Lung-MAP: Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer
Lung-MAP: Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer
This screening and multi-sub-study randomized phase II/III trial will establish a method for
 genomic screening of similar large cancer populations followed by assigning and accruing
 simultaneously to a multi-sub-study hybrid ?Master Protocol? (S1400). The type of cancer
 trait (biomarker) will determine to which sub-study, within this protocol, a participant will
 be assigned to compare new targeted cancer therapy, designed to block the growth and spread
 of cancer, or combinations to standard of care therapy with the ultimate goal of being able
 to approve new targeted therapies in this setting. In addition, the protocol includes a
 ?non-match? sub-study which will include all screened patients not eligible for any of the
 biomarker-driven sub-studies. This sub-study will compare a non-match therapy to standard of
 care also with the goal of approval.
PRIMARY OBJECTIVES:

 Screening component:

 I. To establish a National Clinical Trials Network (NCTN) mechanism for genomically screening
 large but homogeneous cancer populations and subsequently assigning and accruing
 simultaneously to a multi-sub-study ?Master Protocol.? II. To evaluate the screen success
 rate defined as the percentage of screened patients that register for a therapeutic
 sub-study.

 Sub-study-specific Objectives:

 Design #1: Phase II/III Design:

 III. To evaluate if there is sufficient evidence to continue to the Phase III component of
 the sub-study by comparing investigator-assessed progression-free survival (IA-PFS) between
 investigational therapy versus standard therapy (SoC) in patients with advanced stage
 refractory squamous cell carcinoma (SCCA) of the lung. (Phase II) IV. To determine if there
 is both a statistically and clinically-meaningful difference in IA-PFS among advanced stage
 refractory SCCA of the lung randomized to receive investigational therapy versus SoC. (Phase
 III) V. To compare overall survival (OS) in patients with advanced stage refractory SCCA of
 the lung randomized to investigational therapy versus SoC. (Phase III)

 Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III):

 VI. To evaluate the objective response rate (confirmed and unconfirmed, complete and
 partial). (Phase II) VII. To determine if there is both a statistically and
 clinically-meaningful difference in IA-PFS among advanced stage refractory SCCA of the lung
 randomized to receive investigational therapy versus SoC. (Phase III) VIII. To compare
 overall survival (OS) in patients with advanced stage refractory SCCA of the lung randomized
 to investigational therapy versus SoC. (Phase III)

 SECONDARY OBJECTIVES:

 Sub-study-specific Objectives:

 Design #1: Phase II/III Design:

 I. To compare response rates (confirmed and unconfirmed, complete and partial responses)
 among patients randomized to receive investigational therapy versus SoC. (Phase II) II. To
 evaluate the frequency and severity of toxicities associated with investigational therapy
 versus SoC. (Phase II) III. To evaluate the duration of response (DoR) among patients who
 achieve a complete response (CR) or a partial response (PR) by Response Evaluation Criteria
 in Solid Tumors (RECIST) (1.1). (Phase II) III. To compare the response rates (confirmed and
 unconfirmed, complete and partial) among patients randomized to receive investigational
 therapy versus SoC. (Phase III) IV. To evaluate the frequency and severity of toxicities
 associated with investigational therapy versus SoC. (Phase III)

 Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III):

 V. To evaluate PFS and OS with investigational therapy. (Phase II) VI. To evaluate the DoR
 among patients who achieve a CR or PR (confirmed and unconfirmed) by RECIST 1.1. (Phase II)
 VII. To evaluate the frequency and severity of toxicities associated with investigational
 therapy. (Phase II) VIII. To compare the response rates (confirmed and unconfirmed, complete
 and partial) among patients randomized to receive investigational therapy versus SoC. (Phase
 III) IX. To evaluate the frequency and severity of toxicities associated with investigational
 therapy versus SoC. (Phase III)

 TERTIARY OBJECTIVES:

 I. To evaluate the treatment arm randomization acceptance rate (TARAR) within each treatment
 arm of each sub-study defined as the percentage of patients randomized to a treatment arm
 that receive any protocol treatment. (Design #1: Phase II/III Design) II. To identify
 additional predictive tumor/blood biomarkers that may modify response or define resistance to
 the targeted therapy (TT)/targeted therapy combination (TTC) beyond the chosen biomarker for
 biomarker-driven sub-studies.

