Docetaxel With or Without FGFR Inhibitor AZD4547 in Treating Patients With Recurrent Non-Small Cell Lung Cancer

• Sponsor: ECOG-ACRIN Cancer Research Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01824901
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 2
• Locations: 5
• Arms: 4
• Duration (Months): 19
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase I/II trial studies the side effects and best dose of fibroblast growth factor receptor (FGFR) inhibitor AZD4547 when given with docetaxel and to see how well it works in treating patients with recurrent non-small cell lung cancer. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. FGFR inhibitor AZD4547 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether docetaxel and FGFR inhibitor AZD4547 are more effective when given together or separately.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer	Drug: docetaxel; Drug: AZD4547	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determination of a recommended phase II dose for the combination of docetaxel and AZD4547 (FGFR inhibitor AZD4547). (Phase I) II. Estimation and comparison of progression-free survival (PFS) of each treatment arm. (Phase II)

SECONDARY OBJECTIVES:

1. Pharmacokinetic evaluation of docetaxel with or without concomitant AZD4547. Pharmacokinetic evaluation of AZD4547 with concomitant docetaxel. (Phase I) II. Safety assessment and toxicity characterization of the combination. (Phase I) III. Initial assessment of clinical activity of the combination. (Phase I) IV. Response rate. (Phase II)
2. Overall survival. (Phase II) VI. Estimation of response to single agent AZD4547 among patients who crossover from single agent docetaxel. (Phase II) VII. Further safety assessment and toxicity characterization of AZD4547 alone and in combination with docetaxel. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of FGFR inhibitor AZD4547 followed by a randomized phase II study.

PHASE I:

Patients receive docetaxel intravenously (IV) over 60 minutes on day 1 and FGFR inhibitor AZD4547 orally (PO) twice daily (BID) on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II, STEP I: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive docetaxel IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who experience progressive disease may then receive FGFR inhibitor AZD4547 PO BID on days 1-14.

ARM II: Patients receive docetaxel IV as in Arm I and FGFR inhibitor AZD4547 PO BID on days 1-14.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II, STEP II:

Patients receive FGFR inhibitor AZD4547 PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

This study opened to accrual on September 19, 2013 and was suspended to accrual on January 29, 2014 after each of the first two patients had been registered to the first dose level of the phase I and experienced dose limiting toxicities (DLTs) during week 1 of cycle 1. The study was subsequently terminated on April 17, 2014 after having met the predefined criteria for closure per the phase I study design.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/Randomized Phase II Study of Docetaxel With or Without AZD4547 in Recurrent FGFR1-Amplified Squamous Non-Small Cell Lung Cancer
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jul 9, 2014
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: docetaxel; Given IV; Other Names: Taxotere NSC 628503 ; Drug: AZD4547; Given PO; Other Names: NSC 765338
Experimental: Arm I (docetaxel; phase II step I) Patients receive docetaxel IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who experience progressive disease may then register to step II treatment and receive FGFR inhibitor AZD4547 PO BID on days 1-14.	Drug: docetaxel; Given IV; Other Names: Taxotere NSC 628503
Experimental: Arm II (docetaxel and AZD4547; phase II step I) Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 1-14. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: docetaxel; Given IV; Other Names: Taxotere NSC 628503 ; Drug: AZD4547; Given PO; Other Names: NSC 765338
Experimental: Phase II step II Patients receive FGFR inhibitor AZD4547 PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: AZD4547; Given PO; Other Names: NSC 765338

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of FGFR Inhibitor AZD4547 [Assessed during cycle 1 (21 days)]

   A total of 3 dose levels of AZD4547 were planned: 40mg (level 1), 60mg (level 2), and 80mg (level 3) in combination with a standard dose of docetaxel (75mg/m^2). The starting dose level of AZD4547 was 40 mg. This portion of the study used a standard 3+3 design with patients enrolled in cohorts of 3. The plan was to recommend the maximum tolerated dose (MTD) as the dose level to be used in the phase II portion of the study. MTD is defined as the highest dose level at which less than or equal to 1 of 6 subjects experience dose limiting toxicity (DLT).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Phase I:

