Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer
Conditions
Brief summary
Randomized phase III trial to determine the effectiveness of carboxyamidotriazole in treating patients who have stage III or stage IV non-small cell lung cancer. Chemotherapeutic agents are modestly effective for the treatment of advanced lung cancer, with rapid tumor relapse and growth even after initial response to therapy. It is not yet known whether carboxyamidotriazole is more effective than no further treatment after standard chemotherapy for non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine whether oral administration of the carboxyaminoimidazole (CAI) is more effective than placebo in prolonging the overall survival in patients with non-small cell lung cancer stage III or stage IV non-small cell lung cancer who have been stable or had tumor regression following chemotherapy. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of oral CAI following chemotherapy. II. To determine whether CAI prolongs time-to-disease progression relative to a placebo. III. To evaluate whether a substantive effect in quality of life (QOL) can be detected between the CAI and placebo groups using the FACT-L and the UNISCALE. IV. To document the response rate to CAI in patients with measurable or evaluable disease. TERTIARY OBJECTIVES: I. To evaluate genotypes at GSH-related loci as predictors of overall survival. OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to timing of first-line therapy (prior to registration vs after registration), disease stage (IIIA vs IIIB vs IV), therapy components (chemotherapy and thoracic radiotherapy vs chemotherapy only), ECOG performance status (0 vs 1 vs 2) and participating center. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral carboxyamidotriazole daily. ARM II: Patients receive oral placebo daily. Treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and then monthly during study. Patients are followed every 3 months for 5 years.
Interventions
OTHERlaboratory biomarker analysis
Correlative studies
Given PO
OTHERplacebo
Given PO
PROCEDUREquality-of-life assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* TRACK I: Histologically or cytologically confirmed NSCLC stage III or IV; disease must be stable or responding after standard chemotherapy (with or without TRT) for a minimum of 3 or a maximum of 6 months * TRACK I: Not required to have measurable or evaluable disease at study entry * TRACK I: Must have had one and only one prior chemotherapy regimen for NSCLC (radiosensitizers are allowed) * TRACK I: =\< 6 weeks from last dose of chemotherapy or TRT * TRACK I: ECOG PS 0, 1, or 2 * TRACK I: ANC \>= 1500/mm\^3 * TRACK I: PLT \>= 100,000/mm\^3 * TRACK I: HgB \>= 10.0 g/dL * TRACK I: Total bilirubin =\< 1.5 x UNL * TRACK I: Alkaline phosphatase =\< 3 x UNL * TRACK I: AST =\< 3 x UNL * TRACK I: Creatinine =\< 1.5 x UNL * TRACK I: Expected survival of at least three months * TRACK II AT REGISTRATION: Histologically or cytologically confirmed NSCLC stage III or IV * TRACK II AT REGISTRATION: No prior chemotherapy for NSCLC * TRACK II AT REGISTRATION: Expected survival of at least six months * TRACK II AT REGISTRATION: Willingness to provide blood sample * TRACK II AT RANDOMIZATION: STAB, PR, CR, REGR following 3-6 months of chemotherapy with or without radiation therapy * TRACK II AT RANDOMIZATION: Must have had one and only one prior chemotherapy regimen for NSCLC (radiosensitizers are allowed) * TRACK II AT RANDOMIZATION: =\< 6 weeks from last dose of chemotherapy or TRT * TRACK II AT RANDOMIZATION: ECOG PS 0, 1, or 2 * TRACK II AT RANDOMIZATION: ANC \>= 1500/mm\^3 * TRACK II AT RANDOMIZATION: PLT \>= 100,000/mm\^3 * TRACK II AT RANDOMIZATION: HgB \>= 10.0 g/dL * TRACK II AT RANDOMIZATION: Total bilirubin =\< 1.5 x UNL * TRACK II AT RANDOMIZATION: Alkaline phosphatase =\< 3 x UNL * TRACK II AT RANDOMIZATION: AST =\< 3 x UNL * TRACK II AT RANDOMIZATION: Creatinine =\< 1.5 x UNL * TRACK II AT RANDOMIZATION: Expected survival of at least three months
Exclusion criteria
* TRACK I: Pregnant, nursing women, females or sexual partners of childbearing potential not using adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device \[IUD\], or abstinence, etc.) while on study treatment and for two months after discontinuing study treatment as this regimen may be harmful to a developing fetus or nursing child * TRACK I: Untreated brain metastases * TRACK I: Concomitant participation in a phase III lung cancer treatment trial * TRACK I: Planned concurrent chemotherapy, immunotherapy or radiotherapy * TRACK II AT RANDOMIZATION: Pregnant, nursing women, females or sexual partners of childbearing potential not using adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device \[IUD\], or abstinence, etc.) while on study treatment and for two months after discontinuing study treatment as this regimen may be harmful to a developing fetus or nursing child * TRACK II AT RANDOMIZATION: Untreated brain metastases * TRACK II AT RANDOMIZATION: Planned concurrent chemotherapy, immunotherapy, or radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | up to 5 years | OS was defined as the time from randomization to death of any cause. Participants who did not die or were lost to follow-up were censored at the time of last evaluation/follow-up date. Patients were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Severe Non-hematologic Adverse Events | every cycle during treatment | Severe non-hematologic adverse events were defined as adverse events grade 3 or higher, regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC version 2.0) |