 III. To evaluate potentially predictive biomarkers for non-match therapy (NMT) in the
 non-match studies.

 IV. To identify potential resistance biomarkers at disease progression. V. To establish a
 tissue/ blood repository from patients with refractory SCCA of the lung.

 OUTLINE: Patients are assigned to a biomarker-driven targeted therapy phase II study. If the
 objectives response rate observed is judged sufficient, patients proceed to a randomized
 phase III trial and are randomized to biomarker-driven targeted therapy or standard of care.

 S1400A: (CLOSED TO ACCRUAL 12/18/2015) Patients with tumors that do not match one of the
 currently active drug-biomarker combinations or did not meet the eligibility requirements for
 that bio-marker driven sub-study are assigned to Arm I. Upon evidence of progression
 following discontinuation of 12 months of treatment, patients may restart treatment for up to
 12 months with the same treatment guidelines followed during the initial 12-month treatment
 period (Arm III).

 ARM I: (CLOSED TO ACCRUAL 12/18/2015) Patients receive anti-B7H1 monoclonal antibody MEDI4736
 intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for 12 months in
 the absence of disease progression or unacceptable toxicity.

 ARM II (CLOSED TO ACCRUAL 4/2015): Patients receive docetaxel IV on day 1. Courses repeat
 every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
 accrual with Revision #2 4/22/15)

 ARM III: For patients assigned to Arm 1, MEDI4736: Upon evidence of progression following
 discontinuation of 12 months of treatment, patients may restart treatment with Arm 3,
 MEDI4736 for up to 12 months with the same treatment guidelines followed during the initial
 12-month treatment period. Patients will only be able to restart treatment once; thus a
 maximum of two 12-month periods will be allowed. Patients receive anti-B7H1 monoclonal
 antibody MEDI4736 intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14
 days for 12 months in the absence of disease progression or unacceptable toxicity.

 S1400B (CLOSED TO ACCRUAL 12/12/2016): Patients with tumors positive for phosphoinositide
 3-kinase (PI3KCA) are assigned to Arm I. Patients currently on Arm 2, docetaxel will be given
 the option to re-register to Arm 3, GCD-0032 after disease progression on current treatment
 (Arm III).

 ARM I: Patients receive taselisib orally (PO) daily 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 IV on day 1. Courses repeat
 every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
 accrual with Revision #3 12/18/2015)

 ARM III: Re-Registration Treatment with GDC-0032 (Taselisib) Upon progression patients in Arm
 2 may be eligible for Re-Registration to receive GDC-0032. Patients receive taselisib orally
 (PO) daily on days 1-21. Courses repeat every 21 days in the absence of disease progression
 or unacceptable toxicity.

 S1400C (CLOSED TO ACCRUAL 09/01/2016): Patients with tumors positive for cyclin dependent
 kinase 4 (CDK4), cyclin D1 (CCND1), cyclin D2 (CCND2), and cyclin D3 (CCND3) are assigned to
 Arm I. Patients currently on Arm 2, docetaxel will be given the option to re-register to Arm
 3, palbociclib, after disease progression on current treatment (Arm III).

 ARM I: Patients receive palbociclib 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 IV on day 1. Courses repeat
 every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
 accrual with Revision #3 12/18/2015)

 ARM III: Re-Registration Treatment with Palbociclib. Upon progression patients in Arm 2 may
 be eligible for Re-Registration to receive palbociclib. Patients receive palbociclib PO on
 days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable
 toxicity.

 S1400D (CLOSED TO ACCRUAL 10/31/2016): Patients with tumors positive for fibroblast growth
 factor receptor (FGFR) 1, FGFR2, and FGFR3 are assigned to Arm I. Patients currently on Arm
 2, docetaxel will be given the option to re-register to Arm 3, AZD4547, after disease
 progression on current treatment (Arm III).

