A BIOMARKER-DRIVEN MASTER PROTOCOL FOR PREVIOUSLY TREATED SQUAMOUS CELL LUNG CANCER - A PHASE II STUDY OF GDC-0032 (TASELISIB) FOR PREVIOUSLY TREATED PI3K POSITIVE PATIENTS WITH STAGE IV SQUAMOUS CELL LUNG CANCER

(In addition to S1400 Lung-MAP criteria)

5.1 Disease Related Criteria

a. Patients must be assigned to S1400B. S1400B biomarker eligibility defined as PI3K Positive is as follows:

Gene Alteration type Eligible alteration
PIK3CA Substitution R38C, R38H, E81K, R88Q, R93Q, R93W, P104L, P104R, G106V, G106R, P104_G106>R, R108H, E110del, E110K, K111E, K111N, K111del, G118D, V344G, V344M, N345K, N345I, E365K, C378F, E418K, C420R, E453K, E453Q, P539R, E542K, E542A, E542V, E542G, E542Q, E545A, E545G, E545K, E545Q, E545D, Q546E, Q546H, Q546K, Q546L, Q546P, Q546R, E726K, G1007R, D1017H, Y1021C, Y1021H, T1025A, A1035V, A1035T, M1043I, M1043L, M1043V, H1047L, H1047R, H1047Y, H1047N, H1047Q, G1049R, G1049S, I1058L
Fusion None
Amplification None

5.2 Clinical Laboratory Criteria

a. Patients must have a HbA1c < 7% and fasting glucose < 125 mg/dL obtained within 28 days prior to sub-study registration.

b. Patients must not have Type I or II diabetes that requires anti-hyperglycemic medication.

c. Patients must not have active or a history of small or large intestine inflammation such as Crohn�s disease or ulcerative colitis.

d. Patients must not require daily supplemental oxygen.

e. Patients must be able to take oral medications. Patients may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of GDC-0032 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

f. Patients must not be taking, nor plan to take while on protocol treatment and for 14 days post the last dose of study treatment, drugs, herbal supplements or foods that are known to be strong/moderate CYP3A4 substrates. A list of these medications can be found in Section 7.4 of this sub-study.

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

5.3 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 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 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 Sections 15.0 and 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 of 0-1 1 (see 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 Section 18.1b).

m. Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection.

n. Patients with a known history of HIV seropositivity:

1. Must have undetectable viral load using standard HIV assays in clinical practice.
2. Must have CD4 count => 400/mcL.
3. Must not require prophylaxis for any opportunistic infections (i.e., fungal, mAC, or PCP prophylaxis).
4. Must not be newly diagnosed within 12 months prior to sub-study registration.

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 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 Step 2 GDC-0032 Re-Registration

a. Patients must have progressed (as defined in Section 10.2d in S1400) on Arm 2 (docetaxel) of this sub-study.

b. Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within within 21 days prior to Step 2 re-registration. Patients must have recovered (< Grade 1) from any side effects of prior therapy.

c. Patients must have measurable disease (see 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 Section 10.1c. 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. See Sections 15.0 and 18.1c for guidelines and submission instructions for required central radiology review.

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

e. 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.

f. Patients must have an ANC => 1,500/mcl, platelet count => 100,000 mcl, and hemoglobin => 9 g/dL obtained within 28 days prior to Step 2 Re-Registration.

g. 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 Step 2 Re-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).

h. Patients must have a HbA1c < 7% and fasting glucose < 125 mg/dL obtained within 28 days prior to Step 2 Re-Registration.

i. 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 Step 2 Re-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.

j. Patients must have Zubrod performance status of 0-1 (see Section 10.4) documented within 28 days prior to Step 2 Re-Registration.

k. 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 Section 18.1b).

l. Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection.

m. Patients with a known history of HIV seropositivity:

1. Must have undetectable viral load using standard HIV assays in clinical practice.
2. Must have CD4 count => 400/mcL.
3. Must not require prophylaxis for any opportunistic infections (i.e., fungal, mAC, or PCP prophylaxis).
4. Must not be newly diagnosed within 12 months prior to re-registration.

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

o. 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.

p. 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.

q. 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.

r. 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).

s. 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