Inclusion Criteria:

• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy

• Women of childbearing potential and sexually active males must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Measurable or non-measureable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to registration

• Histologically or pathologically confirmed squamous NSCLC; patients whose tumors contain mixed NSCLC histologies are eligible if squamous morphology is predominant; mixed tumors with small cell anaplastic elements are not eligible

• Life expectancy >= 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1

• Adequate organ and marrow function

• Mean resting corrected QT interval (QTc) < 470 msec obtained from 3 consecutive electrocardiograms

Exclusion Criteria:

• Pregnant or breast-feeding women

• Clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. complete left bundle branch block, third degree heart block

• Factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval

• Prior treatment with docetaxel (except in the adjuvant setting), or AZD4547

• Prior treatment with any other chemotherapy, immunotherapy or anticancer agents within 2 weeks prior to registration

• Current evidence or previous history of retinal pigmented epithelium detachment (RPED)

• Previous laser treatment or intra-ocular injection for treatment of macular degeneration

• Current evidence or previous history of dry or wet age-related macular degeneration

• Current evidence or previous history of retinal vein occlusion (RVO)

• Current evidence or previous history of retinal degenerative diseases (e.g. hereditary)

• Current evidence or previous history of any other clinically relevant chorioretinal defect

• Uncontrolled brain metastases

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD4547, docetaxel or other agents used in the study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the investigational drug, previous significant bowel resection, or any other significant gastrointestinal disorder that could, in the opinion of the Investigator, interfere with the absorption of AZD4547

• Major surgical procedure within 3 weeks prior to registration

• Grade 3 or higher peripheral neuropathy, as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE),version 4.02

• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

• Known human immunodeficiency virus (HIV) with cluster of differentiation (CD)4 count is =< 200 cell/mm^3 or receiving antiretroviral therapy due to potential unfavorable interactions of the agents with the study treatment

• Receiving any other investigational agents while on study

• Medications that are potent inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), or substrates of CYP3A4 prior to the first dose of study treatment

Phase II pre-registration:

• Patient must have paraffin-embedded tumor specimen available for submission for determination of fibroblast growth factor receptor 1(FGFR1) amplification status

Phase II Step I - Randomization:

• Besides the eligibility criteria in Step I, patient must have positive tumor FGFR1 gene amplification (score FISH6) as determined by an AstraZeneca approved central laboratory.

Phase II Step II:

Inclusion Criteria:

• Patient was randomized to docetaxel only on step 1 and progressed per RECIST v1.1 criteria; registration to step 2 must occur within 4 weeks of confirmation/determination of disease progression

• Confirmed measurable disease based on RECIST 1.1; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to registration

Exclusion Criteria:

• Pregnant or breast-feeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Northwestern University	Chicago	Illinois	United States	60611
3	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936
4	Eastern Cooperative Oncology Group (ECOG) Research Base	Brookline	Massachusetts	United States	02445-7648
5	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• ECOG-ACRIN Cancer Research Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Charles Rudin, Eastern Cooperative Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ECOG-ACRIN Cancer Research Group
• ClinicalTrials.gov Identifier: NCT01824901
• Other Study ID Numbers: E2512; NCI-2012-01940; U10CA021115; E2512
• First Posted: Apr 5, 2013
• Last Update Posted: Feb 22, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by ECOG-ACRIN Cancer Research Group: AZD4547; recurrent non-small cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Recurrence; Docetaxel

Study Results

Participant Flow

Recruitment Details	This study opened to accrual on September 19, 2013 and was suspended to accrual on January 29, 2014 after each of the first two patients had been registered to the first dose level of the phase I and experienced DLTs. The study was subsequently closed on April 17, 2014 after having met the predefined criteria for closure per study design.

