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swog cancer research network

TITLE
LUNGMAP, A MASTER PROTOCOL TO EVALUATE BIOMARKER-DRIVEN THERAPIES AND
IMMUNOTHERAPIES IN PREVIOUSLY-TREATED NON-SMALL CELL LUNG CANCER (LUNG-MAP
SCREENING STUDY)
S1900C, A PHASE II STUDY OF TALAZOPARIB PLUS AVELUMAB IN PATIENTS WITH STAGE IV
OR RECURRENT NON-SQUAMOUS NON-SMALL CELL LUNG CANCER BEARING PATHOGENIC
STK11 GENOMIC ALTERATIONS (LUNG-MAP SUB-STUDY)
NCT\#04173507 This is an **FDA Registration Trial. Additional site requirements include:**
- maintenance of a Trial Master File (https://www.swog.org/sites/default/files/docs/201710/Guidance%20on%20FDA%20Inspection.pdf )
- completion of a protocol specific Delegation of Task Log (DTL) (see **Section 13.2)**
- additional monitoring (see LUNGMAP **Appendix 18.2)**
LUNGMAP and its sub-studies are being conducted under SWOG IND 143217 and CIRB. The LUNGMAP study is considered a single study under one IND, consisting of the screening protocol and multiple sub-studies. Each sub-study protocol operates independently and has its own version date. For CIRB Continuing Reviews, LUNGMAP **and its sub-studies will be processed**
separately but have the same expiration date as the LUNGMAP screening protocol.
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sub-study chairs

Ferdinandos Skoulidis, M.D., Ph.D., MRCP
NCTN Group: SWOG
UT/MD Anderson Cancer Center 1400 Holcombe Boulevard Houston, Texas 77030 Phone: 713/792-6363 Fax: 713/792-1221 E-mail: FSkoulidis@mdanderson.org Jennifer Marie Suga, M.D., MPH
NCTN Group: SWOG
Kaiser Permanente Cancer Research Center 975 Sereno Drive Vallejo, CA 94589 Phone: 707/651-1077 Fax: 707-651-2798 E-mail: Jennifer.M.Suga@kp.org
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biostatisticians

Mary Redman, Ph.D.  
 Katherine Minichiello, M.S.  
SWOG Statistic & Data Management Center 1100 Fairview Ave N, M3-C102 Seattle, WA 98109-1024 Phone: 206/667-4623 FAX: 206/667-4408 E-mail: mredman@fredhutch.org E-mail: kmini@fredhutch.org  
  
  
| U.S.-Only Participants:                                                                        |
|------------------------------------------------------------------------------------------------|
| ALLIANCE/Alliance for Clinical Trials in Oncology                                              |
| ECOG-ACRIN/ECOG-ACRIN Cancer Research Group NRG/NRG Oncology SWOG/SWOG Cancer Research Network |  
Page 3  
  
