Small Cell Lung Cancer
Conditions
Keywords
Hsp90 Inhibitor, relapsed, refractory
Brief summary
Small cell lung cancer (SCLC) is a chemotherapy and radiotherapy sensitive tumor, but with very high rates of relapse and metastasis, resulting in a very poor outcome. Among limited-stage patients, the relapse rate is at least 80% and among extensive-stage patients, the relapse rate is 95-98%. The impetus to develop more effective therapies against novel targets in SCLC is therefore high. Hsp-90 inhibitors are a new class of drugs with important anti-malignant potential in a variety of tumor types because of the reliance of multiple oncoproteins on Hsp90 function. Although small cell neuroendocrine tumors generally carry many mutated oncoproteins, without clearly defined clients for Hsp90 mediating inhibitor effects in these cells, a recent study demonstrated that Hsp90 inhibition causes massive apoptosis by activating the intrinsic apoptotic pathway in a number of SCLC cell lines. SCLC is a particularly attractive target for apoptosis inducing drugs because of high growth rates and evidence of molecular alterations affecting apoptotic mechanisms. STA-9090 is a novel, small-molecule inhibitor of Hsp90. Unlike earlier generations of Hsp90 inhibitors, STA-9090 has been shown to be a potent inducer of apoptosis in a variety of cell lines and has anti-tumor activity in multiple types of human xenografts. As was seen with other Hsp90 inhibitors, STA-9090 also induces apoptosis in a number of SCLC cell lines. Based on the anti-tumor potential seen pre-clinically with Hsp90 inhibition, the potent effects of STA-9090 seen pre-clinically as compared with other inhibitors in the same class, as well as early data suggesting safety and tolerability of this drug in the Phase I setting, we propose to study the single-agent activity of STA-9090 in a Phase II trial of patients with relapsed or refractory small cell lung cancer.
Detailed description
OBJECTIVES: Primary Objective * To determine the progression-free rate at 8 weeks in participants with relapsed or refractory small cell lung cancer who have received \<3 prior regimens of systemic chemotherapy Secondary Objectives * To determine the response rate using radiologic assessment according to standard RECIST 1.1 criteria * To determine median progression free survival and overall survival * To characterize the toxicity profile of STA-9090 in this patient population Exploratory Objectives * To analyze levels of circulating tumor cells (CTCs) from blood samples obtained serially throughout the study and assess the utility of measuring these cell subsets as a marker of disease burden as well as response to therapy * To analyze the participant population by identification of gene expression profiles (measured in RNA from available tumor biopsies) associated with the efficacy and resistance to STA-9090
Interventions
DRUGSTA-9090
Sponsors
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Synta Pharmaceuticals Corp.
David M. Jackman, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of small cell lung cancer and confirmed progressive disease by radiographic study * \</= 3 prior chemotherapy regimens * Subjects with brain metastases will be allowed if they have been treated with surgery and/or radiation therapy \> 21 days prior, are asymptomatic, and are stable for at least 1 week off steroids * Must have measurable disease * \>/= 18 years of age * Life expectancy of greater than 12 weeks * EGOG performance status 0 or 1 * Lab values must be within limits outlined in the protocol * Not pregnant or breastfeeding * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Chemotherapy or radiotherapy within 3 weeks or within 5 half-lives of previous therapy * History of severe allergic or hypersensitivity reactions to taxanes. * Subjects who have not recovered from adverse events or toxicities due to agents administered more than 4 weeks earlier to a grade 1 or less * Not receiving any other study agents * History of or current coronary artery disease, myocardial infarction, angina pectoris, angioplasty or coronary bypass surgery. * Baseline QTc \> 470 msec or previous history of QT prolongation while taking other medications. * Ventricular ejection fraction of \< 55%. * History or current uncontrolled dysrhythmias, or requirement for antiarrhythmic medications, or Grade 2 or greater left bundle branch block. * ECG with clinically significant ventricular arrhythmias or ischemia * Major surgery within 4 weeks of starting treatment * Poor venous access necessitating use of indwelling catheter for IV therapy * Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance * History of another malignancy unless disease-free for 3 years and deemed to be at low risk for recurrence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 8-Week Progression-Free Rate | Disease was evaluated radiographically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Relevant for this endpoint was the first 8 week disease re-assessment. | The 8-week progression free rate is defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria by the time of the first disease assessment (8 weeks). Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD; and SD is neither sufficient decrease to qualify as PR nor sufficient increase to qualify as progressive disease (PD). PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. Response needed confirmation within 4 weeks. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Disease was evaluated radiographically at baseline and every 8 weeks on treatment. Treatment duration was a median of 2 cycles (parallel to 2 months given the 4 week cycle length) and range of 1-2 cycles in this study cohort. | The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