| Time to Disease Progression (TTP) | up to 5 years | TTP is defined as the time from randomization to first documented disease progression(PD). Patients who were lost to follow-up were censored at the time of last evaluation. For patients who died without clear documentation, PD was assumed at the midpoint of the time interval between last evaluation and death. Median TTP was estimated using the Kaplan Meier method. Measurable PD: ≥25% increase in the sum of the products of two greatest perpendicular diameters of all indicator lesions or appearance of new lesion(s). Evaluable PD: definite increase in tumor size or appearance of new lesion(s) |
| Clinically Significant (10-point) Decrease in UNISCALE Quality of Life (QOL)Assessment From Baseline to Week 8 | Baseline to week 8 | The UNISCALE was used to assess QOL. UNISCALE is a single item global measure of QOL. Participant were to complete the questionnaire at baseline and every 8 weeks, prior to assessment by the treating physician. A high score indicates a higher quality of life while a low score represents a lower quality of life. A 10 point or greater decline (from baseline to week 8) in UNISCALE QOL score was considered clinically significant. |
| Clinically Significant (10-point) Decrease in Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) Quality of Life (QOL)Assessment From Baseline to Week 8 | Baseline to week 8 | The FACT-L is a 36-item Likert instrument that combines frequency of symptomatic/QOL problems with perceived relative importance of each issue. It includes 4 constructs of well being: physical, social/family, emotional and functional, and a fifth construct, additional concerns, dealing solely with tumor related symptoms. Questionnaires were completed at baseline and 8 weeks. Questions within each construct were summated to obtain a construct score. A higher score relates to higher quality of life. A 10 point or greater decline (from baseline to week 8) was considered clinically significant. |
| Number of Patients With a Confirmed Tumor Responses Treated With CAI. | During Treatment (up to 5 years) | Confirmed response was defined as a complete response (CR) or partial response (PR) for patients with measurable disease or as a CR or regression (REGR) for patients with evaluable disease noted on 2 consecutive evaluations at least 4 weeks apart. * CR: total disappearance of all tumor; * PR: \>=50% reduction of the sum of the products of the two greatest perpendicular diameters of all indicator lesions; * REGR: Definite decrease in tumor size and no new lesion(s). |
Countries
United States
Participant flow
Recruitment details
Between April 1999 and January 2004, 194 patients were accrued to this study. This trial was closed to accrual prior to meeting the protocol projected 360 randomized patients due to slow accrual.
Pre-assignment details
186 patients were randomized to either arm
Participants by arm
| Arm | Count |
|---|---|
| Carboxyamidotriazole 250 mg carboxyamidotriazole administered daily | 94 |
| Placebo 250 mg placebo administered daily | 92 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 3 |
| Overall Study | Alternative treatmnt, medical problems | 5 | 4 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Withdrawal by Subject | 21 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Carboxyamidotriazole |
|---|---|---|---|
| Age, Customized <= 65 years | 50 participants | 87 participants | 37 participants |
| Age, Customized > 65 years | 42 participants | 99 participants | 57 participants |
| Eastern Cooperative Oncology Group Performance Score 0 - Fully Active | 38 Participants | 75 Participants | 37 Participants |
| Eastern Cooperative Oncology Group Performance Score 1 - Ambulatory, restricted strenuous activity | 48 Participants | 95 Participants | 47 Participants |
| Eastern Cooperative Oncology Group Performance Score 2 - Ambulatory, unable to perform work activities | 6 Participants | 16 Participants | 10 Participants |
| Histology Adenocarcinoma | 55 participants | 106 participants | 51 participants |
| Histology Bronchoalveolar/large cell | 13 participants | 19 participants | 6 participants |
| Histology NOS (not otherwise specified) NSCLC/not avaliable | 11 participants | 27 participants | 16 participants |
| Histology Squamous | 13 participants | 34 participants | 21 participants |
| Prior Response to Chemotherapy Complete | 4 participants | 9 participants | 5 participants |
| Prior Response to Chemotherapy Partial | 45 participants | 83 participants | 38 participants |
| Prior Response to Chemotherapy Regression | 8 participants | 17 participants | 9 participants |
| Prior Response to Chemotherapy Stable | 35 participants | 77 participants | 42 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 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 | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 89 Participants | 180 Participants | 91 Participants |
| Sex: Female, Male Female | 37 Participants | 79 Participants | 42 Participants |
| Sex: Female, Male Male | 55 Participants | 107 Participants | 52 Participants |
| Smoking Status Current | 15 participants | 35 participants | 20 participants |
| Smoking Status Former (quit >= 6 months) | 57 participants | 111 participants | 54 participants |
| Smoking Status Never | 10 participants | 21 participants | 11 participants |
| Smoking Status Not Reported | 10 participants | 19 participants | 9 participants |
| TNM Stage IIIA/IIIB | 19 participants | 41 participants | 22 participants |
| TNM Stage IV | 73 participants | 145 participants | 72 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 87 / 90 | 84 / 92 |
| serious Total, serious adverse events | 9 / 90 | 6 / 92 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death of any cause. Participants who did not die or were lost to follow-up were censored at the time of last evaluation/follow-up date. Patients were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.