| TABLE OF CONTENTS                                                                                                                                               |                                                                                                                                                                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TITLE                                                                                                                                                           | ..                                                                                                                                                                     |
| TABLE OF CONTENTS                                                                                                                                               |                                                                                                                                                                        |
| PROTOCOL CONTACT INFORMATION                                                                                                                                    |                                                                                                                                                                        |
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION .........................6                                                                    |                                                                                                                                                                        |
| SCHEMA                                                                                                                                                          |                                                                                                                                                                        |
| 1.0                                                                                                                                                             | OBJECTIVES .                                                                                                                                                           |
| 1.1                                                                                                                                                             | Primary Objectives .                                                                                                                                                   |
| 1.2                                                                                                                                                             | Secondary Objectives ................................................................................................................................................8 |
| Translational Medicine Objectives ............................................................................................................................8 |                                                                                                                                                                        |
| 1.3                                                                                                                                                             |                                                                                                                                                                        |
| 2.0                                                                                                                                                             | BACKGROUND                                                                                                                                                             |
| 2.1                                                                                                                                                             | Rationale for Biomarker and Drug Selection ............................................................................................................8               |
| 2.2                                                                                                                                                             | Rationale for Inclusion in Lung-MAP                                                                                                                                    |
| 2.3                                                                                                                                                             | Study Design .                                                                                                                                                         |
| 2.4                                                                                                                                                             | RATIONALE                                                                                                                                                              |
| 2.5                                                                                                                                                             | DATA                                                                                                                                                                   |
| 2.6                                                                                                                                                             | Inclusion of Women and Minorities and Planned Enrollment Report ........................................................13                                             |
| 3.0                                                                                                                                                             | DRUG INFORMATION .                                                                                                                                                     |
| Talazoparib (PF-06944076) (NSC 771561) (IND143217) .                                                                                                            |                                                                                                                                                                        |
| 3.1                                                                                                                                                             |                                                                                                                                                                        |
| 3.2                                                                                                                                                             | Avelumab (MSB0010718C; Bavencio®) (NSC 799232) (IND 143217) ....................................................19                                                     |
| 3.3                                                                                                                                                             | NCI-Supplied Agent Ordering and Agent Accountability .                                                                                                                 |
| 4.0                                                                                                                                                             | STAGING CRITERIA                                                                                                                                                       |
| 5.0                                                                                                                                                             | ELIGIBILITY CRITERIA .                                                                                                                                                 |
| 5.1                                                                                                                                                             | Disease Related Criteria .                                                                                                                                             |
| 5.2                                                                                                                                                             | Prior/Concurrent Therapy Criteria                                                                                                                                      |
| 5.3                                                                                                                                                             | Clinical/Laboratory Criteria                                                                                                                                           |
| 5.4                                                                                                                                                             | Specimen Submission Criteria .                                                                                                                                         |
| 5.5                                                                                                                                                             | Regulatory Criteria                                                                                                                                                    |
| 6.0                                                                                                                                                             | STRATIFICATION FACTORS                                                                                                                                                 |
| 7.0                                                                                                                                                             | TREATMENT PLAN .                                                                                                                                                       |
| 7.1                                                                                                                                                             | Precautions                                                                                                                                                            |
| 7.2                                                                                                                                                             | Pre-Medication and Supportive Care .                                                                                                                                   |
| 7.3                                                                                                                                                             | D Disease Assessment .                                                                                                                                                 |
| 7.4                                                                                                                                                             | T Treatment - S1900C .                                                                                                                                                 |
| 7.5                                                                                                                                                             | Drug Compliance Documentation                                                                                                                                          |
| 7.6                                                                                                                                                             | Criteria for Removal from Protocol Treatment .                                                                                                                         |
| 7.7                                                                                                                                                             | Discontinuation of Treatment .                                                                                                                                         |
| 7.8                                                                                                                                                             | Follow-Up Period                                                                                                                                                       |
| TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS                                                                                                               |                                                                                                                                                                        |
| 8.0                                                                                                                                                             |                                                                                                                                                                        |
| 8.1                                                                                                                                                             | NCI Common Terminology Criteria for Adverse Events .                                                                                                                   |
| 8.2                                                                                                                                                             | General Considerations .                                                                                                                                               |
| 8.3                                                                                                                                                             | Dose Interruptions - Avelumab                                                                                                                                          |
| 8.4                                                                                                                                                             | Dose Modifications - Talazoparib                                                                                                                                       |
| 8.5                                                                                                                                                             | Dose Modification Contacts .......................................................................................................................46                   |
| 8.6                                                                                                                                                             | Adverse Event Reporting Requirements                                                                                                                                   |
| 8.7                                                                                                                                                             | Serious Adverse Event Reporting Requirements .................................................................................47                                       |
| 9.0                                                                                                                                                             | STUDY CALENDAR                                                                                                                                                         |
| 9.1                                                                                                                                                             | Talazoparib and Avelumab .                                                                                                                                             |
| 10.0                                                                                                                                                            | CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS                                                                                                                          |
| 10.1                                                                                                                                                            | Measurability of Lesions                                                                                                                                               |
| 10.2                                                                                                                                                            | Objective Status at Each Disease Evaluation                                                                                                                            |
| 10.3                                                                                                                                                            | Best Response                                                                                                                                                          |
| 10.4                                                                                                                                                            | Performance Status .                                                                                                                                                   |
| 10.5                                                                                                                                                            | Time to Death                                                                                                                                                          |
| Investigator-Assessed Progression-Free Survival                                                                                                                 |                                                                                                                                                                        |
| 10.6                                                                                                                                                            | Progression-Free Survival by Central Review                                                                                                                            |
| 10.7                                                                                                                                                            |                                                                                                                                                                        |  
| S1900C                                                                                                                                                          |                                                                                                                                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Page 4                                                                                                                                                          |                                                                                                                                                           |
| Version Date 4/7/21                                                                                                                                             |                                                                                                                                                           |
| 10.8                                                                                                                                                            | Duration of Response (DoR)                                                                                                                                |
| 10.9                                                                                                                                                            | Disease Control Rate at 12 Weeks (DCR12) .                                                                                                                |
| 1.0                                                                                                                                                             | STATISTICAL CONSIDERATIONS .                                                                                                                              |
| 11.1                                                                                                                                                            | Sample Size with Power Justification .                                                                                                                    |
| 12.0                                                                                                                                                            | DISCIPLINE REVIEW                                                                                                                                         |
| 12.1                                                                                                                                                            | Radiology Review .                                                                                                                                        |
| 13.0                                                                                                                                                            | REGISTRATION GUIDELINES                                                                                                                                   |
| 13.1                                                                                                                                                            | Registration Timing                                                                                                                                       |
| ..                                                                                                                                                              |                                                                                                                                                           |
| 13.2                                                                                                                                                            |                                                                                                                                                           |
| 14.0                                                                                                                                                            |                                                                                                                                                           |
| 14.1                                                                                                                                                            | Data Submission Requirement ...........................................................................................................................63 |
| Master Forms .                                                                                                                                                  |                                                                                                                                                           |
| 14.2                                                                                                                                                            |                                                                                                                                                           |
| 14.3                                                                                                                                                            | Data Submission Procedures ..........................................................................................................................63   |
| 14.4                                                                                                                                                            | Data Submission Overview and Timepoints ..............................................................................................65                  |
| 15.0                                                                                                                                                            | SPECIAL INSTRUCTIONS                                                                                                                                      |
| 15.1                                                                                                                                                            | Specimen Flow Diagram                                                                                                                                     |
| 15.2                                                                                                                                                            | SWOG Specimen Tracking System (STS) .................................................................................................67                   |
| 15.3                                                                                                                                                            | LUNGMAP ctDNA Assay - Peripheral Whole Blood ( REQUIRED FOR PATIENTS ) .....................67                                                            |
| 15.4                                                                                                                                                            | Translational Medicine and Banking ( OPTIONAL FOR PATIENT ) .......................................................69                                     |
| 15.5                                                                                                                                                            | RADIOLOGY REVIEW (REQUIRED)                                                                                                                               |
| 16.0                                                                                                                                                            | ETHICAL AND REGULATORY CONSIDERATIONS                                                                                                                     |
| 17.0                                                                                                                                                            | BIBLIOGRAPHY                                                                                                                                              |
| 18.0                                                                                                                                                            | A APPENDIX                                                                                                                                                |
| New York Heart Association Classification ...............................................................................................78                     |                                                                                                                                                           |
| 18.1                                                                                                                                                            |                                                                                                                                                           |
| 18.2                                                                                                                                                            | Monitoring Plan                                                                                                                                           |
| 18.3                                                                                                                                                            | Instructions for the SWOG Biospecimen Bank ...............................................................................................80              |
| Patient Diary - Talazoparib      SWOG Study: S1900C .........................................................................................................84 |                                                                                                                                                           |
| 18.4                                                                                                                                                            |                                                                                                                                                           |
| 18.5                                                                                                                                                            |                                                                                                                                                           |
| 18.6                                                                                                                                                            | Site Temperature Excursion Report Form ........................................................................................................86         |
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protocol contact information

| Patient Advocate:                                                                                                          | Judy Johnson, MBA E-mail: judyjohnson.519@gmail.com Phone: 314/477-6139                          |                                     |
|----------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|-------------------------------------|
| Eligibility, RAVE, Data Submission:                                                                                        | SWOG Statistics and Data Management Center  E-mail: LUNGMAPquestion@crab.org Phone: 206/652-2267 |                                     |
| Regulatory, Protocol, Informed Consent:                                                                                    | SWOG Operations Office  E-mail: protocols@swog.org Phone: 210/614-8808                           |                                     |
| Medical Queries                                                                                                            | (treatment or toxicity related                                                                   | E-mail: S1900CMedicalQuery@swog.org |
| questions): Investigational Drug questions:                                                                                | See Protocol Section 3.0                                                                         |                                     |
| Requests for Investigator's Brochures: Temperature Excursion Reports:                                                      | GCSTempExcursionSupport@pfizer.com                                                               |                                     |
| Specimen Tracking System (STS) Amendments,  Errors, Connectivity Issues and Technical issues  with the SWOG CRA Workbench: | technicalquestion@crab.org                                                                       |                                     |
| Foundation Medicine, Inc.                                                                                                  | (for ordering ctDNA                                                                              | FMI Client Services                 |
| blood collection kits only):                                                                                               | E-mail: lung.map@FoundationMedicine.com Phone: 1-888/988-3639                                    |                                     |
| Cancer Therapy and Evaluation Program -                                                                                    | To review CTEP-IAM account (new requests,                                                        |                                     |
| Identity and Access Management (CTEP-IAM):                                                                                 | reset passwords): https://ctepcore.nci.nih.gov/iam/index.jsp                                     |                                     |
| Access to iMedidata Rave or Delegation of Task                                                                             | See Protocol Section 14.3 or contact                                                             |                                     |
| Log (DTL):                                                                                                                 | CTSU Help Desk: Phone: 1-888-823-5923 or Email:  ctsucontact@westat.com                          |                                     |
| Questions related to                                                                                                       | See LUNGMAP Protocol Section 13.2 or contact                                                     |                                     |
| Oncology Patient Enrollment Network (OPEN):                                                                                | CTSU Help Desk: Phone: 1-888-823-5923 or Email:  ctsucontact@westat.com                          |                                     |
| Patient Transfers:                                                                                                         | patienttransfer@crab.org                                                                         |                                     |
| TRIAD installations:                                                                                                       | https://triadinstall.acr.org/triadclient/ Questions: TRIAD-Support@acr.org                       |                                     |
| Adverse Event Reporting questions:                                                                                         | See Section 8.6 E-mail: adr@swog.org                                                             |                                     |  
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION CONTACT INFORMATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                        |                                                                                                                                                                   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| For regulatory requirements:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | For patient enrollments:                                                                                                                                                                                               | For data submission:                                                                                                                                              |
| Regulatory documentation must  be submitted to the CTSU via the Regulatory Submission  Portal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Refer to the patient enrollment  section of the protocol for  instructions on using the  Oncology Patient Enrollment  Network (OPEN). OPEN is accessed at  https://www.ctsu.org/OPEN_SYS TEM/or https://OPEN.ctsu.org. | Data collection for this study will  be done exclusively through  Medidata Rave. Refer to the  data submission section of the  protocol for further instructions. |
| (Sign in at www.ctsu.org, and  select the Regulatory >  Regulatory Submission.) Institutions with patients waiting  that are unable to use the Portal  should alert the CTSU  Regulatory Office immediately  at 1-866-651-2878 to receive  further instruction and support.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Contact the CTSU Help Desk with  any OPEN-related questions by  phone or email : 1-888-823-5923,  or ctsucontact@westat.com.                                                                                           |                                                                                                                                                                   |
| Contact the CTSU Regulatory  Help Desk at 1-866-651-2878  for regulatory assistance. The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific page located on the CTSU members' website(https://www.ctsu.org). Access  to the CTSU members' website is managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-IAM  username and password. For patient eligibility or data submission questions contact the SWOG Statistics and Data  Management Center (SDMC) by phone or email: 206/652-2267 LUNGMAPQuestion@crab.org For treatment or toxicity related questions contact S1900CMedicalQuery@swog.org. For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data  submission) Contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line - 1-888-823-5923, or ctsucontact@westat.com. All calls and  correspondence will be triaged to the appropriate CTSU representative. |                                                                                                                                                                                                                        |                                                                                                                                                                   |
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lungmap registration a

