Metastatic NSCLC, Non-small Cell Lung Cancer (NSCLC), Stage IV NSCLC
Conditions
Keywords
Non-small cell lung cancer, Cabazitaxel-XRP6258, P-glycoprotein, taxane, Advanced NSCLC
Brief summary
Lung cancer is the leading cause of cancer death worldwide and in the United States. The majority of lung cancers are non-small cell lung cancer (NSCLC). The majority of NSCLC cases are advanced at the time of diagnosis. Chemotherapy has improved overall survival but remains limited at \< 12 months median overall survival. New approaches are needed for second line chemotherapy treatment. Cabazitaxel-XRP6258 has shown increased overall survival in metastatic prostate cancer and it is hopeful it can do the same in advanced NSCLC.
Detailed description
A substantial number of patients with lung cancer progress after first line treatment and require second line chemotherapy. Lung cancer appears to account for 40-50% of all known brain metastasis. The incidence of brain metastases among lung cancer patients ranges from 16-20%. Chemotherapy has had limited utility due to problems crossing the blood brain barrier. Currently there are three drugs approved by the FDA for second line treatment of NSCLC but each has distinct toxicities. Cabazitaxel-XRP6258 is a potent novel taxane with enhanced activity against an increased number of cell lines including lung, prostate, colon, pancreas, head and neck, kidney, gastric, glioblastoma, and melanoma. It also has the ability to cross the blood brain barrier. Cabazitaxel-XRP6258 was found to have an improved antiproliferative activity than other chemotherapy agents against insensitive cell lines. The Phase I studies of Cabazitaxel-SRP6258 have determined dosage and schedule recommendations in advanced NSCLC patients to be utilized for a Phase II multicenter study. Subjects will be placed on one of two schedules (A or B) each with a specified dosage and administration schedule. All subjects will be followed for survival/progression after every 2 cycles of therapy with imaging studies. A two stage design will be used for each of the two schedules. Fourteen subjects will be accrued for each schedule in the first stage with possible accrual of an additional 34 subjects per schedule depending upon the first stage results.
Interventions
DRUGCabazitaxel-XRP6258 (3-week cycle)
Subjects in Schedule A will begin with an initial dose of 20 mg/m2 every 3 weeks as a 1 hour IV infusion. If no dose limiting toxicities are experienced after cycle 1, then the dose will be escalated to 25 mg/m2. Treatment with Cabazitaxel-XRP6258 will continue for a total of 6 cycles unless there is evidence of disease progression, intolerable toxicity or withdrawal of consent. Further treatment after 6 cycles of treatment in patients who achieved an objective response or stable disease, and no significant toxicity will be an individual decision from the investigator.
DRUGCabazitaxel-XRP6258 (5-week cycle)
Subjects in Schedule B will begin with an initial dose of 8.4 mg/m2 as a 1 hour IV infusion on days 1, 8, 15, and 22 of a 5-week cycle. If no dose limiting toxicities are experienced after cycle 1, then the dose will be escalated to 10 mg/m2. Treatment with Cabazitaxel-XRP6258 will continue for a total of 6 cycles unless there is evidence of disease progression, intolerable toxicity or withdrawal of consent. Further treatment after 6 cycles of treatment in patients who achieved an objective response or stable disease, and no significant toxicity will be an individual decision from the investigator.
Sponsors
Sanofi
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic diagnosis of NSCLC (squamous or non-squamous or NSCLC-not specified) * Subjects who have failed first line chemotherapy (platinum doublets or non- platinum doublets \[previous taxane exposure is allowed\]) for Stage IV NSCLC. * Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Age \> 18 years old * Adequate bone marrow, liver and renal function, defined as: * Absolute neutrophil count (ANC) greater than or equal to 1500/ul * Hemoglobin greater than or equal to 10 g/dl * Platelet count greater than or equal to 100,000/ul * Total bilirubin less than or equal to 1.5 x upper limit of normal (except in subjects with documented Gilbert's syndrome) * AST/ALT less than or equal to 1.5 x upper limit of normal * Serum creatinine less than or equal to 1.8 mg/dl * Fully recovered from any previous surgery (at least 4 weeks since major surgery) * Fully recovered from previous radiation therapy (at least 2 weeks) * All subjects must agree to practice approved methods of birth control (if applicable). A negative pregnancy test must be documented during the screening period for women of childbearing potential. * Written informed consent and authorization to use and disclose health information (HIPAA) must be signed by the subject. * Subjects with symptomatic brain metastases should be adequately treated and controlled prior to the initiation of the study. Subjects with asymptomatic brain metastases will be allowed in the study without any prior therapy for brain metastases.