Time frame: up to 5 years
Population: Overall survival was analyzed on all randomized participants on an intent to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboxyamidotriazole | Overall Survival (OS) | 11.4 Months |
| Placebo | Overall Survival (OS) | 10.5 Months |
p-value: 0.54Log Rank
Secondary
Clinically Significant (10-point) Decrease in Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) Quality of Life (QOL)Assessment From Baseline to Week 8
The FACT-L is a 36-item Likert instrument that combines frequency of symptomatic/QOL problems with perceived relative importance of each issue. It includes 4 constructs of well being: physical, social/family, emotional and functional, and a fifth construct, additional concerns, dealing solely with tumor related symptoms. Questionnaires were completed at baseline and 8 weeks. Questions within each construct were summated to obtain a construct score. A higher score relates to higher quality of life. A 10 point or greater decline (from baseline to week 8) was considered clinically significant.
Time frame: Baseline to week 8
Population: Participants who completed the baseline and week 8 FACT-L assessment are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboxyamidotriazole | Clinically Significant (10-point) Decrease in Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) Quality of Life (QOL)Assessment From Baseline to Week 8 | 27 participants |
| Placebo | Clinically Significant (10-point) Decrease in Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) Quality of Life (QOL)Assessment From Baseline to Week 8 | 33 participants |
p-value: 0.18Fisher Exact
Secondary
Clinically Significant (10-point) Decrease in UNISCALE Quality of Life (QOL)Assessment From Baseline to Week 8
The UNISCALE was used to assess QOL. UNISCALE is a single item global measure of QOL. Participant were to complete the questionnaire at baseline and every 8 weeks, prior to assessment by the treating physician. A high score indicates a higher quality of life while a low score represents a lower quality of life. A 10 point or greater decline (from baseline to week 8) in UNISCALE QOL score was considered clinically significant.
Time frame: Baseline to week 8
Population: Participants who completed the baseline and week 8 UNISCALE assessment are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboxyamidotriazole | Clinically Significant (10-point) Decrease in UNISCALE Quality of Life (QOL)Assessment From Baseline to Week 8 | 28 participants |
| Placebo | Clinically Significant (10-point) Decrease in UNISCALE Quality of Life (QOL)Assessment From Baseline to Week 8 | 32 participants |
p-value: 0.04Fisher Exact
Secondary
Number of Patients With a Confirmed Tumor Responses Treated With CAI.
Confirmed response was defined as a complete response (CR) or partial response (PR) for patients with measurable disease or as a CR or regression (REGR) for patients with evaluable disease noted on 2 consecutive evaluations at least 4 weeks apart. * CR: total disappearance of all tumor; * PR: \>=50% reduction of the sum of the products of the two greatest perpendicular diameters of all indicator lesions; * REGR: Definite decrease in tumor size and no new lesion(s).
Time frame: During Treatment (up to 5 years)
Population: This data was not (and will never be) analyzed as it was not submitted consistently due to the trial design. (Patients were required to be SD or better to be randomized to carboxyamidotriazole or placebo.)
Secondary
Participants With Severe Non-hematologic Adverse Events
Severe non-hematologic adverse events were defined as adverse events grade 3 or higher, regardless of attribution to study drug. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC version 2.0)
Time frame: every cycle during treatment
Population: All treated participants; all participants who received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboxyamidotriazole | Participants With Severe Non-hematologic Adverse Events | 38 Participants |
| Placebo | Participants With Severe Non-hematologic Adverse Events | 30 Participants |
p-value: 0.18Fisher Exact
Secondary
Time to Disease Progression (TTP)
TTP is defined as the time from randomization to first documented disease progression(PD). Patients who were lost to follow-up were censored at the time of last evaluation. For patients who died without clear documentation, PD was assumed at the midpoint of the time interval between last evaluation and death. Median TTP was estimated using the Kaplan Meier method. Measurable PD: ≥25% increase in the sum of the products of two greatest perpendicular diameters of all indicator lesions or appearance of new lesion(s). Evaluable PD: definite increase in tumor size or appearance of new lesion(s)
Time frame: up to 5 years
Population: TTP was analyzed on all randomized patients on an intent to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboxyamidotriazole | Time to Disease Progression (TTP) | 2.8 Months |
| Placebo | Time to Disease Progression (TTP) | 2.4 Months |
p-value: 0.5Log Rank