Common Broad Platform CLIA Biomarker Profiling b Non-Squamous with pathogenic STK11 *genomic alterations* c
schema
s1900c registration

Talazoparib plus Avelumab Off Protocol Treatment Reasons Met d  
  
a. See **LUNGMAP** Section 5.1 for registration information.  
b. Notification of sub-study assignment will be provided by the SWOG Statistics and Data Management Center (SDMC) (see **LUNGMAP** Section 11.0 for details).  
c. See **S1900C** Section 5.1 for the definition of eligible *STK11* genomic alterations by Foundation Medicine Inc. criteria.  
d. Upon progression (as defined in Section 10.2), patients may be eligible for another sub-study. The new sub-study assignment will be determined by the SWOG SDMC (see Section 14.4).
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1.0 objectives

1.1 Primary Objectives  
a. To evaluate the objective response rate (ORR) (confirmed and unconfirmed, complete and partial) with talazoparib plus avelumab in patients with Stage IV or recurrent non-squamous non-small cell lung cancer bearing pathogenic *STK11* genomic alterations that were previously-treated with anti-PD-1/PD-L1 therapy and platinum-based chemotherapy.  
b. To evaluate disease control rate at 12 weeks (DCR12) after registration.
1.2 Secondary Objectives a. To evaluate investigator assessed progression-free survival (IA-PFS).  
b. To evaluate overall survival (OS). c. To evaluate duration of response (DOR) among responders.
d. To evaluate the frequency and severity of toxicities.  
1.3 Translational Medicine Objectives  
a. To collect, process, and bank cell-free DNA (cfDNA) at baseline, Cycle 3 Day 1, progression, and end of treatment for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA) and examine molecular mechanisms of resistance to talazoparib and avelumab.
Note: The translational medicine proposal to use these specimens will be submitted as a revision to CTEP for approval, prior to SDMC review of assay results.  
b. To establish a tissue/blood repository from patients with refractory non-small cell lung cancer (NSCLC).  
c. To evaluate clinical outcomes (ORR, IA-PFS, OS) in patients with concurrent somatic mutations in *KEAP1* detected on the Foundation Medicine Inc. (FMI) panel from the **LUNGMAP** screening protocol.  
d. To evaluate clinical outcomes (ORR, IA-PFS, OS) in patients with concurrent mutations in ATM or other DNA damage response genes detected on the FMI
panel from the **LUNGMAP** screening protocol.  
e. To evaluate the association between tumor mutational burden (TMB) measured on the FMI panel from the **LUNGMAP** screening protocol and clinical outcomes
(ORR, IA-PFS, OS).
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2.0 background

2.1 Rationale for Biomarker and Drug Selection Inactivating genomic alterations in the *STK11* tumor suppressor gene represent one of the  
  
most common somatic genetic events in non-small cell lung cancer (NSCLC) (17% of all lung adenocarcinomas-LUAC) and frequently co-occur with mutant *KRAS* (~25% of all KRAS-mutant NSCLC harbor *STK11* co-mutations). (1*,2) STK11* encodes *LKB1*, a serine threonine kinase with an established role in the regulation of cellular growth, metabolism and polarity through phosphorylation of AMP-activated protein kinase (AMPK) and 14 AMPK-related kinases (ARKs). (3) *STK11* somatic mutations are typically spread across the *STK11* gene without major hotspots, and are, in their vast majority, inactivating. *(4,5)* Loss of function genomic alterations in *STK11* (non-synonymous mutations or bi-allelic loss) have been previously identified as a major determinant of primary resistance to PD1/PD-L1 axis blockade in *KRAS*-mutant NSCLC and more broadly among non-squamous non-small cell lung cancer regardless of *KRAS* status. *(6,7,8, 9)* Loss of *STK11* is associated with establishment of a "cold", non-T-cell inflamed tumor immune microenvironment with low density of infiltrating CD8+ lymphocytes and low expression of PD-L1 on tumor cells. *(10,11,12,13)* Importantly, establishment of an inert tumor immune microenvironment in *STK11*-deficient NSCLC occurs despite the presence of intermediate or high tumor mutation burden. *(14,15,16)* It is also notable that the PD-1 inhibitor recalcitrant phenotype of *STK11* somatic genomic alterations extends to PD-L1 positive (PD-L1 tumor proportion score ≥1%) non-squamous non-small cell lung cancer, and is therefore at least partially independent of PD-L1 status. *(17)* In immune-competent murine models of non-small cell lung cancer (syngeneic as well as genetically engineered murine models) loss of *STK11* directly promotes PD-1 inhibitor resistance, supporting a causal effect. *(18,19)* Thus, *STK11*-deficient NSCLC represents a prevalent, molecularly-defined subgroup of NSCLC with *de novo* resistance to PD-1/PD-L1 inhibitor monotherapy, despite the presence of intermediate or high tumor mutation burden. More recently, *STK11* genomic alterations were also associated with worse clinical outcomes with pemetrexed/carboplatin (or cisplatin)/pembrolizumab. In addition, *STK11*-mutant patients harboring co-mutations in *KEAP1* exhibited lower ORR and shorter PFS and OS with chemo-immunotherapy. These findings support focused clinical efforts to identify rational combination therapeutic strategies aimed at re-establishing effective anti-tumor immunity in *STK11*-deficient tumors.
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the rationale for combining parp-inhibitors

