Evaluating Crizotinib in the Neoadjuvant Setting in Patients With Non-small Cell Lung Cancer

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT03088930
• Collaborator: Pfizer (Industry)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 37
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy of crizotinib as induction therapy in participants with surgically resectable ALK rearrangement, ROS1 rearrangement, or MET exon 14 mutation positive NSCLC.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer, Nonsmall Cell	Drug: Crizotinib	Phase 2

Detailed Description

Participants with stage IA-IIIA, surgically resectable lung adenocarcinoma with an activating alteration in ALK, ROS1 or MET will receive neoadjuvant treatment with crizotinib. This neoadjuvant treatment will last 6 weeks and on the last day of dosing of crizotinib, participants will undergo surgical resection, followed by 5 years of follow-up via chart review.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial to Evaluate Crizotinib in the Neoadjuvant Setting in Patients With Surgically Resectable, ALK, ROS1, or MET-oncogene Positive Non-small Cell Lung Cancer
• Actual Study Start Date: Dec 13, 2017
• Actual Primary Completion Date: Jan 13, 2021
• Actual Study Completion Date: Jan 13, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neoadjuvant treatment with Crizotinib Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review.	Drug: Crizotinib; Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.; Other Names: Xalkori

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With an Objective Tumor Response Rate [6 weeks]

   Participants' tumor response to treatment will be compared from initial/pretreatment scan to 6 week scan using RECIST 1.1

Secondary Outcome Measures

1. The Number of Participants With Pathologic Response Rate [37 months]

   Pathologic response rate is defined as < 50% of viable tumor present histologically in the resected tumor specimen.

2. Number of Participants With an Objective Response Rate [6 weeks post treatment]

   Number of participants with response rate per RECIST 1.1

3. The Number of Participants With Disease-free Survival (DFS) [37 months]

   DFS is defined as the time from treatment to the first of either disease recurrence or death from any cause.

4. Overall Survival (OS) Measured in Months [37 months]

   OS is defined as the time from study enrollment to death from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Stage IA-IIIA NSCLC by 8th edition AJCC staging (that is deemed to be surgically resectable by a board certified thoracic surgeon.

2. Staging by PET-CT scan and MRI brain showing no evidence of metastatic disease (mediastinoscopy is not required unless imaging is indeterminate and is then considered standard of care)

3. Documented evidence of an ALK rearrangement (by FISH, IHC, or NGS), ROS1 rearrangement (by FISH or NGS), or MET oncogene as defined by MET exon 14 skipping (NGS), MET Y1003X mutation or MET gene fusion (NGS) in NSCLC tumor specimen by a CLIA-approved laboratory.

4. Measurable disease defined by RECIST 1.1 criteria.

5. Life expectancy of at least 24 months.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

7. Age ≥ 18 years

8. Have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) of ≤ 450 ms in males or ≤ 470 ms in females

9. Adequate organ function:

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelets ≥75,000/µL

• Hemoglobin ≥ 10g/dL

• AST /ALT ≤ 2.5 x upper limit of normal (ULN)

• Total serum bilirubin ≤ 1.5 x ULN

• Serum creatinine ≤ 1.5 x UNL

• Serum amylase/lipase ≤ 1.5 x UNL

1. Negative serum pregnancy test within 7 days of D1 of treatment in women of child bearing potential.

2. If fertile, willing to use highly effective form of contraception (defined as a combination of at least two of the following methods: condom or other barrier methods, oral contraceptives, implantable contraceptives, intrauterine devices) during the dosing period and for at least 4 months after the dosing period.

