A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC

Study Overview
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Brief Summary
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The purpose of this study is to determine whether combining ganetespib (STA-9090) with docetaxel is more effective than docetaxel alone in the treatment of patients with advanced non-small cell lung cancer.

Detailed Description
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Preliminary signals of clinical activity of ganetespib as a single agent have been observed in patients with advanced NSCLC. A Phase 2b/3 Study (9090-08) was initiated to evaluate the safety and activity of ganetespib in combination with docetaxel vs. docetaxel alone in NSCLC. Study 9090-08 is ongoing. Results from an interim analysis show that the combination has been well tolerated and an encouraging improvement in efficacy, including overall survival (OS) has been observed. Update: An independent data monitoring committee (DMC) was established to review accumulating unblinded safety data, and efficacy data at two specified Interim Analyses. The DMC monitored the conduct of the trial (including the accrual/retention of patients) and reviewed the risks and benefits. The study was stopped after the first Interim Analysis due to futility. The efficacy portion of this report is based on a 05 October 2015 data cut after the number of protocol-defined death events (336) for the first interim analysis had been achieved. The safety portion is based on the final database locked on 23 December 2015.

Official Title
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A Randomized, Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced Non-Small-Cell Lung Adenocarcinoma

Conditions
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Non-Small-Cell Lung Adenocarcinoma, Non-small Cell Lung Cancer Stage IIIB, Non-small Cell Lung Cancer Stage IV, Non-small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Ganetespib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced Stage IIIB or IV non-small-cell lung cancer (NSCLC) Eastern Oncology Cooperative Group (ECOG) Performance Status 0 or 1 Prior therapy defined as 1 prior systemic therapy for advanced disease Documented disease progression during or following most first line therapy for advanced disease Adequate hematologic, hepatic, renal function Exclusion Criteria: Epidermal growth factor receptor (EGFR) mutations Anaplastic lymphoma kinase (ALK) translocations Predominantly squamous, adenosquamous or unclear histologic type Active or untreated central nervous system (CNS) metastases Active malignancies other than NSCLC within the last 5 years with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri or basal or squamous cell carcinoma of the skin Serious cardiac illness or medical conditions Pregnant or lactating women Uncontrolled intercurrent illness