There is compelling rationale for combining PARP inhibitors with PD-1/PD-L1 inhibitors in order to enhance anti-tumor immune responses. Recent work in small cell lung cancer demonstrated that treatment with the PARP inhibitor olaparib can significantly potentiate the anti-tumor effect of PD-L1 blockade and trigger dramatic and sustained tumor regressions in immune competent animal models of small cell lung cancer. *(20)* Critically, the impressive clinical activity of combination therapy occurred despite the lack of significant anti-tumor activity of each individual agent, suggesting that sensitization to antiPD-L1 therapy occurs as a result of the therapeutic combination. In agreement with this, combination therapy - but not each treatment alone - increased the densities of infiltrating CD3+ and CD8+ T lymphocytes. Notably, PARP inhibitor therapy resulted in increased tumor PD-L1 expression. *(21)*
Mechanistically, exposure to olaparib activates the STING/TBK1/IRF3 innate immune  
 pathway that responds to cytosolic DNA. (22, *23, 24)* Engagement of innate immune signaling leads to increased tumor cell expression of PD-L1 and production of IFNβ that promotes a type I interferon response. Importantly, activation of innate immune signaling results in the production of increased levels of CCL5 and CXCL10, chemokines that mediate the recruitment and activation of cytotoxic T lymphocytes. *(25)* Thus, engagement of innate immune signaling pathways mediates the profound synergy between olaparib and anti-PD-L1 therapy. In addition to promoting activation of the STING/TBK1/IRF3 pathway, DNA damage can further promote increased antigen presentation and increased expression of natural killer cell ligands (for example NKG2D), thus providing additional, non-mutually exclusive pathways through which PARP inhibition may synergize with PD1/PD-L1 blockade. *(26)*
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pre-clinical evidence of parp inhibitor

There is direct experimental evidence that *STK11*-deficient NSCLC cell lines are selectively sensitive to talazoparib and engage innate immune signaling following exposure to modest talazoparib concentrations. In order to assess the impact of *STK11* status on sensitivity to talazoparib in NSCLC, four previously established *STK11* proficient/deficient NSCLC pairs were utilized by re-introducing full-length functional *STK11* or empty vector in the H460, H2030, A549 and H23 *STK11*-mutant NSCLC lines that do not express *STK11* protein.  
(27,28) STK11-isogenic cell line pairs were then exposed to increasing concentrations of talazoparib *in vitro* for 72 hours. Strikingly, *STK11*-deficient derivatives of all four NSCLC lines (referred to as Control) were more sensitive to talazoparib compared with their *STK11* proficient counterparts (referred to as *LKB1* OE) that were resistant to talazoparib (Figure 1). These results suggest that in NSCLC cell lines, sensitivity to talazoparib is at least partially dependent on *STK11* status. Critically, exposure of the four *STK11*-deficient NSCLC cell lines (A549, H460, H2030 and H23) to low concentrations of talazoparib (50nM-100nM) for 48 hours resulted in elevated levels of phospho-TBK1 Ser172 protein, indicating that PARP inhibition engages innate immune signaling in this context (Figure 2).  
Thus, there is direct experimental evidence that exposure to talazoparib can result in immune pathway activation in *STK11*-deficient NSCLC cell lines. These results suggest that *STK11*-mutant NSCLC may be particularly amenable to combination therapy with talazoparib and avelumab. These results are further supported by work from other groups that showed that *STK11* deficiency is associated with sensitivity to different PARP inhibitors (29), as well as to genetic and pharmacological inhibition of CHK1 *(30,31)* and pharmacological inhibition of the WEE1 kinase. *(32)* In addition, it was recently reported that *STK11* protein is recruited to sites of double-strand DNA breaks (marked by accumulation of ɣH2AX) upon genotoxic stress and plays a role in the regulation of BRCA1 expression through a post-transcriptional mechanism. *(33)* Thus, it has been postulated that *STK11* may exert a more direct role in the DNA damage response which may underpin the enhanced sensitivity of *STK11*-deficient NSCLC cell to PARP inhibitors.  
Taken together these findings constitute rationale for combination therapy with PARP  
 inhibitors and checkpoint inhibitor blockade to overcome the intrinsic resistance of *STK11*- mutant NSCLC to PD-1/PD-L1 inhibitor monotherapy.  
  
Figure 1. Sensitivity of NSCLC cell lines to talazoparib is at least partially dependent on *STK11* **status.**  
  
  
Dose response curves of four *STK11* deficient /proficient isogenic non-small cell lung cancer cell line pairs to the PARP1 inhibitor talazoparib. Cell viability was measured after exposure to the indicated concentrations of talazoparib for 120 hours using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc). Note that in each of the four isogenic pairs *STK11* deficiency is associated with increased sensitivity to talazoparib, whereas re-introduction of full-length *STK11* **confers resistance.**
Figure 2. Engagement of innate immune signaling following exposure to talazoparib in *STK11***-mutant**
NSCLC cell lines. Immunoblotting for phospho-TBK1 (Ser172), a marker of innate immune pathway activation following exposure to the indicated concentrations of talazoparib for 72 hours in four naturally *STK11*-deficient non-small cell lung cancer cell lines. Cleaved PARP is a marker of apoptosis and GAPDH serves as loading control. Note that exposure to modest concentrations of talazoparib results in increased expression of phospho-TBK1 in all four *STK11* deficient NSCLC cell lines. These results indicate that treatment with talazoparib results in activation of innate immune signaling in *STK11*-deficient NSCLC cell lines.  
2.2 Rationale for Inclusion in Lung-MAP
The Lung-MAP study is a master protocol for genomic screening and multi-sub-study testing of drug/biomarker combinations in a Phase II/III setting compatible with subsequent FDA approval. Genomic screening of a large patient resource provided by sites participating in the NCI National Clinical Trials Network (NCTN) identifies a series of molecular targets/biomarkers which are matched to new drugs, leading to appropriate substudy assignment and drug treatment. Each molecular target in Lung-MAP is represented by a biomarker for which there is an analytically validated diagnostic assay. This approach provides the basis for this large-scale screening/clinical registration trial with the ability to screen patients, either through genomic analysis or immunohistochemistry-based assays, with homogeneous eligibility criteria and direct them to a sub-study based on the results of screening diagnostic tests.  
Based on the results of the tumor analysis, patients will either be assigned to one of the biomarker-driven sub-studies or to a 'non-match' sub-study for patients with none of the eligibility biomarkers. The biomarker-driven sub-studies are designed around a genotypically-defined alteration in the tumor and a drug that targets it. The non-match studies are designed around an investigational agent with the potential for efficacy in a broader population. For a full description and justification of the study design, refer to the LUNGMAP Screening Protocol. Prevalence of *STK11* somatic mutations and bi-allelic loss in non-squamous non-small cell
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lung cancer

