase of CTCAE grade 1 or greater * Platelets \<50 000/mm3 with bleeding (CTCAE ≥3) * neutropenia of any grade or duration accompanied by fever \>38.5°C * neutropenia grade 4 without fever of \>7 days duration * Inability to resume nintedanib dosing within 21 days after stopping due to toxicity. |
Countries
France, Germany
Participant flow
Recruitment details
This study is an open-label Phase I of oral nintedanib plus weekly docetaxel therapy in subjects with locally advanced or metastatic lung adenocarcinoma after failure of platinum-based first-line chemotherapy.
Pre-assignment details
All subjects who signed informed consent were screened for eligibility prior to participation in the trial. Subjects were assigned to trial drug if they met all inclusion criteria and none of the exclusion criteria. Subjects attended a specialist site in oncology.
Participants by arm
| Arm | Count |
|---|---|
| 150 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 150 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 100 mg twice a day, a second dose reduction was not allowed. | 7 |
| 200 mg Nintedanib + Docetaxel In a treatment cycle of 28 days, 200 milligram (mg) nintedanib was administered orally twice a day with a dose interval of 12 hours with 250 milliliter (mL) of water after food intake except on the days of docetaxel infusion. Docetaxel (35 mg per square meter of body surface (mg/m2)) was administrated as a intravenous infusion over 60 minutes on Days 1, 8 and 15. The 28-day treatment cycles could be repeated until disease progression. In case of nintedanib-related adverse events, the dose of nintedanib was to be reduced to 150 mg twice a day with a possible second dose reduction to 100 mg twice a day. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lack of benefit and side effects | 1 | 0 |
| Overall Study | Progressive disease | 6 | 3 |
| Overall Study | Withdrawal from the trial | 0 | 1 |
Baseline characteristics
| Characteristic | 200 mg Nintedanib + Docetaxel | Total | 150 mg Nintedanib + Docetaxel |
|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 7.8 | 63.6 years STANDARD_DEVIATION 8.2 | 67.0 years STANDARD_DEVIATION 7.6 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Not reported due to local law restrictions | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 6 / 7 | 6 / 7 |
| serious Total, serious adverse events | 3 / 7 | 2 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel
Maximum tolerated dose (MTD) of nintedanib administered in combination with docetaxel. The MTD was defined as the highest dose combination studied for which the incidence of DLTs was no more than 1 out of 6 subjects experiencing a DLT during the first treatment cycle i.e. the incidence of DLTs was no more than 17%. In case dose escalation reached dose level 3 (200 mg bid nintedanib administered without interruption on days of docetaxel infusion) and no more than 1 out of 6 subjects experienced a DLT during the first 28-day cycle at this dose level, dose level 3 was considered the MTD.
Time frame: First treatment cycle, the first 28 days following the start of trial medication.
Population: Maximum tolerated dose (MTD) Evaluation Set: All subjects who received at least one dose of study medication and were evaluable for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib + Docetaxel | Maximum Tolerated Dose (MTD) of Nintedanib Administered in Combination With Docetaxel | NA milligram |
Primary
Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle
Number of participants with DLT occurring during the first treatment cycle. DLT was defined as any of the following adverse events related to nintedanib: * Non-haematological drug-related Common Terminology Criteria for AEs (CTCAE) grade 3 or greater * diarrhoea CTCAE grade 2 for \>7 days despite supportive care * nausea CTCAE grade 3 or greater despite supportive care * vomiting CTCAE grade 2 or greater despite supportive care * increase in Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) to CTCAE grade 3 or greater * A increase in ALT and/or AST to CTCAE grade 2 or greater in conjunction with * total bilirubin increase of CTCAE grade 1 or greater * Platelets \<50 000/mm3 with bleeding (CTCAE ≥3) * neutropenia of any grade or duration accompanied by fever \>38.5°C * neutropenia grade 4 without fever of \>7 days duration * Inability to resume nintedanib dosing within 21 days after stopping due to toxicity.
Time frame: First treatment cycle, the first 28 days following the start of trial medication.
Population: Maximum tolerated dose (MTD) Evaluation Set: All subjects who received at least one dose of study medication and were evaluable for MTD determination.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nintedanib + Docetaxel | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 1 Participants |
| 200 mg Nintedanib + Docetaxel | Number of Participants With Dose-limiting Toxicity (DLT) During the First Treatment Cycle | 1 Participants |