Lung-MAP: AZD4547 as Second-Line Therapy in Treating FGFR Positive Patients With Recurrent Stage IV Squamous Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II/III trial studies how well FGFR inhibitor AZD4547 (AZD4547) works in treating patients with stage IV squamous cell lung cancer that has come back after previous treatment. This is a sub-study that includes all screened patients positive for the fibroblast growth factor receptor (FGFR) biomarker. FGFR can cause tumor cells to grow more quickly. AZD4547 may decrease the activity of FGFR and may be able to shrink tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate if there is sufficient evidence to continue to the Phase III component by evaluating the objective response rate (ORR) with AZD4547 in FGFR-positive patients. (Phase II) II. If the study meets the criteria specified in S1400, the study will be amended to include a follow-on randomized Phase III trial. (Phase III) SECONDARY OBJECTIVES: I. To evaluate investigator-assessed progression free survival (IA-PFS) and overall survival (OS) in FGFR-positive patients treated with AZD4547. (Phase II) II. To evaluate the duration of response (DoR) among FGFR positive patients treated with AZD4547 who achieve a complete response (CR) or partial response (PR) (confirmed and unconfirmed) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase II) III. To evaluate the frequency and severity of toxicities associated with AZD4547 in FGFR positive patients. (Phase II) TRANSLATIONAL MEDICINE OBJECTIVES: I. To identify additional predictive tumor/blood biomarkers that may modify response or define resistance to the AZD4547 beyond the chosen biomarker for biomarker-driven sub-studies. II. To identify potential resistance biomarkers at disease progression. III. To establish a tissue/ blood repository from patients with refractory squamous cell carcinoma (SCCA) of the lung. OUTLINE: As of 12/18/2015, patients are assigned to Arm I. ARM I: Patients receive FGFR inhibitor AZD4547 orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II (CLOSED TO ACCRUAL 12/18/2015): Patients receive docetaxel intravenously (IV) on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, patients may be eligible to re-register to Arm III. ARM III: Patients in Arm II eligible for re-registration receive FGFR inhibitor AZD4547 PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, all patients are followed up every 6 months for the first 2 years and then at the end of the year 3 from date of sub-study/re-registration.

Official Title
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A Phase II Study of AZD4547 for Previously Treated FGFR-Positive Patients With Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

Conditions
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FGFR1 Gene Amplification, FGFR1 Gene Mutation, FGFR2 Gene Amplification, FGFR2 Gene Mutation, FGFR3 Gene Amplification, FGFR3 Gene Mutation, Recurrent Squamous Cell Lung Carcinoma, Stage IV Squamous Cell Lung Carcinoma AJCC v7

