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A Study of RO5424802 in Patients With Non-Small Cell Lung Cancer Who Have ALK Mutation and Failed Crizotinib Treatment

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01801111
First received: February 20, 2013
Last updated: July 4, 2017
Last verified: July 2017
  Purpose
This open-label, non-randomized, multicenter phase I/II study will evaluate the safety and efficacy of RO5424802 in patients with non-small cell lung cancer who have ALK mutation and failed crizotinib treatment. In Part 1, cohorts of patients will receive escalating doses of RO5424802 orally twice daily. In Part 2, patients will receive the recommended phase II dose of RO5424802 as determined in Part 1. Treatment will continue in Part 1 and Part 2 on the same dose until disease progression. In Part 3, following disease progression, patients without EGFR mutation will be offered continued treatment with RO5424802, patients with EGFR mutations will be offered a combination of RO5424802 and Tarceva (erlotinib).

Condition Intervention Phase
Non-Squamous Non-Small Cell Lung Cancer Drug: erlotinib [Tarceva] Drug: RO5452802 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: AN OPEN-LABEL, NON-RANDOMIZED, MULTICENTER PHASE I/II TRIAL OF RO5424802 GIVEN ORALLY TO NON - SMALL CELL LUNG CANCER PATIENTS WHO HAVE ALK MUTATION AND FAILED CRIZOTINIB TREATMENT

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Recommended Phase II Dose of Alectinib [ Time Frame: Cycle 1 (up to 28 days) ]
    RP2D was to be determined based on the safety and tolerability profile of the study treatment.

  • Percentage of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (up to 28 days) ]
    DLTs were to be assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.3. DLTs: drug-related toxicities that meet any one of the following criteria: Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 neutropenia continuing for ≥7 consecutive days or neutropenic fever; Non-hematological toxicity of Grade 3 or higher; Adverse events that require interruption of treatment for a total of ≥7 days.

  • Area Under the Plasma Concentration Time Curve From Time 0 to 10 Hour Post-dose (AUC[0-10]) of Alectinib [ Time Frame: Day 1 and Day 21 of Cycle 1 ]
  • Percentage of Participants Achieving Objective Response (Complete Response [CR] or Partial Response [PR]) as Assessed by Independent Radiological Review Committee (IRC) in Response Evaluable (RE) Population [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by IRC according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.

  • Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Pretreated Participants [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by IRC according to RECIST version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.


Secondary Outcome Measures:
  • Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by IRC in Chemotherapy-Naive Participants [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by IRC according to RECIST version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.

  • Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Response Evaluable Population [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.

  • Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Pretreated Participants [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.

  • Percentage of Participants Achieving Objective Response (CR or PR) as Assessed by Investigator in Chemotherapy-Naive Participants [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response was assessed by investigator according to RECIST version 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). CR and PR was to be confirmed by repeat assessments ≥4 weeks after initial documentation.

  • Duration of Response [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Duration of response was defined as the time from the first observation of an objective tumor response until first observation of disease progression using RECIST version 1.1 or death from any cause. Duration of response was estimated by Kaplan-Meier method and 95% confidence interval (CI) was assessed using the method of Brookmeyer and Crowley. Duration of response was assessed by IRC and by investigator as well as in subgroups of participants who received prior chemotherapy and who did not received prior chemotherapy.

  • Percentage of Participants With Progression or Death [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Progression (according to RECIST version 1.1) was defined as at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion. Progression was assessed by IRC and by the investigator in safety population as well as in subgroups of participants who received prior chemotherapy and who did not received prior chemotherapy.

  • Progression Free Survival (PFS) [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    PFS was defined as the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Progression (according to RECIST version 1.1) was defined as at least a 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion. Progression was assessed by IRC and by the investigator in safety population as well as in subgroups of participants who received prior chemotherapy and who did not receive prior chemotherapy. PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

  • Percentage of Participants Who Died [ Time Frame: Baseline up to death (any cause) or data cut off (18 August 2014, maximum follow up 53 weeks) ]
  • Overall Survival (OS) [ Time Frame: Baseline up to death (any cause) or data cutoff (18 August 2014, maximum follow up 53 weeks) ]
    OS was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

  • Percentage of Participants Achieving CR, PR or Stable Disease (SD, Lasting ≥16 Weeks) in Response Evaluable Population [ Time Frame: Baseline; every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reasons deemed by the investigator, or data cutoff (18 August 2014, maximum follow up 53 weeks) ]
    Disease control (CR,PR or SD) was measured by RECIST version 1.1. by IRC and Investigator. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size is <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum 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 diameters while on study.

  • Percentage of Participants Achieving Objective Response (CR or PR) of Baseline Central Nervous System (CNS) Lesions As Assessed by IRC Based on RECIST [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response (CR and PR) of CNS lesions was assessed based on IRC review of radiographs by RECIST version 1.1 in participants with measurable CNS lesions at baseline. CR was defined as disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the screening sum diameters) and no progression of target lesions.