 ARM I: Patients receive FGFR inhibitor AZD4547 PO 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 IV on day 1. Courses repeat
 every 21 days in the absence of disease progression or unacceptable toxicity. (closed to
 accrual with Revision #3 12/18/2015)

 ARM III: Re-Registration Treatment with AZD4547. Upon progression patients in Arm 2 may be
 eligible for Re-Registration to receive AZD4547. Patients receive FGFR inhibitor AZD4547 PO
 BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or
 unacceptable toxicity.

 S1400E (CLOSED TO ACCRUAL 11/25/2014): Patients with tumors positive for met proto-oncogene
 (MET) are randomized to 1 of 2 treatment arms. (permanently closed to accrual on 11/25/14)

 ARM I: Patients receive rilotumumab IV on day 1 and erlotinib hydrochloride PO daily on days
 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
 toxicity.

 ARM II: Patients receive erlotinib hydrochloride PO daily on days 1-21. Courses repeat every
 21 days in the absence of disease progression or unacceptable toxicity.

 S1400F: Patients with disease progression during or after prior anti-PD-1 or anti-PD-L1
 antibody monotherapy as their most recent line of treatment receive durvalumab (IV over 60
 minutes) and tremelimumab (IV over 60 minutes) on day 1 for courses 1-4 and durvalumab IV
 alone on day 1 of course 5 and subsequent courses until disease progression or unacceptable
 toxicity. Courses repeat every 28 days.

 S1400G: Patients with tumors positive for homologous recombination repair deficiency receive
 talazoparib PO daily on days 1-21. Courses repeat every 21 days in the absence of disease
 progression or unacceptable toxicity.

 S1400I: Patients with tumors that do not match one of the currently active drug-biomarker
 combinations or did not meet the eligibility requirements for that bio-marker driven
 sub-study are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 60
 minutes on day 1 of every third course. Courses repeat every 14 days in the absence of
 disease progression or unacceptable toxicity.

 ARM II: Patients receive nivolumab IV over 30 minutes on day 1. Courses repeat every 14 days
 in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, all patients are followed up periodically for up to 3
 years from date of screening registration.
Inclusion Criteria:

 -  SCREENING/PRE-SCREENING REGISTRATION:

 -  Patients must have pathologically proven squamous cell carcinoma (SCCA) cancer of the
 lung confirmed by tumor biopsy and/or fine-needle aspiration; disease must be stage IV
 SCCA, or recurrent; the primary diagnosis of SCCA should be established using the
 current World Health Organization (WHO)/International Association for the Study of
 Lung Cancer (IASLC)-classification of Thoracic Malignancies; the diagnosis is based on
 hematoxylin and eosin (H&E) stained slides with or without specific defined
 immunohistochemistry (IHC) characteristic (p40/p63 positive, transcription termination
 factor [TTF1] negative) if required for diagnosis; mixed histologies are not allowed

 -  Patients must either be eligible to be screened at progression on prior treatment or
 to be pre-screened prior to progression on current treatment; patients will either
 consent to the screening consent or the pre-screening consent, not both; these
 criteria are:

 -  Screening at progression on prior treatment: to be eligible for screening at
 progression, patients must have received at least one line of systemic therapy
 for any stage of disease (stages I-IV) and must have progressed during or
 following their most recent line of therapy; for patients whose prior systemic
 therapy was for stage I-III disease only (i.e. patient has not received any
 treatment for stage IV or recurrent disease), the prior systemic therapy must
 have been a platinum-based chemotherapy regimen and disease progression on the
 platinum-based chemotherapy must have occurred within one year from the last date
 that patient received that therapy; for patients whose prior therapy was for
 stage IV or recurrent disease, the patient must have received at least one line
 of a platinum-based chemotherapy regimen or checkpoint inhibitor therapy (e.g.
 nivolumab or pembrolizumab)