Based on data from the TCGA as well as the Foundation Medicine database, the frequency of pathogenic somatic mutations and bi-allelic deletions in *STK11* is ~17% of nonsquamous NSCLC. In view of the low prevalence of *STK11* genomic alterations in pure squamous cell lung cancer and the lack of preliminary data regarding the impact of *STK11* genomic alterations on clinical outcomes with PD-1 axis blockade in this histological subtype, patients with pure squamous non-small cell lung cancer will not be included in this study.
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2.3 study design

This is a single arm, open label signal seeking study assessing the efficacy of talazoparib plus avelumab in patients with non-squamous NSCLC with pathogenic *STK11* genomic alterations (mutations or bi-allelic deletion using the FoundationOne assay), whose disease has progressed following initiation of platinum-doublet chemotherapy and anti-PD1 or anti-PD-L1 therapy, administered concurrently or sequentially. The co-primary objectives are to evaluate the response rate and disease control rate at 12 weeks for talazoparib and avelumab among patients found to have pathogenic *STK11* genomic alterations on tumor genomic profiling using the FoundationOne assay.
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2.4 rationale

Inactivating *STK11* genomic alterations are prevalent in non-squamous NSCLC (~17%)
and constitute a major driver of primary resistance to PD-1 axis blockade, irrespective of tumor cell PD-L1 expression and tumor mutational burden. Given the high prevalence of STK11 alterations in non-squamous NSCLC, identification of rational therapeutic approaches to restore effective anti-tumor immunity in this molecular subset constitutes a major unmet clinical need. Combination of talazoparib, a potent catalytic PARP inhibitor with additional PARP trapping activity with avelumab, a fully human PD-L1 inhibitory antibody, represents a rational therapeutic strategy for this immunotherapy resistant subgroup of NSCLC. If successful, this approach has the potential to result in meaningful prolongation of overall survival and improved quality of life for non-squamous NSCLC
patients bearing *STK11* mutant tumors.
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2.5 data

Avelumab (10mg/kgr IV every 2 weeks) was compared with docetaxel for patients with  
  
Stage IIIB, IV or recurrent NSCLC and disease progression after treatment with a platinumcontaining doublet in the randomized open label JAVELIN Lung 200 Phase 3 clinical trial.  
(34) Among 529 PD-L1 positive patients (≥1% cutoff) the ORR with avelumab was 19%
compared to 12% in the docetaxel group (OR 1.76, 95% CI 1.08-2.86; P=0.011). Overall survival did not differ significantly between the two groups (mOS 11.4 months [95% CI 9.413.9] vs 10.3 months [8.5-13.0]; HR 0.90 [96% CI 0.72-1.12]; one sided P=0.16). Avelumab was overall well tolerated with grade 3-5 adverse events observed in 10% of avelumabtreated patients. In the avelumab group, the most common treatment-related adverse events (All grade) were infusion-related reactions (17%) and decreased appetite (9%) and the most common grade 3 or worse treatment-related adverse events were infusion-related reaction (2%) and increased lipase (1%). Talazoparib was evaluated in the first-in-human multicenter Phase I study NCT01286897 consisting of a dose-escalation (Part 1) cohort in patients with solid tumors and a dose expansion (Part 2) cohort in patients with tumors predicted to be potentially sensitive to PARP inhibition, including patients with germline pathogenic BRCA1/2 mutations; triplenegative breast cancer; high grade serous papillary and/or undifferentiated ovarian, fallopian tube or peritoneal cancers; castration-resistant prostate and pancreatic cancers, Ewing's sarcoma and small cell lung cancer. *(35)* The MTD and RP2D was determined to be 1 mg/day, with an elimination half-life of 50 hours. The most common G3/G4 treatmentrelated adverse events were anemia (24%), thrombocytopenia (18%) and neutropenia
(10%). Among 23 patients with small cell lung cancer enrolled in the dose expansion cohort and treated with 1 mg/day of talazoparib the ORR was 9% and the clinical benefit rate
(defined as PR/CR + SD lasting ≥16 weeks) was 26%.  
The combination of avelumab plus talazoparib is being evaluated in the open-label phase 1b/2 JAVELIN PARP Medley (B9991025, NCT03330405) clinical trial in ~316 PD-1/PD-L1 inhibitor- naïve patients with selected solid tumors, including patients with NSCLC.  
Different daily doses of talazoparib plus avelumab at a fixed dose of 800mg IV Q2W are administered during the Phase 1b to define the RP2D for the combination. As of May 18, 2018 among 12 patients enrolled at dose level D0 (talazoparib 1.0mg PO QD, avelumab 800mg IV Q2W) in 3 sequential cohorts (n=9 CRPC; n=2 TNBC, n=1 ovarian cancer) that completed the DLT monitoring period and were evaluable for DLT only 1 SAE of anemia was reported, with no G3 AEs other than hematologic toxicities and no Grade 4-5 AEs.  
Therefore, the RP2D for the talazoparib/avelumab combination was talazoparib 1 mg PO
QD days 1-28 and avelumab 800mg IV Q2W. Phase 2 enrollment opened on June 01, 2018 and is ongoing (communication with Pfizer).
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2.6 inclusion of women and

This study was designed to include women and minorities but was not designed to measure  
  
differences of intervention effects. The anticipated accrual in the ethnicity/race and sex categories is shown in the table below.  
| DOMESTIC PLANNED ENROLLMENT REPORT Ethnic Categories   |                    |        |      |    |    |
|--------------------------------------------------------|--------------------|--------|------|----|----|
| Not Hispanic or Latino                                 | Hispanic or Latino | Total  |      |    |    |
| Female                                                 | Male               | Female | Male |    |    |
| American  Indian/                                      | 0                  | 0      | 0    | 0  | 0  |
| Alaska Native Racial  Categories Asian                 | 0                  | 1      | 0    | 0  | 1  |
| Native  Hawaiian or                                    | 0                  | 0      | 0    | 0  | 0  |
| Other Pacific  Islander Black or  African              | 1                  | 2      | 0    | 0  | 3  |
| American White                                         | 17                 | 21     | 1    | 1  | 40 |
| More Than  One Race                                    | 0                  | 0      | 0    | 0  | 0  |
| Total                                                  | 18                 | 24     | 1    | 1  | 44 |
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3.0 drug information investigator brochures

For information regarding Investigator Brochures, please refer to SWOG Policy 15. For this sub-study, talazoparib and avelumab are investigational and are being provided under an IND held by SWOG. For INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of the protocol. In such instances submission of the protocol to the IRB should suffice for providing the IRB with information about the drug. However, in cases where the IRB
insists on having the official Investigator's Brochure from the company, requests may be submitted to the CTSU website by completing the CTSU Request for Clinical Brochure.  
3.1 Talazoparib (PF-06944076) (NSC 771561) (IND143217)
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a. pharmacology

Mechanism of Action: Talazoparib is a highly potent and specific inhibitor of PARP1 and 2 with activity in tumor cell lines bearing DNA repair deficiencies.  
Treatment with a PARP inhibitor results in cell cycle arrest and apoptosis.
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b. pharmacokinetics

