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Title Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer

IRB S1400

CC 14-894

Hospital Fairview, Hillcrest, Independence, Main Campus, Mansfield, North Coast Cancer, Strongsville, Wooster

Phase Phase 2, Phase 3

Disease Lung

Description

Primary Objective of the Master Protocol

The overarching goal for this protocol is 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". Biomarker-driven sub-studies in this protocol will compare new targeted therapy (TT) or targeted therapy combinations (TTC) to standard of care (SoC) therapy based on designated therapeutic biomarker-drug combinations, with the ultimate goal being approval of 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 (NMT) to SoC also with the goal of approval. We hypothesize that this Master Protocol mechanism will yield definable and measurable efficiencies in terms of improving genomic screening of cancer patients for clinical trial entry, and improved time lines for drug-biomarker testing allowing for inclusion of the maximum numbers of otherwise eligible patients in comparison with currently employed "single screen-single trial" approaches.

Primary Objectives of Each Sub-Study

1. Phase II Component

   The primary objective within the Phase II component of each biomarker-driven sub-study is 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 targeted therapy (TT) or targeted therapy combinations (TTC) versus standard therapy (SoC) in patients with advanced stage refractory squamous cell carcinoma (SCCA) of the lung.

   The primary objective within the Phase II component of the non-match sub-study is 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 the non-match therapy (NMT) versus standard therapy (SoC) in patients with advanced stage refractory squamous cell carcinoma (SCCA) of the lung.

2. Phase III Component

   The co-primary objectives of the Phase III component of each biomarker-driven sub-study are:

   • 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 TT/TTC versus SoC.
   • To compare overall survival (OS) in patients with advanced stage refractory SCCA of the lung randomized to TT/TTC versus SoC.

   The primary objectives of the Phase III component of the non-match sub-study are:

   • 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 NMT versus SoC.
   • To compare overall survival (OS) in patients with advanced stage refractory SCCA of the lung randomized to NMT versus SoC.

Secondary Objectives of Each Sub-Study

1. Phase II Component

   The secondary objectives of the Phase II component of each sub-study are:

   • To compare response rates (confirmed and unconfirmed, complete and partial responses) among patients randomized to receive TT/TTC/NMT versus SoC.
   • To evaluate the frequency and severity of toxicities associated with TT/TTC/NMT versus SoC.

2. Phase III Component

   The secondary objectives of each sub-study are:

   • To compare the response rates (confirmed and unconfirmed, complete and partial) among patients randomized to receive TT/TTC/NMT versus SoC.
   • To evaluate the frequency and severity of toxicities associated with TT/TTC/NMT versus SoC.

Screening Success Rate Objective

To evaluate the screen success rate defined as the percentage of screened patients that register for a therapeutic sub-study. Screen success rates will be evaluated for the total screened population and by the subset of patients screened following progression on previous therapy or pre-screened during first line therapy.

Treatment Arm Randomization Acceptance Rate Objective

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.

Translational Medicine Objectives

1. To identify additional predictive tumor/blood biomarkers that may modify response or define resistance to the TT beyond the chosen biomarker.
2. To identify potential resistance biomarkers at disease progression.
3. To establish a tissue/ blood repository from patients with refractory squamous cell carcinoma (SCCA) of the lung.

Inclusion Criteria

Screening/Pre-Screening Registration

1. 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 as defined in Section 4.0 or recurrent. The primary diagnosis of SCCA should be established using the current WHO/IASLC-classification of Thoracic Malignancies. (9) The diagnosis is based on H&E stained slides with or without specific defined IHC characteristic (p40/p63 positive, TTF1 negative) if required for diagnosis. Mixed histologies are not allowed.
2. Patients must either be eligible to be screened at progression on prior treatment or to be pre-screened prior to progression on first-line 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). At least one of these lines of therapy must have been a platinum-based chemotherapy regimen. Patients must have progressed following the most recent line of therapy. For patients who received platinum-based chemotherapy for Stage I-III disease progression must have occurred within one year from receiving that therapy.

   • Pre-Screening prior to progression on first-line treatment:

     To be eligible for pre-screening, patients must have received at least one dose of Cycle 1 of a first-line platinum-based chemotherapy regimen for Stage IV disease. Patients 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 on First-Line Therapy is submitted.

3. Patients must not have received docetaxel as treatment for Stage IV disease. Patients may have received docetaxel for Stage I-III disease as long as they did not experience disease progression within one year after completing the docetaxel-containing regimen.
4. Patients must have adequate tumor tissue available, defined as ≥ 20% tumor cells and ≥ 0.2 mm3 tumor volume. The local interpreting pathologist must review and sign off on the S1400 Local Pathology Review Form prior to screening/pre-screening registration. Patients must agree to have this tissue submitted to Foundation Medicine for common broad platform CLIA biomarker profiling (see Section 15.1). 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 DNA sequencing (NGS) will be repeated if done outside this study for sub-study assignment.
5. Patients must not have a known EGFR mutation or ALK fusion.
6. Patients must have Zubrod performance status ≤ 2 (see Section 10.4) documented within 28 days prior to screening/pre-screening registration.
7. Patients must be ≥ 18 years of age.
8. Patients must also be offered participation in banking for future use of specimens as described in Section 15.0.
9. Patients must be willing to provide prior smoking history as required on the S1400 Onstudy Form.
10. 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.

Sub-study Registration (Common Eligibility Criteria for all Sub-Studies)

For patients screened at progression on prior treatment, a sub-study assignment from the SWOG Statistical Center should be received within 16 days of Screening Registration. For patients pre-screened prior to progression on first-line therapy, submission of the S1400 Notice of Progression on First-Line Therapy Form is required to receive a sub-study assignment. The sub-study assignment should be received from the SWOG Statistical Center within 1 day of submission of the S1400 Notice of Progression on First-Line Therapy (provided at least 16 days have passed since the screening registration). Patients must then register to the assigned sub-study in order to receive their treatment randomization assignment. Patient must meet the eligibility criteria in Section 5.2 as well as any additional criteria listed in Section 5.0 of the assigned sub-study. If patient does not meet the additional criteria listed in Section 5.0 of the assigned sub-study, submit the S1400 Request for Sub-Study Reassignment Form. (See Section 18.1a for biomarker reporting.)

1. 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 per table in the protocol.
2. Patients must not have received radiation therapy within 28 days prior to the assigned sub-study registration.
3. Patients must not have received any prior systemic chemotherapy 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 must be completed ≥ 14 days prior to sub-study registration.
4. 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.
5. 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.
6. Patient must have fully recovered from the effects of surgery prior to sub-study registration.
7. 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.
8. 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.
9. 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).
10. Patients must have a serum creatinine ≤ the IULN OR measured or calculated creatinine clearance ≥ 50 cc/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.
11. Patients must have Zubrod performance status ≤ 2 (see Section 10.4) documented within 28 days prior to sub-study registration.
12. 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).
13. Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection.
14. Patients with a known history of HIV seropositivity:
    • Must have undetectable viral load using standard HIV assays in clinical practice.
    • Must have CD4 count ≥ 400/mcL.
    • Must not require prophylaxis for any opportunistic infections (i.e., fungal, mAC, or 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.
15. 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.
16. 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.
17. 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.
18. 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).

Exclusion Criteria

Exclusion Criteria Not Available