  • Percentage of Participants Achieving Objective Response (CR or PR) of Baseline Central Nervous System (CNS) Lesions As Assessed by IRC Based on Radiology Assessment in Neuro-Oncology (RANO) Criteria [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Objective response (CR and PR) of CNS lesions was assessed based on IRC review of radiographs by RANO criteria. CR was achieved if all of the following criteria met: Complete disappearance of all enhancing measurable and non-measurable disease; Stable or improved non-enhancing (T2/FLAIR) lesions; No new lesions; Participant must be off corticosteroids (or on physiologic replacement doses only), and clinically stable or improved. PR was achieved if all of the following criteria met: at least 50% decrease compared with screening in the sum of the products of the diameters (SPD) of measurable enhancing measurable lesions; No progression of non-measurable disease (enhancing and non-enhancing [T2/FLAIR] lesions); No new lesions; Participant must be off corticosteroids (or on physiologic replacement doses only), and clinically stable or improved. For both CR and PR, responses had to be sustained for at least 4 weeks.

  • Duration of Response in Participants With CNS Response (CR or PR) as Assessed by IRC Based on RECIST [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Duration of response in participants with CNS response was defined as the time from the first observation of a CNS response (CR or PR) until first observation of CNS progression or death from any cause based on IRC review of radiographs by RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the screening sum diameters) and no progression of target lesions. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase of at lease 5 mm, progression of existing non-target lesions, or presence of new lesion. Duration of response was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

  • Duration of Response in Participants With CNS Response (CR or PR) as Assessed by IRC Based on RANO [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    Duration of response in participants with CNS response was defined as the time from the first observation of a CNS response (CR or PR) until first observation of CNS progression or death from any cause based on IRC review of radiographs by RANO criteria. CR and PR were as defined in outcome 39. Progression was defined by any of the following: at least 25% increase in sum of products of diameters of measurable enhancing (measurable) lesions compared to best response after initiation of therapy (nadir), or screening if screening was nadir value on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR non-enhancing lesions not caused by co-morbid events on stable or increasing doses of corticosteroids; Any new lesions; Clear progression of enhancing non-measurable disease. Clinical deterioration not attributable to other non-tumour causes. Duration of response was estimated by Kaplan-Meier method and 95% CI was assessed using method of Brookmeyer and Crowley.

  • Percentage of Participants With CNS Progression As Assessed by IRC Based on RECIST [ Time Frame: Baseline; assessments every 8 week post-baseline until progressive disease, unacceptable toxicity, consent withdrawal, death, other reason deemed by investigator; then survival follow-up; data until cutoff (18 August 2014) are reported, maximum 53 weeks ]
    CNS progression was defined as the percentage of participants who developed a new CNS lesion or have disease progression in pre-existing CNS lesions based on IRC review of radiographs by RECIST version 1.1. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase of at lease 5 mm, progression of existing non-target lesions, or presence of new lesion


Enrollment: 138
Actual Study Start Date: June 20, 2013
Estimated Study Completion Date: August 31, 2017
Primary Completion Date: October 24, 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RO5424802 Drug: erlotinib [Tarceva]
Post progression: Continued treatment with RO542802 after disease progression will be in combination with Tarceva (100 mg orally daily) in patients with EGFR mutations
Drug: RO5452802
multiple oral doses

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients, >/= 18 years of age
  • Locally advanced or metastatic non-small cell lung cancer (stage IIIB or IV by AJCC 7th)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Documented ALK rearrangement based on FDA approved test
  • Prior treatment with crizotinib and progression according to RECIST v1.1 criteria with the last dose of crizotinib within 60 days from enrolment; patients can either be chemotherapy-naïve or have received at least one line of platinum-based chemotherapy
  • Adequate hematologic, hepatic and renal function
  • Patients with brain or leptomeningeal metastases are allowed on study if the lesions are asymptomatic without neurological signs and clinically stable for at least 2 weeks
  • Measurable disease according to RECIST v1.1 prior to administration of study drug

Exclusion Criteria:

  • Receipt of any other ALK inhibitors in addition to crizotinib
  • Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to Day 1. Patients who received crizotinib or any other tyrosine kinase inhibitors need to have a minimum 2-week washout period before the first dose
  • Active uncontrolled infectious diseases requiring treatment
  • NCI CTCAE (version 4.03) Grade 3 or higher toxicities due to prior therapy that have not shown improvement and are considered to interfere with current study medication
  • History of organ transplant
  • Co-administration of anti-cancer therapies other than those administered in this study
  • Baseline QTc > 470 ms or baseline symptomatic bradycardia < 45 beats per minute
  • Pregnant or breastfeeding women
  • Known HIV positivity or AIDS-related illness
  • History of significant drug-related allergy (such as anaphylaxis)
  • Any clinically significant concomitant disease or condition that could interfere with, or for which treatment might interfere with, the conduct of the study, or absorption of oral medications, or that would, in the opinion of the principal investigator, pose an unacceptable risk to the subject in the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01801111

  Show 84 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01801111     History of Changes
Other Study ID Numbers: NP28673
2012-004455-36 ( EudraCT Number )
Study First Received: February 20, 2013
Results First Received: August 19, 2015
Last Updated: July 4, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Erlotinib Hydrochloride
Crizotinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 21, 2017