1. Absorption: Absorption of talazoparib is rapid and peak concentrations were generally achieved 1 to 8 hours post dose. At steady state, the mean Cmax was 21 ng/mL, the mean plasma trough concentration (Cmin) was 3.72 ng/mL, the mean AUC was 202 ng●h/mL, and the mean peak-totrough ratio was approximately 6 hours. Food delays absorption of talazoparib but has no effect on the extent of absorption.  
2. Distribution: Protein binding of talazoparib is 78.7% in human plasma. The apparent volume of distribution (V/F) decreases with increasing doses. At 1000 mcg/day, the mean V/F is 415 L. After repeated administration at
1000 mcg/day, talazoparib accumulated approximately 2.4-fold relative to a single dose.  
3. Metabolism: Overall, talazoparib is largely cleared via excretion of unchanged parent drug and metabolized to a minor extent via oxidation and dehydrogenation.  
4. Elimination: Elimination follows biphasic kinetics, with a mean half-life ranging from 52.9 to 229 hours. Renal excretion is a major elimination pathway for unchanged parent talazoparib. Following oral administration, 44 to 90.6% of the dose was recovered in the urine as unchanged parent drug.
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c. adverse effects

1. Adverse Effects:
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE)
associated with an agent using a uniform presentation of events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 553 patients. Below is the CAEPR for Talazoparib (MDV3800, BMN 673).  
| Version 2.4, October 24, 20201                                                                                                                                                                                                                                                                 |                     |                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Adverse Events with Possible                                                                                                                                                                                                                                                                   |                     |                        |
| Relationship to Talazoparib (MDV3800, BMN 673) (CTCAE 5.0 Term) [n= 553]                                                                                                                                                                                                                       |                     |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                  | Less Likely (<=20%) | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                                                                                                                                                                                                                                    | Febrile neutropenia |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain Constipation Diarrhea Dyspepsia Mucositis oral Nausea Vomiting GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Fever Pain INFECTIONS AND INFESTATIONS Infection2 INVESTIGATIONS Lymphocyte count  decreased Neutrophil count  decreased |                     |                        |  
| Relationship to Talazoparib (MDV3800, BMN 673) (CTCAE 5.0 Term) [n= 553]                                                                                                                                                                                                                                                    |                             |                        |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|------------------------|
| Likely (>20%)                                                                                                                                                                                                                                                                                                               | Less Likely (<=20%)         | Rare but Serious (<3%) |
| Platelet count  decreased                                                                                                                                                                                                                                                                                                   | White blood cell  decreased |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND  POLYPS) Leukemia secondary to  oncology chemotherapy Myelodysplastic  syndrome Treatment related  secondary malignancy NERVOUS SYSTEM DISORDERS Dizziness Headache SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia |                             |                        |  
  
1This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.  
3Neuropathy peripheral may include both Peripheral sensory neuropathy and Peripheral motor neuropathy under the NERVOUS SYSTEM DISORDERS SOC. Adverse events reported on talazoparib (MDV3800, BMN 673) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that talazoparib (MDV3800, BMN 673) caused the adverse event:
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blood and lymphatic system disorders

lymphatic system disorders - Other (pancytopenia)
CARDIAC DISORDERS - Atrial flutter; Sinus bradycardia GASTROINTESTINAL DISORDERS - Abdominal distension; Flatulence; Intra-abdominal hemorrhage; Small intestinal obstruction; Toothache GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; General disorders and administration site conditions - Other (accidental overdose); Non-cardiac chest pain HEPATOBILIARY DISORDERS - Hepatic failure; Sinusoidal obstruction syndrome INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Weight loss METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hypokalemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (glioblastoma multiforme); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (metastases to meninges); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (metastatic breast cancer)
NERVOUS SYSTEM DISORDERS - Dysgeusia; Intracranial hemorrhage; Nervous system disorders - Other (neuropathy peripheral)3; Nervous system disorders - Other (nonserious axonal sensorimotor polyneuropathy); Syncope; Transient ischemic attacks PSYCHIATRIC DISORDERS - Anxiety; Insomnia; Psychiatric disorders - Other (mental status changes)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Oropharyngeal pain; Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other (obstructive airways disorder)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Rash maculo-papular VASCULAR DISORDERS - Thromboembolic event Note: Talazoparib (MDV3800, BMN 673) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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2. pregnancy and lactation

Studies in pregnant animals to evaluate the effect of talazoparib on pregnancy have not been performed. Women of childbearing potential should use highly effective contraceptive measures during and for at least 7 months after completion of treatment. Non-sterilized males who are sexually active with a female partner should use highly effective contraceptive measures during and for at least 4 months after completion of treatment. Male patients must not make sperm donations during treatment and for 4 months following the last dose of treatment. Studies in lactating animals to evaluate the effect of talazoparib have not  
  
been performed. It is not known whether talazoparib is excreted in human milk. Therefore, breastfeeding should be stopped during talazoparib treatment.  
3. Drug Interactions:
Talazoparib does not inhibit or induce CYP450 isoenzymes. Therefore, drug-drug interactions related to CYP450 inhibition or induction are unlikely to be clinically significant.  
Talazoparib is a substrate for P-gp and BCRP, and plasma talazoparib concentrations may increase or decrease when co-administered with Pgp or BCRP inhibitors or inducers, respectively. Guidelines for concomitant use of talazoparib with inhibitors or inducers of P-gp or inhibitors of BCRP are as follows:  
- Use of strong P-gp inhibitors (e.g., dronedarone, quinidine, ranolazine, verapamil, oral ketoconazole, itraconazole), P-gp inducers (e.g., rifampin, tipranavir/ritonavir), or BCRP inhibitors
(e.g., elacridar [GF120918]) should be avoided.
Caution should be used for coadministration of other P-gp inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, erythromycin, felodipine, lopinavir, quercetin), P-gp inducers (e.g., avasimibe, carbamazepine, phenytoin, St John's wort), or BCRP inhibitors (e.g., cyclosporine, eltrombopag, and gefitinib). Please note that this list is not all-inclusive. Because lists of these agents are constantly changing, it is important to regularly consult a frequently updated list for the most up-to-date listing of agents; medical reference texts such as the Physicians' Desk Reference may also provide this information.  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-developmentand-drug-interactions d. DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan.  
e. HOW SUPPLIED
1. Talazoparib is supplied by Pfizer and distributed by Pharmaceutical Management Branch (PMB).  
Talazoparib is a capsule formulation comprised of a blend of talazoparib tosylate drug substance and silicified microcrystalline cellulose filled into a hypromellose capsule. It is supplied as 1000 mcg (opaque pale-pink, size 4) and 250 mcg (opaque white, size 4) capsules supplied in 30-count highdensity polyethylene (HDPE) bottles with induction-sealed closures.
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f. storage preparation & stability

