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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer(NSCLC)
• Intervention / Treatment: Drug: AT13387; Drug: Crizotinib

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.

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Montreal, Quebec, Canada, H3A 1A1
    • McGill University Health Center
  • Sainte-Foy, Quebec, Canada, G1V 4G5
    • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
  • Toronto, Ontario, Canada, M5G 2M9
    • Princess Margaret Hospital
  • Winnipeg, Canada, R3E OV9
    • Cancer Care Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Atlantic Clinical Cancer Research Unit
• France
  • Besancon Cedex, France, 25030
    • Centre Hospitalier Regional Universitaire Besancon
  • Caen, France, 14033
    • CHU de Caen-Hopital Cote de Nacre
  • Creteil Cedex, France, 94010
    • Hopital Saint Antoine
  • Grenoble, France, 38043
    • Centre Hospitalier de Grenoble
  • Lille cedex, France, 59037
    • CHRU de Lille
  • Marseille, France, 13273
    • Institut Paoli-Calmettes
  • Paris, France, 75020
    • Hopital Tenon
  • Pierre-Benite Cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • Toulouse, France, 31 059
    • CHU Toulouse-Hopital Larrey
  • Villejuif, France, 94800
    • Institut Gustave Roussy
• Korea, Republic of
  • Cheongju-si, Korea, Republic of, 362-711
    • Chungbuk National University Hospital
  • Gyeonggi-do, Korea, Republic of, 442-723
    • The Catholic university of Korea, St. Vincent's Hospital
  • Hwasun-gun Jeonnam, Korea, Republic of, 519-809
    • Chonnam National University Hwasun Hospital
  • Korea, Korea, Republic of, 410-769
    • National Cancer Center
  • Seongnam, Korea, Republic of, 463-707
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital, Yonsei University Health System
• Spain
  • Badalona, Spain, 08916
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain, 08028
    • Hospital Universitari Quiron Dexeus Barcelona
  • Madrid, Spain, 28050
    • Centro Integral Oncológico Clara Campal
  • Malaga, Spain, 29010
    • Hospital Regional Universitario de Malaga
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic-Scottsdale
  • California
    • La Jolla, California, United States, 92093-0698
      • University of California, San Diego Medical Center
    • Los Angeles, California, United States, 90033
      • Usc Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • San Diego, California, United States, 92123
      • Sharp Clinical Oncology Research-Sharp Memorial Hospital
    • Whittier, California, United States, 90603
      • Innovative Clinical Research Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine-Yale Cancer Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Hospital
  • Florida
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center & Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University The Feinberg School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and and Bren Simon Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic-Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center Eppley Cancer Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greensboro, North Carolina, United States, 27409
      • Cone Health Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Cancer Institute
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology in Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • The Pennsylvania State University-Penn State
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The West Clinic
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98109
      • University of Washington Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53579
      • University of Wisconsin-Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men or women 18 years of age or older
2. Must have Non-small Cell Lung Cancer with ALK+ mutation or other mutations or rearrangements potentially sensitive to crizotinib
3. Measurable disease
4. Must have been receiving or have received crizotinib
5. Have adequate cardiac, bone marrow, liver and kidney function
6. Must be willing and able to provide written informed consent and comply with the protocol and study procedures

Exclusion Criteria:

1. Prior anti-cancer treatment with any HSP90 inhibitor
2. Have received chemotherapy, radiation therapy or other anticancer treatment other than crizotinib within 3 weeks prior to the first dose of study drug
3. 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
4. Abnormal heart function
5. Presence of a life-threatening illness, medical condition, organ system dysfunction, or other factors
6. Hypersensitivity of AT13387 or other components of the drug product
7. Treatment with an investigational drug within 3 weeks prior to the first dose of study drug
8. Severe systemic diseases or active uncontrolled infections
9. Known history of human immunodeficiency virus (HIV) or seropositive test for hepatitis C virus or hepatitis B virus

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AT13387 and 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.	Drug: AT13387; HSP90 inhibitor; Drug: Crizotinib; ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor; Other Names: Xalkori
Active Comparator: Crizotinib versus crizotinib + 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.	Drug: AT13387; HSP90 inhibitor; Drug: Crizotinib; ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor; Other Names: Xalkori
Active Comparator: AT13387 or AT13387 + 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.	Drug: AT13387; HSP90 inhibitor; Drug: Crizotinib; ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor; Other Names: Xalkori

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astex Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Jean-Charles Soria, MD, Gustave Roussy, Cancer Campus, Grand Paris

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): May 16, 2017

Study Registration Dates

• First Submitted: October 11, 2012
• First Submitted That Met QC Criteria: October 19, 2012
• First Posted (Estimate): October 23, 2012

Study Record Updates

• Last Update Posted (Actual): January 19, 2018
• Last Update Submitted That Met QC Criteria: January 17, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Crizotinib
• Other Study ID Numbers: AT13387-05; 2012-001575-37 (EudraCT Number)