Lung-MAP: Palbociclib as Second-Line Therapy in Treating Cell Cycle Gene Alteration 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 palbociclib works in treating cell cycle gene alteration positive 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 cell cycle gene alterations which can cause tumor cells to grow more quickly. Palbociclib may slow cell cycle progression 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) for cell cycle gene alteration positive patients registered to S1400C treated with palbociclib. (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) of cell cycle gene alteration-positive patients treated with palbociclib. (Phase II) II. To evaluate the duration of response (DoR) among cell cycle gene alteration positive patients treated with palbociclib 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 palbociclib. (Phase II) TRANSLATIONAL MEDICINE OBJECTIVES: I. To identify additional predictive tumor/blood biomarkers that may modify response or define resistance to palbociclib 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 09/01/2016, all arms are closed to accrual. ARM I (CLOSED TO ACCRUAL 09/01/2016): Patients receive palbociclib orally (PO) on days 1-21. Courses repeat every 28 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 (CLOSED TO ACCRUAL 09/01/2016): Patients in Arm II eligible for re-registration receive palbociclib PO on days 1-21. Courses repeat every 28 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 Palbociclib for Previously Treated Cell Cycle Gene Alteration Positive Patients With Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

Conditions
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Recurrent Squamous Cell Lung Carcinoma, CCND1 Gene Amplification, CCND2 Gene Amplification, CCND3 Gene Amplification, CDK4 Gene Amplification, Stage IV Squamous Cell Lung Carcinoma AJCC v7

Intervention / Treatment
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* Drug: Docetaxel
* Other: Laboratory Biomarker Analysis
* Drug: Palbociclib


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 S1400C Patients must not be taking within 7 days prior to sub-study registration, nor plan to take while on protocol treatment and for 14 days after the last dose of study treatment, strong CYP3A4 inhibitors and/or strong CYP3A4 inducers; moderate inhibitors or inducers of isoenzyme CYP3A4 should be avoided, but if necessary can be used with caution Patients must not be taking within 7 days prior to sub-study registration, nor plan to take while on protocol treatment drugs that are known to prolong the QT interval Patients must not have a screening corrected QT Fridericia?s formula (QTcF) interval > 480 msec based on the average of the triplicate electrocardiograms (EKGs) performed within 28 days prior to registration; NOTE: triplicate EKGs are required at other timepoints; patients must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or torsade de pointes 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 palbociclib (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Patients must have a sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), magnesium (Mg), and glycosylated hemoglobin measurement (HbA1c) performed within 7 days prior to sub-study registration Patients must also be offered participation in banking for future use of specimens STEP 2 PALBOCICLIB 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 step 2 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 step 2 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 step 2 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 and 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 not have a screening QTcF interval > 480 msec based on the average of the triplicate EKGs performed within 28 days prior to step 2 re-registration; NOTE: triplicate EKGs are required at other timepoints; patients must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or torsade de pointes 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 Patients must have a Na, K, Cl, Ca, Mg, and HbA1c performed within 7 days prior to sub-study registration 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: Must have undetectable viral load using standard HIV assays in clinical practice Must have cluster of differentiation (CD)4 count >= 400/mcL Must not require prophylaxis for any opportunistic infections (i.e., fungal, mycobacterium avium complex [mAC], or pneumocystis pneumonia [PCP] prophylaxis) Must not be newly diagnosed within 12 months prior to re-registration Pre-study 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: 18 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 - Palbociclib<br>Participants receive palbociclib PO on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Closed to accrual 09/01/2016 | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Palbociclib<br>* Given PO<br>* Other names: PD-332991;|
| 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 (arm II closed to accrual 12/18/2015)<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm III - Palbociclib re-reg<br>Participants in Arm II eligible for re-registration receive palbociclib PO on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Closed to accrual 09/01/2016 | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Palbociclib<br>* Given PO<br>* Other names: PD-332991;|

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 palbociclib 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 palbociclib arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to progression or treatment discontinuation, up to 2 years and 10 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response Among Participants 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 participants who achieve a complete or partial response. 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 palbociclib arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 10 months or death | 
| Overall Survival With Investigational Therapy | From date of sub-study registration until death due to any cause. It was pre-specified that only the palbociclib arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 10 months or death | 
| Progression-free Survival With Palbociclib. | From date of sub-study registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. It was pre-specified that only the palbociclib arm would be analyzed due to removal of docetaxel as standard of care treatment | From date of registration to maximum of 2 years and 10 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 palbociclib arm would be analyzed due to removal of docetaxel as standard of care treatment | Duration of treatment and follow up to a maximum of 2 years and 10 months post registration or death |