Intervention / Treatment
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* Drug: Docetaxel
* Drug: FGFR Inhibitor AZD4547
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all SCREENING/PRE-SCREENING and SUB-STUDY REGISTRATION COMMON ELIGIBILITY CRITERIA as specified in S1400: Phase II/III Biomarker-Driven Master Protocol for Previously Treated Squamous Cell Lung Cancer (Lung-Map) Patients must be assigned to S1400D Patients must not be taking, nor plan to take while on protocol treatment and for 14 days after the last dose of study treatment, drugs, herbal supplements or foods that are known to be strong/moderate CYP3A4 or CYP2D6 inhibitors and/or inducers Patients must not have received nitrosourea or mitomycin C within 42 days prior to sub-study registration Patients must not have had any prior exposure to any agent with FGFR inhibition as its primary pharmacology Patients must not have a mean resting corrected QT interval (QTc) > 450 msec obtained from 3 consecutive electrocardiograms (ECGs); performed within 28 days prior to sub-study registration; patients must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block); patients must not have any 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 Patients must not be planning to receive any concomitant medication known to prolong QT interval Patients must be able to take oral medications; patient may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of AZD4547 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Patients must not have a history of hypersensitivity to active or inactive excipients of AZD4547 or drugs with a similar chemical structure or class to AZD4547 Patients must not have any of the following ophthalmological criteria: 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); or current evidence or previous history of any other clinically relevant chorioretinal defect Patients must have an eye exam performed within 28 days prior to sub-study registration; patients with uncontrolled glaucoma or intra-ocular pressure >= 21 mm Hg at screening should be referred for ophthalmological management and the condition controlled prior to registration Patients must have albumin, urinalysis, and Troponin I obtained within 7 days prior to sub-study registration Patients must have corrected calcium and phosphate < upper limit or normal (ULN) obtained within 7 days prior to sub-study registration Patients must have multigated acquisition (MUGA)/echocardiogram performed within 28 days prior to sub-study registration Patients must also be offered participation in banking for future use of specimens STEP 2 TO AZD4547 RE-REGISTRATION: Patients must have progressed on Arm 2 (docetaxel) of this sub-study Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to re-registration; patients must have recovered (=< grade 1) from any side effects of prior therapy Patients must have measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI); the CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality; measurable disease must be assessed within 28 days prior to re-registration; pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease; non-measurable disease must be assessed within 42 days prior to re-registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form; patients whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to Step 2 Re-registration; patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment prior to re-registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to re-registration Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment; concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable Patients must have albumin, urinalysis, and Troponin I obtained within 7 days prior to substudy registration Patients must have corrected calcium and phosphate < ULN obtained within 7 days prior to sub-study registration Patients must have MUGA/echocardiogram performed within 28 days prior to sub-study registration Patients must not have any of the following ophthalmological criteria: 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); or current evidence or previous history of any other clinically relevant chorioretinal defect; patients must have an eye exam performed within 28 days prior to Step 2 re-registration; patients with uncontrolled glaucoma or intra-ocular pressure >= 21 mm Hg at screening should be referred for ophthalmological management and the condition controlled prior to crossover registration Patients must not be taking, nor plan to take while on protocol treatment and for 14 days after the last dose of study treatment, drugs, herbal supplements or foods that are known to be strong/moderate CYP3A4 or CYP2D6 substrates Patients must not have a mean resting corrected QT interval (QTc) > 450 msec obtained from 3 consecutive electrocardiograms (ECGs); performed within 28 days prior to Step 2 re-registration; patients must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block); patients must not have any 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 Absolute neutrophil count (ANC) >= 1,500/mcl obtained within 28 days prior to Step 2 re-registration Platelet count >= 100,000 mcl obtained within 28 days prior to Step 2 re-registration Hemoglobin >= 9 g/dL obtained within 28 days prior to Step 2 re-registration Serum bilirubin =< institutional upper limit of normal (IULN); for patients with liver metastases, bilirubin must be =< 5 x IULN within 28 days prior to Step 2 re-registration Either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within 28 days prior to Step 2 re-registration (if both ALT and AST are done, both must be =< 2 IULN); for patients with liver metastases, either ALT or AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN) Patients must have a serum creatinine =< the IULN OR measured or calculated creatinine clearance >= 50 mL/min using the Cockroft-Gault formula Patients must have Zubrod performance status of 0-1 documented within 28 days prior to Step 2 re-registration Patients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection Patients with a known history of human immunodeficiency virus (HIV) seropositivity: 1. Must have undetectable viral load using standard HIV assays in clinical practice; 2. Must have cluster of differentiation (CD)4 count >= 400/mcL; 3. Must not require prophylaxis for any opportunistic infections (i.e., fungal, mycobacterium avium complex [mAC], or pneumocystis pneumonia [PCP] prophylaxis); 4. Must not be newly diagnosed within 12 months prior to re-registration Prestudy history and physical exam must be obtained within 28 days prior to re-registration No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator) Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I - AZD4547<br>Participants receive FGFR inhibitor AZD4547 PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: FGFR Inhibitor AZD4547<br>* Given PO<br>* Other names: AZD4547;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II - Docetaxel<br>Participants receive docetaxel IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, participants may be eligible to re-register to Arm III. -closed to accrual 12/18/2015 | Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm III - AZD4547 re-registration<br>Participants in Arm II eligible for re-registration receive FGFR inhibitor AZD4547 PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: FGFR Inhibitor AZD4547<br>* Given PO<br>* Other names: AZD4547;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Confirmed and Unconfirmed, Complete and Partial) | The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with AZD4547 per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. It was pre-specified that only the AZD4547 arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 4 months or death. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response Among Patients Who Achieve a Complete Response or Partial Response by Response Evaluation Criteria in Solid Tumors 1.1 | From date of first documentation of response (complete or partial) to date of first documentation of progression assessed by local review, or symptomatic deterioration or death due to any cause among patients who achieve complete or partial response per RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. It was pre-specified that only the AZD4547 arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 4 months or death. | 
| Overall Survival | From date of sub-study registration on study until death from any cause. Observations for participants last known to be alive were censored. It was pre-specified that only the AZD4547 arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 4 months or death | 
| Progression-free Survival | From date of sub-study registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. It was pre-specified that only the AZD4547 arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 4 months or death. | 
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported per CTCAE Version 5.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. It was pre-specified that only the AZD4547 arm would be analyzed due to removal of docetaxel as standard of care treatment | Duration of treatment and follow up, up to 2 years and 4 months post registration or death. |