Non-small Cell Lung Cancer
Conditions
Keywords
NSCLC, custirsen sodium, OGX-011, Stage IIIB or IV advanced non-small cell lung cancer
Brief summary
This clinical study will help determine if giving OGX-011 (custirsen sodium) in combination with gemcitabine (GEM) and cisplatin (CIS) or carboplatin (CARB) is a safe and effective treatment for patients with lung cancer. This study will help to assess the safety and anti-tumor effect of OGX-011 when given to patients in combination with GEM and CIS/CARB.
Detailed description
OGX-011 is an experimental drug that has been shown to increase the effectiveness of commonly used cancer therapies such as chemotherapy, radiation and hormone therapy in several kinds of cancer types in animals. OGX-011 is being studied in the treatment of cancer patients in combination with chemotherapy. In humans, OGX-011 in combination with hormone therapy has been shown to decrease the tissue levels of a protein called clusterin, which can be overproduced in cancer cells. Clusterin has been found to block cell death and makes cells more resistant to cancer therapy. Gemcitabine (GEM), cisplatin (CIS) and carboplatin (CARB) have been approved by Health Canada and the Food and Drug Administration in the United States for the treatment of patients with lung cancer. OGX-011 was administered as a 2-hr intravenous (IV) infusion on Days -7, -5, and -3 prior to Cycle 1, then weekly on Days 1, 8, 15 of each 21-day cycle; GEM was infused IV after OGX-011 on Days 1 and 8; either CIS or CARB was infused IV after GEM on Day 1 of each cycle. Six cycles of treatment were planned. Most patients received OGX-011 at 640 mg, but 3 patients received OGX-011 at 480 mg dose; OGX-011 dose groups were combined due to the small number of patients who received 480 mg.
Interventions
DRUGcustirsen sodium
Custirsen sodium (OGX-011) was to be infused intravenously over 2 hours on Days -7, -5, and 3 of Cycle 1 (pretreatment loading dose). OGX 011 was then to be infused for 2 hours weekly on Days 1, 8, and 15 of a 21-day cycle. Gemcitabine (GEM) was to be infused intravenously for 30 minutes on Days 1 and 8 and either cisplatin (CIS) or carboplatin (CARBO) were to be infused intravenously on Day 1 of this 21-day cycle. Patients were to receive a maximum of 6 cycles (1 cycle = 21 days)
Sponsors
Achieve Life Sciences
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
1. Patients must have a histologically or cytologically confirmed diagnosis of NSCLC and must not have had chemotherapy or biological therapy for their disease. 2. Stage IIIB (N3 and/or pleural or pericardial effusion) or IV disease that is not amenable to either surgery or radiation therapy of curative intent. 3. Life expectancy of ≥ 12 weeks 4. If patient has had prior radiation therapy: lesion(s) used for determination of response was not previously irradiated or has increased in size since the completion of radiotherapy; and patient has recovered from any toxicity from the radiotherapy. 5. Radiotherapy to lesion(s) used for determination of response was completed at least 6 weeks prior to treatment; radiotherapy to other sites was completed at least 2 weeks prior to treatment. 6. At least one unidimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumors \[RECIST\] (at least 10 mm in longest diameter by spiral computed tomography \[CT\] scan, or at least 20 mm by standard techniques). 7. ECOG status must be ≤ 1
Exclusion criteria
1. Prior chemotherapy or biological therapy (approved or experimental) for NSCLC, including adjuvant and neoadjuvant treatment. 2. Presence of central nervous system (CNS) metastases, unless the patient has completed successful local therapy for CNS metastases, with the exception of leptomeningeal disease for which patients will be excluded. Patients must be off corticosteroids for at least 21 days prior to starting treatment. 3. Second primary malignancy (except in situ carcinoma of the cervix, adequately treated non-melanomatous skin cancers, clinically localized prostate cancer, superficial bladder cancer or other malignancy treated at least 3 years previously with no evidence of recurrence). 4. Patients eligible for combined modality therapy with curative intent as defined by the combination of chemotherapy, radiation therapy and/or surgery. (This criteria is intended to exclude patients with stage IIIB disease, as defined by the presence of N3 nodal status, who have been reported to have cure rates as high as 10% when treated with combined modality therapy.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate of OGX-011 in Combination With Gemcitabine/Platinum-based Regimen | Based on assessments at baseline and after Cycles 2, 4, and 6. All subjects were followed for survival for a minimum of 3 years after the first dose of OGX-011 or until death. | Per RECIST Criteria V 1.0 and based on radiographic evaluations a subject was defined as having an objective response (OR) if the subject achieved either a confirmed partial response (PR) or confirmed complete response (CR). The evaluations were conducted after every two cycles of treatment for a maximum of 6 cycles. CR: disappearance of clinical/radiological evidence of tumor. PR: \>= 30% decrease in the sum of the longest diameter of target lesions. SD: did not fulfill the criteria for CR or PR but not progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | All subjects were followed for a minimum of 3 years after the first dose of OGX-011 or until death. | Overall survival was defined as time from date of first treatment with OGX-011 to the date of death from any cause. Overall survival was censored at date of last contact for subjects who were still alive at end of study. |
