A BIOMARKER-DRIVEN MASTER PROTOCOL FOR PREVIOUSLY TREATED SQUAMOUS CELL LUNG CANCER (LUNG-MAP) - A PHASE II STUDY OF MEDI4736 FOR PREVIOUSLY TREATED PATIENTS WITH STAGE IV SQUAMOUS CELL LUNG CANCER AND NO MATCHING BIOMARKERS (LUNG-MAP SUB-STUDY)

(In addition to S1400 Lung-MAP criteria)

5.1 Registration Step #1 Disease Related Criteria

a. Patients must have been assigned to S1400A.

b. Patients must not have any prior exposure to immunotherapy such as, but not limited to anti-PD-1 or anti-PD-L1 antibodies. Prior exposure to the following is allowed: anti-CTLA-4 antibodies, live attenuated vaccines, anti-EGFR agents and GM-GSF.

c. Patients must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study registration.

d. Patients must not have any active or prior documented autoimmune or inflammatory disease (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome) within 3 years prior to sub-study registration. Patients with vitiligo, alopecia, Grave�s disease, or psoriasis requiring systemic treatment within the past 3 years are not eligible.

e. Patients must not have any history of primary immunodeficiency.

5.2 Registration Step #1 Clinical/Laboratory Criteria

a. Patients must not have received any immunosuppressive medication within 28 days prior to sub-study registration and must not be planning to receive any such agents while on protocol treatment. However, intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent are allowed.

b. Patients must not have any prior Grade => 3 immune-related adverse event (irAE) or any unresolved irAE > Grade 1.

c. Patients must not have any history of organ transplant that requires use of immunosuppressives.

d. Patients must not have any known allergy or reaction to any component of the MEDI4736 formulation.

e. Patients must not have a known history of tuberculosis.

f. Patients must not have received a live attenuated vaccination within 28 days prior to sub-study registration.

g. Patients must not have known HIV, Hepatitis B or Hepatitis C positivity. [This criterion replaces common eligibility criteria in Section 5.3m and 5.3n]

h. Patients must also be offered participation in banking for future use of specimens as described in Section 15.0.

5.3 Registration Step #1 - Common Eligibility Criteria for all Sub-Studies

The S1400 Common Eligibility Criteria have been incorporated into Section 5.0 of each sub-study for ease of reference.

a. Patients whose biomarker profiling results indicate the presence of an EGFR mutation or EML4/ALK fusion are not eligible. Due to existence of approved therapies the biomarker exclusion rules are as follows:

Gene Alteration type Ineligible Alteration
EGFR Substitution L858R, T790M, A289V, G719A, S768I, G719C, R108K, G598V, R222C, L62R, L861Q, P596L, V774M
Indel non-frame shifting insertions or deletions between amino acids 740 and 780, in exons 19 and 20, transcript NM_005228
Fusion None
Amplification None
ALK Substitution None
Indel None
Fusion EML4-ALK, CLIP4-ALK, CLTC-ALK, KIF5B-ALK, NPM1-ALK, RANB2-ALK, STRN-ALK, TFG-ALK
Amplification None

b. Patients must have progressed per RECIST 1.1 (see Section 10.1) following the most recent line of therapy.

c. 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. Localized palliative radiation therapy is allowed for symptom management, provided treatment is completed => 14 days prior to sub-study registration. All other types of radiation must be completed > 28 days prior to sub-study registration.

d. Patients must have measurable disease (see S1400 Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality as defined in S1400 Section 10.1c. 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. See S1400A Sections 15.0 and S1400 Section 18.1c for guidelines and submission instructions for required central radiology review.

e. Patients must have a CT or MRI scan of the brain to evaluate for 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 (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 1 day prior to sub-study registration.

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

g. 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.

h. Patients must have an ANC => 1,500/mcl, platelet count => 100,000 mcl, and hemoglobin => 9 g/dL obtained within 28 days prior to sub-study registration.

i. Patients must have adequate hepatic function as defined by serum bilirubin =< Institutional Upper Limit of Normal (IULN) and either ALT or 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, bilirubin and either ALT or AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN).

j. Patients must have a serum creatinine =< the IULN OR measured or calculated creatinine clearance => 50 mL/min using the following Cockroft-Gault Formula:

Calculated Creatinine Clearance = (140 - age) X (actual body weight in kg�)
72 x serum creatinine*

Multiply this number by 0.85 if the patient is a female. These tests must have been performed within 28 days prior to sub-study registration.