3. Ability to provide signed informed consent and willing and able to comply with all study requirements.

Exclusion Criteria:

1. Stage IIIB or IV NSCLC.

2. History or the presence of pulmonary interstitial disease, or drug-related pneumonitis.

3. Malabsorption syndrome or other GI illness that could affect oral absorption of the study drug

4. Inability to swallow oral medications

5. Have significant, uncontrolled or active cardiovascular disease, specifically including but restricted to:

• Myocardial infarction (MI) within 6 months of trial enrollment

• Unstable angina within 6 months of trial enrollment

• Congestive heart failure (CHF) with 6 months prior to trial enrollment

• Any history of ventricular arrhythmia

• Cerebrovascular accident or transient ischemic attack within 6 months of D1 of treatment

• Clinically significant atrial arrhythmia or severe baseline bradycardia defined as resting heart rate < 50 beat per minute

• Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 100 on 3 separate clinic visits or past history of hypertensive urgency, emergency or encephalopathy

1. Have active infection requiring antibiotics

2. Pregnant or lactating female.

3. Prior treatment with an ALK, ROS1 or MET inhibitor

4. Any prior anticancer therapy for this diagnosis

5. Any active cancer diagnosis (basal or squamous cell cancers allowed) within the last 5 years for which the patient is receiving active therapy or which is untreated. Any cancer diagnosis within the last 5 years that is considered "treated" and/ or on surveillance may be included in the trial.

6. Have any condition or illness that, in the opinion of the investigator would compromise patient safety or interfere with evaluation of the study drug (including but not limited to HIV and HCV)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Pfizer

Investigators

• Principal Investigator: Tejas Patil, MD, PhD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 20, 2020
• Informed Consent Form - Nov 24, 2020

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03088930
• Other Study ID Numbers: 16-2025.cc
• First Posted: Mar 23, 2017
• Last Update Posted: Feb 11, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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; Crizotinib

Study Results

Participant Flow

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 66.7%
>=65 years	1 33.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 33.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 33.3%
More than one race	0 0%
Unknown or Not Reported	1 33.3%
Region of Enrollment (Count of Participants)
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With an Objective Tumor Response Rate
Description	Participants' tumor response to treatment will be compared from initial/pretreatment scan to 6 week scan using RECIST 1.1
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Measure Participants	3
Number [participants]	3 100%

2. Secondary Outcome

Title	The Number of Participants With Pathologic Response Rate
Description	Pathologic response rate is defined as < 50% of viable tumor present histologically in the resected tumor specimen.
Time Frame	37 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Measure Participants	3
Count of Participants [Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neoadjuvant Treatment With Crizotinib
	Comments	Three subjects enrolled. No statistical analysis completed due to low accrual.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Summary statistics
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Three subjects enrolled. No statistical analysis completed due to low accrual.

3. Secondary Outcome

Title	Number of Participants With an Objective Response Rate
Description	Number of participants with response rate per RECIST 1.1
Time Frame	6 weeks post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Measure Participants	3
Number [participants]	0 0%

4. Secondary Outcome

Title	The Number of Participants With Disease-free Survival (DFS)
Description	DFS is defined as the time from treatment to the first of either disease recurrence or death from any cause.
Time Frame	37 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Measure Participants	3
Count of Participants [Participants]	0 0%

5. Secondary Outcome

Title	Overall Survival (OS) Measured in Months
Description	OS is defined as the time from study enrollment to death from any cause.
Time Frame	37 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
Measure Participants	3
Median (Full Range) [months]	37

Adverse Events

Time Frame	3 years
Arm/Group Title	Neoadjuvant Treatment With Crizotinib
Arm/Group Description	Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review. Crizotinib: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.
All Cause Mortality
	Neoadjuvant Treatment With Crizotinib
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Serious Adverse Events
	Neoadjuvant Treatment With Crizotinib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Neoadjuvant Treatment With Crizotinib
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
creatinine increased	1/3 (33.3%)	1
ALT increased	1/3 (33.3%)	2
Cardiac disorders
bradycardia	1/3 (33.3%)	1
Eye disorders
blurred vision	2/3 (66.7%)	2
Gastrointestinal disorders
Nausea	1/3 (33.3%)	1
Diarrhea	2/3 (66.7%)	2
epigastric discomfort	1/3 (33.3%)	1
dysgeusia	1/3 (33.3%)	1
General disorders
Insomnia	1/3 (33.3%)	1
headache	1/3 (33.3%)	1
fatigue	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Influenza	1/3 (33.3%)	1
cough	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
dermatitis	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.