Exclusion criteria
* Concurrent cancer chemotherapy, biologic therapy or radiotherapy * Administration of any investigational agent within 28 days prior to administration of current therapy * Untreated symptomatic brain metastases * Greater than or equal to Grade 2 neuropathy * Concurrent serious infection * Concomitant severe or uncontrolled underlying medical disease unrelated to the tumor, which is likely to compromise subject safety and affect the outcome of the study. * Treatment for a cancer other the NSCLC within 5 years prior to enrollment, with the exception of basal cell carcinoma or carcinoma in situ of the cervix * Any evidence of history of hypersensitivity for the taxane class of chemotherapy drugs * History of positive serology for HIV * Psychiatric disorder that prevents subjects from providing informed consent or following protocol instructions * Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Baseline up to 28 months | The objective response is defined as the percentage of patients that achieve a complete and/or partial response according to The Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Baseline up to 28 months | Progression Free Survival is defined from the initiation of treatment until radiological-clinical evidence of progression according to the RECIST (v 1.1). |
| Number of Patients With Any Graded Adverse Event | Baseline up to 28 months | Safety will be assessed using the National Cancer Institute Common Toxicity Criteria (Version 4.0) and all adverse events will be recorded prior to each treatment regimen. |
| Overall Survival | 28 months | Assessment will be made in subjects with Stage IV NSCLC who receive Cabazitaxel-SRP6258 after progressing with first line platinum-based chemotherapy. |
Countries
United States
Participant flow
Recruitment details
Subjects will be randomized to one of two schedules (A or B) each with a specified dosage and administration schedule. A two stage design will be used for each of the two schedules. Fourteen subjects will be accrued for each schedule in Stage I with an additional 34 subjects in Stage II per schedule depending upon the first stage results.
Pre-assignment details
New approaches are needed for 2nd line chemotherapy treatment. Cabazitaxel-XRP6258 has shown increased overall survival in metastatic prostate cancer and it is hopeful to do the same in advanced Non-Small Cell Lung Cancer (NSCLC).This phase II study will evaluate the efficacy of cabazitaxel chemotherapy in 2nd line setting in patients with NSCLC.
Participants by arm
| Arm | Count |
|---|---|
| Schedule A Cabazitaxel 20 mg/m2 every 3 weeks as a 1 hour IV infusion with a planned dose escalation of to 25 mg/m2 if no dose limiting toxicities (DLTs) were observed. | 14 |
| Schedule B Cabazitaxel 8.4 mg/m2 weekly on Days 1, 85, 15, and 22 of a 5 week cycle with a planned dose escalation to 10 mg/m2 weekly if no dose limiting toxicities (DLTs) were observed. | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
Baseline characteristics
| Characteristic | Schedule B | Schedule A | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 9 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 5 Participants | 15 Participants |
| Age, Continuous | 64 Years | 68 Years | 65 Years |
| Region of Enrollment United States | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 1 / 14 |
| other Total, other adverse events | 5 / 14 | 6 / 14 |
| serious Total, serious adverse events | 7 / 14 | 1 / 14 |
Outcome results
Primary
Objective Response Rate
The objective response is defined as the percentage of patients that achieve a complete and/or partial response according to The Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1).
Time frame: Baseline up to 28 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Schedule A | Objective Response Rate | 0 participants |
| Schedule B | Objective Response Rate | 1 participants |
Secondary
Number of Patients With Any Graded Adverse Event
Safety will be assessed using the National Cancer Institute Common Toxicity Criteria (Version 4.0) and all adverse events will be recorded prior to each treatment regimen.
Time frame: Baseline up to 28 months
Population: 14 patients in each cohort were included in the toxicity assessment and 13 patients in each cohort in the efficacy assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Schedule A | Number of Patients With Any Graded Adverse Event | 14 Participants |
| Schedule B | Number of Patients With Any Graded Adverse Event | 14 Participants |
Secondary
Overall Survival
Assessment will be made in subjects with Stage IV NSCLC who receive Cabazitaxel-SRP6258 after progressing with first line platinum-based chemotherapy.
Time frame: 28 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A | Overall Survival | 6 months |
| Schedule B | Overall Survival | 13 months |
Secondary
Progression Free Survival
Progression Free Survival is defined from the initiation of treatment until radiological-clinical evidence of progression according to the RECIST (v 1.1).
Time frame: Baseline up to 28 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Schedule A | Progression Free Survival | 3 months |
| Schedule B | Progression Free Survival | 3 months |