1. Store talazoparib at room temperature (15-30 ºC; 59-86 ºF). Contact Pfizer for temperature excursion information.  
If a storage temperature excursion is identified, do not use the affected  
 investigational product. The investigational product must be stored separately in an appropriate location pending the final disposition decision. Return the investigational product that underwent the temperature excursion in the appropriate storage conditions and quarantine until a suitable determination is made. In case of temperature excursion at the site outside of storage range, complete the Site Temperature Excursion Report Form (see Appendix 18.6) and email to GCSTempExcursionSupport@pfizer.com. In the email correspondence, reference the Pfizer tracking number for this study: WI247821.  
Talazoparib is considered a cytotoxic agent; precautions regarding appropriate secure storage and handling must be used by healthcare professionals, including personal protective clothing, disposable gloves, and equipment. Patients should be advised that oral anticancer agents are toxic substances and the patient and caregivers should always use gloves when handling capsules. For additional patient instructions, see Section 7.4.  
3.2 Avelumab (MSB0010718C; Bavencio®) (NSC 799232) (IND 143217)
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a. pharmacology

Mechanism of Action: Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on antitumor CD8+ T cells, resulting in the restoration of cytotoxic T cell response.
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b. pharmacokinetics

Absorption: Avelumab is administered intravenously and is 100% bioavailable. Distribution: Avelumab is expected to be distributed in the systemic circulation and to a lesser extent into the extracellular space. In vitro studies suggest that avelumab binds to human tissues that are known for PD-L1 expression: various epithelial cell types, endothelium, mononuclear cells (including dendritic cells, lymphocytes, monocytes and macrophages), pancreatic islets, placental trophoblasts and decidual cells, smooth muscle cells, and mesenchymal stem cells. The volume of central and peripheral compartments is estimated to be 2.84L and 1.21L in the typical patient, respectively. The geometric mean Vss for a patient receiving 10mg/kg was 4.72L, which is consistent with distribution mainly limited to systemic circulation.  
Metabolism: Avelumab is degraded by proteolytic catabolism. CYP450 does not contribute to its metabolism.  
Elimination: The primary route of elimination of avelumab is through proteolytic degradation. The geometric mean clearance calculated by noncompartmental analyses [Study EMR100070-001] was estimated as 0.362mL/hr/kg for an initial 10mg/kg/dose. The corresponding value for Japanese patients [Study EMR100070-002] was calculated as 0.471mL/hr/kg at the 10mg/kg dose. The estimate of clearance obtained for a typical patient in population pharmacokinetic analysis was 0.0246 L/hr. Population pharmacokinetic analysis and noncompartmental analysis results are comparable.
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c. adverse effects

1. Adverse Effects: The Comprehensive Adverse Events and Potential Risks  
  
list (CAEPR) provides a single list of reported and/or potential adverse Page 20 Version Date 4/7/21 events (AE) associated with an agent using a uniform presentation of events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification.  
| Version 2.0, April 23, 2019 1                                                    |                                                                        |                  |
|----------------------------------------------------------------------------------|------------------------------------------------------------------------|------------------|
| Adverse Events with Possible Relationship  to Avelumab (CTCAE 5.0 Term) [n=1738] |                                                                        |                  |
| Likely                                                                           | Less Likely                                                            | Rare but Serious |
| (> 20%)                                                                          | (4 - ≤ 20%)                                                            | (≤ 3%)           |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia CARDIAC DISORDERS                    | Myocarditis2 Pericarditis2                                             |                  |
| ENDOCRINE DISORDERS                                                              | Adrenal insufficiency2 Hyperthyroidism2 Hypophysitis2 Hypopituitarism2 |                  |
| Hypothyroidism2                                                                  |                                                                        |                  |
| EYE DISORDERS                                                                    | Uveitis2                                                               |                  |
| GASTROINTESTINAL DISORDERS Abdominal pain                                        | Colitis2                                                               |                  |
| Diarrhea Nausea Pancreatitis2 Vomiting                                           |                                                                        |                  |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Fatigue Fever Flu like symptoms3 HEPATOBILIARY DISORDERS Hepatic failure2 Hepatobiliary disorders  - Other (autoimmune  hepatitis, immunerelated hepatitis)2 IMMUNE SYSTEM DISORDERS Autoimmune disorder2 Cytokine release  syndrome3 Immune system  disorders - Other  (sarcoidosis)2 INFECTIONS AND INFESTATIONS Infection4                                                                                  |                                                                        |                  |  
  
| Adverse Events with Possible Relationship  to Avelumab (CTCAE 5.0 Term) [n=1738]   |             |                  |
|------------------------------------------------------------------------------------|-------------|------------------|
| Likely                                                                             | Less Likely | Rare but Serious |
| (> 20%)                                                                            | (4 - ≤ 20%) | (≤ 3%)           |
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related reaction3 INVESTIGATIONS Alanine  aminotransferase  increased Alkaline phosphatase  increased Aspartate  aminotransferase  increased Blood bilirubin increased CPK increased Creatinine increased GGT increased Lipase increased Lymphocyte count  decreased Neutrophil count  decreased Platelet count decreased Serum amylase  increased Thyroid stimulating  hormone increased METABOLISM AND NUTRITION DISORDERS Anorexia Hyperglycemia2 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia2 Generalized muscle  weakness Muscle cramp Myalgia2 Myositis2 Pain in extremity NERVOUS SYSTEM DISORDERS Encephalopathy2 Guillian-Barre  syndrome2 Myasthenia gravis2 Nervous system  disorders - Other (noninfectious  encephalitis)2 Nervous system  disorders - Other (noninfectious meningitis)2 Peripheral motor  neuropathy Peripheral sensory  neuropathy2                                                                                    |             |                  |  
| Adverse Events with Possible Relationship  to Avelumab (CTCAE 5.0 Term) [n=1738]                                                                             |                                                                    |                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|------------------|
| Likely                                                                                                                                                       | Less Likely                                                        | Rare but Serious |
| (> 20%)                                                                                                                                                      | (4 - ≤ 20%)                                                        | (≤ 3%)           |
| RENAL AND URINARY DISORDERS                                                                                                                                  | Renal and urinary  disorders - Other  (immune related  nephritis)2 |                  |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Pneumonitis2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Eczema Pruritus Rash acneiform Rash maculo-papular |                                                                    |                  |  
1This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Immune-mediated adverse reactions have been reported in patients receiving avelumab. Adverse events potentially related to avelumab may be manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of avelumab), administration of corticosteroids and supportive care.  
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release syndrome, which have been observed following administration of avelumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately after administration of avelumab.  
4Infection includes all 75 sites of infection under the INFECTIONS AND
INFESTATIONS SOC.  
Adverse events reported on avelumab trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that avelumab caused the adverse event:
CARDIAC DISORDERS - Palpitations; Sinus tachycardia  
 EYE DISORDERS - Blurred vision; Dry eye GASTROINTESTINAL DISORDERS - Abdominal distension; Constipation; Dry mouth; Dyspepsia; Flatulence; Mucositis oral GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Localized edema; Malaise; Non-cardiac chest pain; Pain INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; Investigations - Other (c-reactive protein increased); Weight gain; Weight loss METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor flare); Tumor pain NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysgeusia; Headache; Tremor RENAL AND URINARY DISORDERS - Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension Note: Avelumab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
2. Pregnancy and Lactation: Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab. There is no information regarding the presence of avelumab in human milk, the effects on the breastfed infant or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise lactating women not to breastfeed during treatment and for at least one month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.  
3. Special Populations: No dedicated clinical studies have been conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of avelumab. Even though a limited number of patients with severe renal impairment have been studies, renal impairment is not expected to have an effect on the pharmacokinetics of avelumab. here are limited data from patients with severe hepatic impairment, and the effect of severe hepatic impairment on the pharmacokinetics of avelumab is not known.  
4. Drug Interactions: No interaction studies have been conducted with avelumab in humans.  
d. DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan.
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e. how supplied