| Effect of OGX-011 on Serum Clusterin Levels | Blood samples were collected at baseline and prior to infusion on Cycle 2 Day 1 and Cycle 3 Day 1 | To measure the effect of OGX-011 on serum clusterin levels. The drug substance, OGX-011, is an antisense product designed to bind to clusterin mRNA, resulting in the inhibition of the production of human clusterin protein. Therefore, serum clusterin levels were expected to decrease. |
| Progression-free Survival | All subjects were followed for a minimum of 3 years after the first dose of OGX-011 or until death. | Progression-free survival (PFS) was defined as time from first treatment with OGX-011 to documented evidence of disease progression or date of death. For subjects without disease progression based on RECIST who initiated subsequent anti-cancer therapy, date of progression was defined as date of initiating new cancer treatment. PFS was censored as of the date of first OGX-011 dose for subjects who failed to return for assessments after screening. For subjects who were still alive and without progressive disease at the time of data cut-off, PFS was censored at date of last disease assessment. |
| t1/2 of OGX-011 | Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2. | Plasma half life of OGX-011 |
| AUC-0-last | Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2. | AUC-0-last is the area under the plasma concentration time curve from time 0 to the last last time point (23.5 hrs) |
| Cmax of OGX-011 | Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2. | Cmax is a plasma pharmacokinetic parameter that is defined as the maximum observed concentration of drug substance in plasma. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were recruited at 15 institutions with a primary focus on oncology and located in the United States and Canada. The date of the first screening visit was November 2004 and the last survival followup was February 2010.
Pre-assignment details
Four subjects who were assigned a study ID number were determined to be ineligible (i.e., failed one or more inclusion/exclusion criteria) and were never treated.
Participants by arm
| Arm | Count |
|---|---|
| OGX-011 - Intent to Treat Analysis Set Custirsen sodium (OGX-011) was to be infused intravenously over 2 hours on Days -7, -5, and -3 of Cycle 1 (Pretreatment loading doses). OGX-011 was then to be infused for 2 hours weekly on Days 1, 8, and 15 of a 21-day cycle. Gemcitabine (GEM) was to be infused IV for 30 minutes on Days 1 and 8 and either cisplatin (CIS) or carboplatin (CARBO) were to be infused IV on Day of the 21-day cycle. Patients were to receive a maximum of 6 cycles (1 cycle =21 days). Most patients received OGX-011 at 640 mg; but 3 patients received a 480 mg dose. The 2 dose groups were combined due to the small number of patients who received 480 mg. All patients who received at least one dose of OGX-011 were included in the Intent to Treat Analysis Set. | 81 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 23 |
| Overall Study | Death | 1 |
| Overall Study | Disease Progression | 21 |
| Overall Study | Physician Decision | 11 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | OGX-011 - Intent to Treat Analysis Set |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 25 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants |
| Age Continuous | 60.4 years |
| Baseline ECOG ECOG 1 | 54 participants |
| Baseline ECOG ECOG 2 | 1 participants |
| Baseline ECOG ECOG O | 26 participants |
| Cancer Stage Stage IIIB | 15 participants |
| Cancer Stage Stage IV | 66 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 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 | 1 Participants |
| Race (NIH/OMB) White | 72 Participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 81 / 81 |
| serious Total, serious adverse events | 32 / 81 |
Outcome results
Primary
Objective Response Rate of OGX-011 in Combination With Gemcitabine/Platinum-based Regimen
Per RECIST Criteria V 1.0 and based on radiographic evaluations a subject was defined as having an objective response (OR) if the subject achieved either a confirmed partial response (PR) or confirmed complete response (CR). The evaluations were conducted after every two cycles of treatment for a maximum of 6 cycles. CR: disappearance of clinical/radiological evidence of tumor. PR: \>= 30% decrease in the sum of the longest diameter of target lesions. SD: did not fulfill the criteria for CR or PR but not progressive disease.