Arm/Group Title	Phase I	Arm I (Docetaxel; Phase II Step I)	Arm II (Docetaxel and AZD4547; Phase II Step I)	Phase II Step II
Arm/Group Description	Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. docetaxel: Given IV AZD4547: Given PO	Patients receive docetaxel IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who experience progressive disease may then register to step II treatment and receive FGFR inhibitor AZD4547 PO BID on days 1-14. docetaxel: Given IV	Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 1-14. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. docetaxel: Given IV AZD4547: Given PO	Patients receive FGFR inhibitor AZD4547 PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. AZD4547: Given PO
Period Title: Overall Study
STARTED	2	0	0	0
COMPLETED	2	0	0	0
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase I
Arm/Group Description	Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	2
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66.5
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	2 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of FGFR Inhibitor AZD4547
Description	A total of 3 dose levels of AZD4547 were planned: 40mg (level 1), 60mg (level 2), and 80mg (level 3) in combination with a standard dose of docetaxel (75mg/m^2). The starting dose level of AZD4547 was 40 mg. This portion of the study used a standard 3+3 design with patients enrolled in cohorts of 3. The plan was to recommend the maximum tolerated dose (MTD) as the dose level to be used in the phase II portion of the study. MTD is defined as the highest dose level at which less than or equal to 1 of 6 subjects experience dose limiting toxicity (DLT).
Time Frame	Assessed during cycle 1 (21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I
Arm/Group Description	Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	2
Number [mg]	NA

Adverse Events

Time Frame	Assessed every 3 weeks while on treatment and for 30 days after the end of treatment.
Adverse Event Reporting Description	Submission of late adverse events is required at follow-up visits up to 3 years.
Arm/Group Title	Phase I
Arm/Group Description	Patients receive docetaxel IV over 60 minutes on day 1 and FGFR inhibitor AZD4547 PO BID on days 2-15 of course 1 and days 1-14 of all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Phase I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Phase I
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Blood and lymphatic system disorders
Anemia	1/2 (50%)
Cardiac disorders
Myocardial infarction	1/2 (50%)
Left ventricular systolic dysfunction	1/2 (50%)
Gastrointestinal disorders
Dysphagia	1/2 (50%)
Mucositis oral	1/2 (50%)
General disorders
Multi-organ failure	1/2 (50%)
Infections and infestations
Mucosal infection	1/2 (50%)
Investigations
Lymphocyte count decreased	2/2 (100%)
Neutrophil count decreased	2/2 (100%)
White blood cell decreased	2/2 (100%)
Metabolism and nutrition disorders
Hypoalbuminemia	1/2 (50%)
Hypocalcemia	1/2 (50%)
Nervous system disorders
Somnolence	1/2 (50%)
Psychiatric disorders
Confusion	1/2 (50%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/2 (50%)
Vascular disorders
Hypotension	2/2 (100%)
Other (Not Including Serious) Adverse Events
	Phase I
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Blood and lymphatic system disorders
Anemia	1/2 (50%)
Gastrointestinal disorders
Constipation	1/2 (50%)
Vomiting	1/2 (50%)
General disorders
Fatigue	1/2 (50%)
Fever	2/2 (100%)
Edema limbs	1/2 (50%)
Infections and infestations
Mucosal infection	1/2 (50%)
Investigations
Alanine aminotransferase increased	2/2 (100%)
Aspartate aminotransferase increased	1/2 (50%)
Lymphocyte count decreased	1/2 (50%)
Platelet count decreased	2/2 (100%)
White blood cell decreased	1/2 (50%)
Metabolism and nutrition disorders
Hypernatremia	1/2 (50%)
Hypoalbuminemia	2/2 (100%)
Hypocalcemia	1/2 (50%)
Hypokalemia	1/2 (50%)
Hypomagnesemia	1/2 (50%)
Hyponatremia	1/2 (50%)
Nervous system disorders
Peripheral sensory neuropathy	1/2 (50%)
Renal and urinary disorders
Proteinuria	1/2 (50%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/2 (50%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.