�The kilogram weight is the patient weight with an upper limit of 140% of the IBW.
*Actual lab serum creatinine value with a minimum of 0.8 mg/ dL.

k. Patients must have Zubrod performance status 0-1 (see S1400 Section 10.4) documented within 28 days prior to sub-study registration.

l. 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 (see S1400 Section 18.1b).

m. [This common eligibility criteria has been removed as it conflicts with the sub-study specific criteria in Section 5.2g. A place holder remains to keep consistency across all sub-studies]

n. [This common eligibility criteria has been removed as it conflicts with the sub-study specific criteria in Section 5.2g. A place holder remains to keep consistency across all sub-studies]

o. Prestudy history and physical exam must be obtained within 28 days prior to sub-study registration.

p. 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.

q. 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

r. As a part of the OPEN registration process (see S1400 Section 13.4 for OPEN access instructions) 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.

s. 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).

t. 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.

5.4 Registration Step #2 - MEDI4736 RE-TREATMENT

Disease Related Criteria

a. Patient must have progressed following 12 months of treatment with MEDI4736. Patients who discontinue MEDI4736 prior to the completion of 12 months (for any reason) are not eligible.

Patients who have already completed two 12-month periods of treatment are not eligible.

b. Patients may have measurable or non-measurable disease (see S1400 Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality as defined in S1400 Section 10.1c. Measurable disease must be assessed within 28 days prior to re-treatment 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-treatment 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 RE-TREATMENT registration. See Sections 15.0 and S1400 Section 18.1c for guidelines and submission instructions for required central radiology review.

c. Patients must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to RE-TREATMENT 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 (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 1 day prior to RE-TREATMENT registration.

d. Patients must not have received any treatment after discontinuing MEDI4736 with the following exceptions. Localized palliative radiation therapy is allowed for symptom management, provided and treatment is completed => 14 days prior to RE-TREATMENT registration.Local treatment for brain metastases as specified in section 5.4.c is allowed.

e. Patients must not have received any immunosuppressive medication within 28 days prior to RE-TREATMENT registration and must not be planning to receive any such agents while on protocol treatment. However, intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent are allowed.

f. Patients must not have any prior Grade => 3 immune-related adverse event (irAE) or any unresolved irAE > Grade 1.

g. Patients must not have received a live attenuated vaccination within 28 days prior to RE-TREATMENT registration.

h. Patients must not have known HIV, Hepatitis B or Hepatitis C positivity.

i. 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.

j. Patients must have an ANC => 1,500/mcl, platelet count => 100,000 mcl, and hemoglobin => 9 g/dL obtained within 28 days prior to RE-TREATMENT registration.

k. Patients must have adequate hepatic function as defined by serum bilirubin =< Institutional Upper Limit of Normal (IULN) and either ALT or AST =< 2 x IULN within 28 days prior to RE-TREATMENT registration (if both ALT and AST are done, both must be < 2 IULN). For patients with liver metastases, bilirubin and either ALT or AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN).

l. Patients must have a serum creatinine =< the IULN OR measured or calculated creatinine clearance => 50 mL/min using the following Cockroft-Gault Formula:

Calculated Creatinine Clearance = (140 - age) X (actual body weight in kg�)
72 x serum creatinine*

Multiply this number by 0.85 if the patient is a female. These tests must have been performed within 28 days prior to RE-TREATMENT registration.
�The kilogram weight is the patient weight with an upper limit of 140% of the IBW.
*Actual lab serum creatinine value with a minimum of 0.8 mg/dL.

m. Patients must have Zubrod performance status of 0-1 (see Section 10.4) documented within 28 days prior to RE-TREATMENT registration.

n. Prestudy history and physical exam must be obtained within 28 days prior to RE-TREATMENT registration.

o. 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.

p. As a part of the OPEN registration process (see Section 13.4 for OPEN access instructions) 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.

q. 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).

r. 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.