Time frame: Based on assessments at baseline and after Cycles 2, 4, and 6. All subjects were followed for survival for a minimum of 3 years after the first dose of OGX-011 or until death.
Population: The efficacy analysis included all 81 subjects that received at least one dose of OGX-011. Of the 25 subjects with CR or PR, 21 subjects had a confirmed response. The other 4 patients did not have confirmatory scans (n=3) or discontinued treatment (N=1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | Objective Response Rate of OGX-011 in Combination With Gemcitabine/Platinum-based Regimen | 26 percentage of participants |
Secondary
AUC-0-last
AUC-0-last is the area under the plasma concentration time curve from time 0 to the last last time point (23.5 hrs)
Time frame: Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2.
Population: Data are reported for the 6 subjects who received 640 mg OGX-011. This is the dose to be used in additional Phase 3 studies of OGX-011
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | AUC-0-last | 260747 ng*h/mL | Standard Deviation 42578 |
Secondary
Cmax of OGX-011
Cmax is a plasma pharmacokinetic parameter that is defined as the maximum observed concentration of drug substance in plasma.
Time frame: Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2.
Population: Data are reported for the 6 subjects who received 640 mg OGX-011. This is the dose to be used in additional Phase 3 studies of OGX-011
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | Cmax of OGX-011 | 64086 ng/mL | Standard Deviation 8756 |
Secondary
Effect of OGX-011 on Serum Clusterin Levels
To measure the effect of OGX-011 on serum clusterin levels. The drug substance, OGX-011, is an antisense product designed to bind to clusterin mRNA, resulting in the inhibition of the production of human clusterin protein. Therefore, serum clusterin levels were expected to decrease.
Time frame: Blood samples were collected at baseline and prior to infusion on Cycle 2 Day 1 and Cycle 3 Day 1
Population: 55 evaluable subjects had baseline value and at least one post-baseline serum clusterin assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | Effect of OGX-011 on Serum Clusterin Levels | -25.5 µg/mL | Standard Deviation 23.1 |
Secondary
Overall Survival
Overall survival was defined as time from date of first treatment with OGX-011 to the date of death from any cause. Overall survival was censored at date of last contact for subjects who were still alive at end of study.
Time frame: All subjects were followed for a minimum of 3 years after the first dose of OGX-011 or until death.
Population: Number of subjects who died (n=70); n=11 subjects were censored at end of study (10 were alive and 1 was lost to follow up)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | Overall Survival | 14.1 months |
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as time from first treatment with OGX-011 to documented evidence of disease progression or date of death. For subjects without disease progression based on RECIST who initiated subsequent anti-cancer therapy, date of progression was defined as date of initiating new cancer treatment. PFS was censored as of the date of first OGX-011 dose for subjects who failed to return for assessments after screening. For subjects who were still alive and without progressive disease at the time of data cut-off, PFS was censored at date of last disease assessment.
Time frame: All subjects were followed for a minimum of 3 years after the first dose of OGX-011 or until death.
Population: Number of patients who progressed or died (n=75); data for 6 patients were censored. (PFS was censored at the date of the first dose of OGX-011 for subjects who failed to return for any disease assessments after screening.)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | Progression-free Survival | 4.3 months |
Secondary
t1/2 of OGX-011
Plasma half life of OGX-011
Time frame: Blood samples were collected as follows. Cycle 1; Day 1: pre-dose, 2 h (EOI), 0.5 h, 1 hr, 1.5 h, 2.5 h, 4 h, 6.5 h and 23.5 h post end of OGX-011 infusion, Day 22: pre-dose Cycle 2.
Population: Data are reported for the 6 subjects who received 640 mg OGX-011. This is the dose to be used in additional Phase 3 studies of OGX-011
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OGX-011 - Intent to Treat Analysis Set | t1/2 of OGX-011 | 3.7 hours | Standard Deviation 0.43 |