A Study of AT13387 in Patients With Non-Small Cell Lung Cancer (NSCLC) Alone and in Combination With Crizotinib

Study Overview
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Brief Summary
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The purpose of the study is to evaluate safety and efficacy of AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer.

Detailed Description
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This is a 3-part phase 1-2 study in patients with anaplastic lymphoma kinase (ALK) + or other potentially crizotinib-sensitive NSCLC who have been receiving crizotinib. Part A is a single-arm, Phase 1, open-label, dose escalation design in patients with NSCLC who have already been receiving crizotinib for at least 8 weeks and continue to tolerate therapy. Part B is a Phase 2, open-label, randomized continuation design comparing crizotinib alone versus the combination of crizotinib + AT13387 at the maximum tolerated dose established in Part A. Part C is an open-label, randomized, Phase 2, Simon's 2 stage design evaluating single agent AT13387 or combination AT13387 + crizotinib at the MTD established in Part A in patients who progressed on crizotinib at any time.

Official Title
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A Study of HSP90 Inhibitor AT13387 Alone and in Combination With Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-small Cell Lung Cancer(NSCLC)

Intervention / Treatment
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* Drug: AT13387
* Drug: Crizotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women 18 years of age or older Must have Non-small Cell Lung Cancer with ALK+ mutation or other mutations or rearrangements potentially sensitive to crizotinib Measurable disease Must have been receiving or have received crizotinib Have adequate cardiac, bone marrow, liver and kidney function Must be willing and able to provide written informed consent and comply with the protocol and study procedures Exclusion Criteria: Prior anti-cancer treatment with any HSP90 inhibitor Have received chemotherapy, radiation therapy or other anticancer treatment other than crizotinib within 3 weeks prior to the first dose of study drug Prior malignancy other than adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, low-grade cervical cancer, non-metastatic prostate cancer, or have been disease-free for at least 3 years Abnormal heart function Presence of a life-threatening illness, medical condition, organ system dysfunction, or other factors Hypersensitivity of AT13387 or other components of the drug product Treatment with an investigational drug within 3 weeks prior to the first dose of study drug Severe systemic diseases or active uncontrolled infections Known history of human immunodeficiency virus (HIV) or seropositive test for hepatitis C virus or hepatitis B virus

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: AT13387 and Crizotinib<br>Part A is a single-arm, Phase 1, open-label, dose-escalation design in patients with NSCLC who have already been receiving crizotinib 250 mg by mouth (PO) twice daily (BID) for at least 8 weeks and are still tolerating treatment at that dose. Patients will continue treatment with crizotinib + escalating doses of AT13387 IV weekly for 3 weeks in a 4-week cycle. Each cohort will consist of at least 6 patients until the maximum tolerated dose (MTD) is reached. An additional 12 patients will be treated at the MTD level of AT13387 in combination with crizotinib to confirm the safety profile of the combination at that dose level. | Drug: AT13387<br>* HSP90 inhibitor<br>Drug: Crizotinib<br>* ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor<br>* Other names: Xalkori;|
| Active Comparator: Crizotinib versus crizotinib + AT13387<br>Part B is a Phase 2, open-label, randomized continuation design comparing crizotinib alone versus the combination of crizotinib + AT13387 at the MTD established in Part A. Part B will enroll 128 patients with NSCLC who have been treated with crizotinib for at least 8 weeks and are still tolerating treatment without evidence of disease progression. | Drug: AT13387<br>* HSP90 inhibitor<br>Drug: Crizotinib<br>* ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor<br>* Other names: Xalkori;|
| Active Comparator: AT13387 or AT13387 + crizotinib<br>Part C is an open-label, randomized, Phase 2, Simon's 2-stage design of AT13387 administered alone once weekly for 3 weeks (QW×3) or in combination with crizotinib at the MTD established in Part A. | Drug: AT13387<br>* HSP90 inhibitor<br>Drug: Crizotinib<br>* ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor<br>* Other names: Xalkori;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: The incidence of dose limiting toxicities when AT13387 is administered in combination with crizotinib. | - Number of patients with adverse events | 12 months | 
| Part B: The comparison of objective response rate by RECIST 1.1 between crizotinib alone and the combination of crizotinib + AT13387. | - Change in tumor measurements by RECIST 1.1 every 8 weeks | 18 months | 
| Part C: The objective overall response rate for AT13387 alone and the objective response rate (CR+PR) for AT13387 + crizotinib at Stage 1 and Stage 2 of the Simon's 2-stage design. | - Change in tumor measurements by RECIST 1.1 every 8 weeks | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics of combination treatment with AT13387 and crizotinib | Area under the plasma concentration versus time curve (AUC) of AT13387 and crizotinib alone and in combination Week 4 Maximum concentration (Cmax) OF AT13387 and crizotinib alone and in combination by Week 4 | 12 months | 
| Part A: Assess antitumor activity of crizotinib + AT13387 combination, circulating tumor cells (CTCs) response, progression free survival (PFS) and overall survival (OS). | Change in tumor measurements by RECIST 1.1 every 8 weeks Change in CTCs from baseline every 4 weeks Assessment of PFS and OS as measured by weeks | 12 months | 
| Part B: Assess safety of AT13387 in combination with crizotinib; compare PFS and OS between crizotinib and crizotinib + AT13387; and assess overall response rate (CR + PR) in crizotinib patients who crossover to crizotinib + AT13387 | Number of patients with adverse events PFS and OS as measured in weeks Response rate as measured by RECIST 1.1 every 8 weeks | 18 months | 
| Part C: Assess safety of AT13387 alone and in combination with crizotinib who progressed on crizotinib treatment; and compare the PFS and OS of AT13387 administered alone or in combination with crizotinib | Number of patients with adverse events PFS and OS as measured in weeks | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small cell lung cancer