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ganetespib and Docetaxel<br>Ganetespib (150 mg/m^2) and docetaxel (75 mg/m^2) were administered as separate 1-hour IV infusions on Day 1 of each 3-week treatment cycle. Administration of ganetespib preceded the administration of docetaxel. Ganetespib was administered again on Day 15 of each cycle. | Drug: Docetaxel<br>* Docetaxel, 75 mg/m^2, was administered according to prevailing practice and Investigator decision, generally until disease progression, intolerability, or patient's withdrawal of consent.<br>* Other names: Docecad;Drug: Ganetespib<br>* Ganetespib, 150 mg/m^2, was administered with docetaxel. After docetaxel treatment ceased, participants whose disease has not progressed continued to receive ganetespib alone until disease progression, unacceptable toxicity, or patient's withdrawal of consent.<br>* Other names: STA-9090;|
| Active Comparator: Docetaxel<br>Docetaxel (75 mg/m^2) was administered on Day 1 of a 3-week treatment cycle by 1-hour IV infusion. | Drug: Docetaxel<br>* Docetaxel, 75 mg/m^2, was administered according to prevailing practice and Investigator decision, generally until disease progression, intolerability, or patient's withdrawal of consent.<br>* Other names: Docecad;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival as of 19 October 2015 | Overall survival (OS) was measured from the date of randomization to the date of death from any cause. | up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as of 19 October 2015 | The progression-free interval is the interval from the date of randomization until tumor progression per modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1), clinical progression, or death from any cause in the absence of progressive disease, whichever occurs first. Data represents the investigator's assessment. Progressive Disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | up to 36 months | 
| Overall Survival (OS) In Participants With an Elevated Screening Lactate Dehydrogenase (eLDH) as of 19 October 2015 | OS was measured from the date of randomization to the date of death from any cause. Elevated LDH includes values above the upper limit of normal. | up to 36 months | 
| Objective Response Rate (ORR) as of 19 October 2015 | Percentage of participants whose best overall response, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST 1.1), was either a complete response (CR) or a partial response (PR). CR was defined as the disappearance (or normalization) of all target lesions. PR was defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. | up to 36 months | 
| Disease Control Rate (DCR) as of 19 October 2015 | Percentage of participants whose best overall response, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST 1.1), was either a complete response (CR), a partial response (PR), or stable disease (SD). CR was defined as the disappearance (or normalization) of all target lesions. PR was defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study. For participants with a best response of SD, duration of SD must be for at least 6 weeks or 12 weeks. | up to 36 months | 
| Kaplan-Meier Estimate of Duration of Response (DOR) as of 19 October 2015 | Only participants who achieved a confirmed response (complete response (CR) or partial response (PR)) were included in the DOR analysis. CR was defined as the disappearance (or normalization) of all target lesions. PR was defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. | up to 36 months | 
| Progression Free Survival (PFS) in Participants With an Elevated Screening Lactate Dehydrogenase (eLDH) as of 19 October 2015 | The progression-free interval is the interval from the date of randomization until tumor progression per modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1), clinical progression, or death from any cause in the absence of progressive disease, whichever occurs first. Data represents the investigator's assessment. Progressive Disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Elevated LDH includes values above the upper limit of normal. | up to 36 months | 
| Objective Response Rate (ORR) in Participants With an Elevated Screening Lactate Dehydrogenase (eLDH) as of 19 October 2015 | Percentage of participants whose best overall response, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST 1.1), was either a complete response (CR) or a partial response (PR). CR was defined as the disappearance (or normalization) of all target lesions. PR was defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Elevated LDH includes values above the upper limit of normal. This study stopped prematurely due to futility and development of this product ceased. The sponsor made a decision at that time to not analyze this outcome. The sponsor no longer has staff or capabilities for further analysis. | up to 36 months | 
| Disease Control Rate (DCR) in Participants With an Elevated Screening Lactate Dehydrogenase (eLDH) as of 19 October 2015 | Percentage of participants whose best overall response, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST 1.1), was a complete response (CR), a partial response (PR), or stable disease (SD). CR was defined as the disappearance (or normalization) of all target lesions. PR was defined as <=30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study. The duration of SD must be for at least 6 weeks or 12 weeks. Elevated LDH includes values above the upper limit of normal. This study stopped prematurely due to futility and development of this product ceased. The sponsor made a decision at that time to not analyze this outcome. The sponsor no longer has staff or capabilities for further analysis. | up to 36 months | 
| Kaplan-Meier Estimate for Time to Emergence of New Metastatic Lesion (TNL) as of 19 October 2015 | TNL was defined as time from the randomization date to the first day of radiological progression that included new metastatic lesions. Participants with no new metastatic lesions were censored at the date of the most recent radiological assessment. | up to 36 months | 
| Percentage of Participants With Progressive Disease Due to Any New Metastatic Lesion as of 19 October 2015 | Progressive disease was due to either new metastatic lesions only or new metastatic lesions and target tumor growth. | up to 36 months | 
| Participants With Treatment-Emergent Adverse Events as of 23 December 2015 | Treatment-emergent adverse events (AEs) were defined as AEs that occurred from the time of first dose through 30 days after the last dose of study medication. The Investigator graded the severity of AEs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death A Serious AE (SAE) is defined as any AE which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or constitutes an important medical event. | up to 36 months | 
| Patient-Reported Quality of Life as Measured by the European Quality Of Life - Five Dimensions - Three Levels (EQ-5D-3L) Survey | The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. An overall EQ-5D-3L index was calculated (see EuroQoL website, http://www.euroqol.org/eq-5d-products/eq-5d-3l.html), with an index of 1.0 representing full health and and 0 represents dead, with some health states being worse than dead (<0). This study stopped prematurely due to futility and development of this product ceased. The sponsor made a decision at that time to not analyze this outcome. The sponsor no longer has staff or capabilities for further analysis. | Day 1 (pre-treatment), Day 63 (Cycle 3 Day 1), Day 105 (Cycle 5 Day 1) and end of trial | 
| Patient-Reported Symptom Improvement as Measured by the Functional Assessment of Cancer Therapy - Lung (FACT-L) Version 4 Test | The FACT-L contains 4 general subscales and a Lung Cancer Subscale (LCS). General subscales include: Physical Well-Being (PWB), Social/ Family Well-Being (SWB), Emotional Well-Being (EWB), and Functional Well-Being (FWB). The LCS assesses symptoms commonly reported by lung cancer patients (e.g., shortness of breath, weight loss, and tightness in the chest). The FACT-L total score ranges from 0 to 136, higher scores represent better QOL. Data were not summarized due to the early termination of the study due to futility. | Day 1 (pre-treatment), Day 63 (Cycle 3 Day 1), Day 105 (Cycle 5 Day 1) and end of trial |