| Progression-Free Survival | Disease was evaluated radiographically at baseline and every 8 weeks on treatment. Treatment duration was a median of 2 cycles (parallel to 2 months given the 4 week cycle length) and range of 1-2 cycles in this study cohort. | Progression-free survival (PFS) based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) based on RECIST 1.1 criteria or death. Participants alive without evidence of PD were censored at the date of last adequate disease assessment. Per RECIST 1.1 for target lesions PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression is appearance of one or more new lesions and/or unequivocal progression on existing non-target lesions. |
| Overall Survival | Long-term follow-up for survival occurred every 4 weeks. As of this analysis, follow-up among survivors was a median (range) of 11.5 months (0.9-47.9). | Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death due to any cause or date last known alive. |
Countries
United States
Participant flow
Recruitment details
Patients enrolled from July 2010 through March 2013.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: STA-9090 Once weekly IV dosing of STA-9090 200mg/m2 was given weeks 1, 2, and 3 of a 4-week cycle. Participants received treatment until evidence of progressive disease or unacceptable toxicity. Participants were stratified at baseline into 2 distinct prognostic groups. Cohort A participants had relapsed \> 60 days following initial chemotherapy completion. | 13 |
| Cohort B: STA-9090 Once weekly IV dosing of STA-9090 200mg/m2 was given weeks 1, 2, and 3 of a 4-week cycle. Participants received treatment until evidence of progressive disease or unacceptable toxicity. Participants were stratified at baseline into 2 distinct prognostic groups. Cohort B participants had not responded or had relapsed \</= 60 days from the completion of initial chemotherapy. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Clinical Progression | 1 | 1 |
| Overall Study | Other | 2 | 3 |
| Overall Study | Progressive Disease | 10 | 8 |
Baseline characteristics
| Characteristic | Cohort A: STA-9090 | Cohort B: STA-9090 | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 59.5 years | 61 years |
| Region of Enrollment United States | 13 participants | 12 participants | 25 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 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 | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 7 / 13 | 8 / 12 |
| serious Total, serious adverse events | 4 / 13 | 3 / 12 |
Outcome results
Primary
8-Week Progression-Free Rate
The 8-week progression free rate is defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria by the time of the first disease assessment (8 weeks). Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD; and SD is neither sufficient decrease to qualify as PR nor sufficient increase to qualify as progressive disease (PD). PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. Response needed confirmation within 4 weeks. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: Disease was evaluated radiographically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Relevant for this endpoint was the first 8 week disease re-assessment.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: STA-9090 | 8-Week Progression-Free Rate | 0.0 percentage of participants |
| Cohort B: STA-9090 | 8-Week Progression-Free Rate | 8.3 percentage of participants |
Secondary
Overall Response Rate
The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiographically at baseline and every 8 weeks on treatment. Treatment duration was a median of 2 cycles (parallel to 2 months given the 4 week cycle length) and range of 1-2 cycles in this study cohort.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: STA-9090 | Overall Response Rate | 0.0 percentage of participants |
| Cohort B: STA-9090 | Overall Response Rate | 0.0 percentage of participants |
Secondary
Overall Survival
Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death due to any cause or date last known alive.
Time frame: Long-term follow-up for survival occurred every 4 weeks. As of this analysis, follow-up among survivors was a median (range) of 11.5 months (0.9-47.9).
Population: The analysis dataset is comprised of treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: STA-9090 | Overall Survival | 4.96 months |
| Cohort B: STA-9090 | Overall Survival | 6.70 months |
Secondary
Progression-Free Survival
Progression-free survival (PFS) based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) based on RECIST 1.1 criteria or death. Participants alive without evidence of PD were censored at the date of last adequate disease assessment. Per RECIST 1.1 for target lesions PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression is appearance of one or more new lesions and/or unequivocal progression on existing non-target lesions.
Time frame: Disease was evaluated radiographically at baseline and every 8 weeks on treatment. Treatment duration was a median of 2 cycles (parallel to 2 months given the 4 week cycle length) and range of 1-2 cycles in this study cohort.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A: STA-9090 | Progression-Free Survival | 1.61 months |
| Cohort B: STA-9090 | Progression-Free Survival | 1.81 months |