 -  Pre-screening prior to progression on current treatment: to be eligible for
 pre-screening, current treatment must be for stage IV or recurrent disease and
 patient must have received at least one dose of the current regimen; patients
 must have previously received or currently be receiving a platinum-based
 chemotherapy regimen or checkpoint inhibitor therapy (e.g. nivolumab or
 pembrolizumab); patients on first-line platinum-based treatment are eligible upon
 receiving cycle 1, day 1 infusion; Note: patients will not receive their
 sub-study assignment until they progress and the S1400 Notice of Progression is
 submitted

 -  Patients must have adequate tumor tissue available, defined as >= 20% tumor cells and
 >= 0.2 mm^3 tumor volume

 -  The local interpreting pathologist must review the specimen

 -  The pathologist must sign the S1400 Local Pathology Review Form confirming tissue
 adequacy prior to screening/pre-screening registration

 -  Patients must agree to have this tissue submitted to Foundation Medicine for
 common broad platform Clinical Laboratory Improvement Act (CLIA) biomarker
 profiling; if archival tumor material is exhausted, then a new fresh tumor biopsy
 that is formalin-fixed and paraffin-embedded (FFPE) must be obtained; a tumor
 block or FFPE slides 4-5 microns thick must be submitted; bone biopsies are not
 allowed; if FFPE slides are to be submitted, at least 12 unstained slides plus an
 H&E stained slide, or 13 unstained slides must be submitted; however it is
 strongly recommended that 20 FFPE slides be submitted; Note: previous
 next-generation deoxyribonucleic acid (DNA) sequencing (NGS) will be repeated if
 done outside this study for sub-study assignment; patients must agree to have any
 tissue that remains after NGS testing retained for the use of the translational
 medicine (TM) studies (if such TM studies are defined) within any sub-study the
 patient is enrolled in

 -  Patients must not have a known epidermal growth factor receptor (EGFR) mutation or
 anaplastic lymphoma kinase (ALK) fusion; EGFR/ALK testing is not required prior to
 registration and is included in the Foundation Medicine Incorporated (FMI) testing for
 screening/prescreening

 -  Patients must have Zubrod performance status 0-1 documented within 28 days prior to
 screening/pre-screening registration

 -  Patients must also be offered participation in banking for future use of specimens

 -  Patients must be willing to provide prior smoking history as required on the S1400
 Onstudy Form

 -  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 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

 -  SUB-STUDY REGISTRATION:

 -  Patients whose biomarker profiling results indicate the presence of an EGFR mutation
 or echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion are not eligible

 -  Patients must have progressed (in the opinion of the treating investigator) following
 the most recent line of therapy

 -  Patients must not have received any prior systemic therapy (systemic chemotherapy,
 immunotherapy or investigational drug) within 21 days prior to sub-study registration;
 patients must have recovered (=< grade 1) from any side effects of prior therapy;
 patients must not have received any radiation therapy within 14 days prior to
 sub-study registration

 -  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
 sub-study 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 sub-study 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 sub-study 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 registration, AND
 (2) patient has no residual neurological dysfunction and has been off corticosteroids
 for at least 24 hours prior to sub-study registration

 -  Patient must have fully recovered from the effects of prior surgery at least 14 days
 prior to sub-study 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

 -  Absolute neutrophil count (ANC) >= 1,500/mcl obtained within 28 days prior to
 sub-study registration

 -  Platelet count >= 100,000 mcl obtained within 28 days prior to sub-study registration

 -  Hemoglobin >= 9 g/dL obtained within 28 days prior to sub-study registration

 -  Serum bilirubin =< institutional upper limit of normal (IULN) within 28 days prior to
 sub-study registration; for patients with liver metastases, bilirubin must be =< 5 x
 IULN

 -  Either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN
 within 28 days prior to sub-study 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)

 -  Serum creatinine =< the IULN OR measured or calculated creatinine clearance >= 50
 mL/min using the following Cockcroft-Gault Formula within 28 days prior to sub-study
 registration

 -  Patients must have Zubrod performance status 0-1 documented within 28 days prior to
 sub-study 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 jiroveci pneumonia [PCP]
 prophylaxis)

 -  Must not be newly diagnosed within 12 months prior to sub-study registration

 -  Prestudy history and physical exam must be obtained within 28 days prior to sub-study
 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 part of the 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 into 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.