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

Phase 1

Completed

Conditions: Non-small Cell Lung Cancer(NSCLC)

Interventions: Drug: AT13387
Drug: Crizotinib

Registration Number: NCT01712217

Lead Sponsor: Astex Pharmaceuticals, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 220

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AT13387 and Crizotinib	AT13387	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.
Crizotinib versus crizotinib + AT13387	AT13387	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.
AT13387 or AT13387 + crizotinib	AT13387	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.
AT13387 and Crizotinib	Crizotinib	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.
Crizotinib versus crizotinib + AT13387	Crizotinib	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.
AT13387 or AT13387 + crizotinib	Crizotinib	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.

Primary Outcome Measures

Name	Time	Method
Part B: The comparison of objective response rate by RECIST 1.1 between crizotinib alone and the combination of crizotinib + AT13387.	18 months	- Change in tumor measurements by RECIST 1.1 every 8 weeks
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.	18 months	- Change in tumor measurements by RECIST 1.1 every 8 weeks
Part A: The incidence of dose limiting toxicities when AT13387 is administered in combination with crizotinib.	12 months	- Number of patients with adverse events

Secondary Outcome Measures

Name	Time	Method
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	18 months	* Number of patients with adverse events * PFS and OS as measured in weeks
Part A: Pharmacokinetics of combination treatment with AT13387 and crizotinib	12 months	* 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
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	18 months	* Number of patients with adverse events * PFS and OS as measured in weeks * Response rate as measured by RECIST 1.1 every 8 weeks
Part A: Assess antitumor activity of crizotinib + AT13387 combination, circulating tumor cells (CTCs) response, progression free survival (PFS) and overall survival (OS).	12 months	* 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

Trial Locations

Locations (65): Mayo Clinic-Scottsdale
🇺🇸
Scottsdale, Arizona, United States
University of California, San Diego Medical Center
🇺🇸
La Jolla, California, United States
USC Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
UCLA Medical Center
🇺🇸
Los Angeles, California, United States
Sharp Clinical Oncology Research-Sharp Memorial Hospital
🇺🇸
San Diego, California, United States
Innovative Clinical Research Institute
🇺🇸
Whittier, California, United States
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
Yale University School of Medicine-Yale Cancer Center
🇺🇸
New Haven, Connecticut, United States
Christiana Hospital
🇺🇸
Newark, Delaware, United States
Florida Hospital Cancer Institute
🇺🇸
Orlando, Florida, United States
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Mayo Clinic-Scottsdale
🇺🇸Scottsdale, Arizona, United States