Avelumab is supplied by Merck KGaA/EMD Serono, Inc./Pfizer and distributed by  
  
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 200 mg vials containing a sterile solution of 10 mL total volume (20 mg/ml). Avelumab is a clear and colorless to slightly yellow concentrate for solution containing Dmannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, and water for injection, and supplied in glass vials closed with a rubber (not made with natural rubber latex) stopper and sealed with an aluminum crimp seal closure fitted with a removable plastic cap.
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f. storage preparation & stability

1. Avelumab must be stored under refrigeration (2-8 C, 36-46º F) and protected from light until use. Avelumab must not be frozen. Rough shaking must be avoided during handling and preparation.
2. Prepare avelumab solution under a laminar flow hood using aseptic technique. If a laminar flow hood is not available, alternative procedures and aseptic handling techniques that prevent microbiological contamination may be used.  
3. Prior to preparation of the dilution for infusion, allow vial(s) to equilibrate to room temperature. The measured dose should be diluted with 250 mL
0.9% Sodium Chloride or 0.45% Sodium Chloride solution. Gently invert the mixture 10 times. Do not shake infusion bag in order to avoid foaming and/or excessive shearing of the protein solution. Carefully inspect the prepared dose to confirm homogeneity of the solution and that it is free of any visible particles or discoloration.  
4. Prepared solutions of avelumab should be used immediately. If not used immediately, diluted avelumab may be stored for up to 4 hours at room temperature (15C-25C) or up to 24 hours under refrigeration (2C to 8C); this includes infusion time. Note that the time interval for stability begins at the time the intact avelumab vials are removed from the refrigerator and allowed to reach room temperature for dose preparation. If finished doses are stored under refrigeration, allow the bag containing avelumab to come to room temperature.  
If a storage temperature excursion is identified, do not use the affected investigational product. The investigational product must be stored separately in an appropriate location pending the final disposition decision. In case of temperature excursion at the site outside of storage range, complete the Site Temperature Excursion Report Form (see Appendix 18.6) and email to GCSTempExcursionSupport@pfizer.com. In the email correspondence, reference the Pfizer tracking number for this study:
WI247821.  
5. No other drugs should be added to the solution of avelumab for infusion.  
6. Administer diluted avelumab solution through infusion tubing with a sterile,  
  
non-pyrogenic, low protein binding, 0.2-micron in-line filter. Do not coadminister other drugs through the same IV line.
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3.3 nci-supplied agent ordering and

NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee) at each participating institution. The CTEP assigned protocol number
(**S1900C**) must be used for ordering all CTEP supplied investigational agents. The eligible participating investigators at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution.  
Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management. No starter supplies may be ordered. Patients must be enrolled and registered to protocol S1900C prior to order submission through OAOP. Useful Links and Contacts
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Investigator Registration (RCR) Help Desk: RCRHelpDesk@nih.gov
- PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm
- PMB Online Agent Order Processing (OAOP) application:
https://ctepcore.nci.nih.gov/OAOP/
- CTEP Identity and Access Management (IAM) account:
https://ctepcore.nci.nih.gov/iam/index.jsp
- CTEP IAM account help:
ctepreghelp@ctep.nci.nih.gov
- PMB e-mail: PMBAfterHours@mail.nih.gov PMB phone and hours of service: 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) a. Drug Return and/or Disposition Instruction  
1. Drug Returns: All unused drug supplies must be returned to the PMB.  
When it is necessary to return study drug (e.g., sealed vials remaining when expired vials are recalled by the PMB), investigators should return the study drug to the PMB using the NCI Return Agent Form available on the NCI home page (http://ctep.cancer.gov).  
2. Drug Accountability: The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator in this protocol.
Questions about drug orders, transfers, returns or accountability should be addressed to  
  
the PMB by calling 240/276-6575 Monday through Friday between 8:30 am and 4:30 pm Eastern Time.
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4.0 staging criteria

Patients must have Stage IV or recurrent disease as outlined below (AJCC Cancer Staging Manual, 8th Edition, 2017):  
| Stage IVA   | Any T   | Any N   | M1a   |
|-------------|---------|---------|-------|
| Any T       | Any N   | M1b     |       |
| Stage IVB   | Any T   | Any N   | M1c   |  
Primary Tumor (T)
TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumor Tis Carcinoma in situ Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤ 3 cm in greatest dimension T1 Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)
T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤ 3 cm in greatest dimension) with a predominantly lepidic pattern and ≤ 5 mm invasion in greatest dimension T1a Tumor ≤ 1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon.  
T1b Tumor ˃ 1 cm but ≤ 2 cm in greatest dimension T1c Tumor ˃ 2 cm but ≤ 3 cm in greatest dimension T2 Tumor ˃ 3 cm but ≤ 5 cm or having any of the following features:
- Involves the main bronchus regardless of distance to the carina, but without involvement of the carina
- Invades visceral pleura (PL1 or PL2)
- Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung T2 tumors with these features are classified as T2a if ≤ 4 cm or if the size cannot be determined and T2b if ˃ 4 cm but ≤ 5 cm.  
T2a Tumor ˃ 3 cm but ≤ 4 cm in greatest dimension T2b Tumor ˃4 cm but ≤ 5 cm in greatest dimension T3 Tumor ˃ 5 cm but ≤ 7 cm in greatest dimension or directly invading any of the following:
parietal pleural (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium, or separate tumor nodule(s) in the same lobe as the primary T4 Tumor ˃ 7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary
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regional lymph nodes (n) distant

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M0 No distant metastasis  
  
M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or malignant pleural or pericardial effusion. nodules or malignant pleural (or pericardial) effusion. **
M1b Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node)
M1c Multiple extrathoracic metastases in a single organ or in multiple organs
** Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is non-bloody and is not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor.
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5.0 eligibility criteria

Each of the criteria in the following section must be met in order for a patient to be considered eligible for registration in OPEN. Section 5 may be printed and used to by the site, but is not to be uploaded in RAVE (unless specially stated). For each criterion requiring test results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0). Any potential eligibility issues should be addressed to the SWOG Statistics and Data Management Center (SDMC) in Seattle at 206/652-2267 or LUNGMAPQuestion@crab.org prior to registration. **NCI policy does not allow for waiver of any eligibility criterion** (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm).  
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28. This allows for efficient patient scheduling without exceeding the guidelines. If Day 7, 14, 16, 28, or 42 falls on a weekend or holiday, the limit may be extended to the next working day.  
5.1 Disease Related Criteria  
a. Patients must be assigned to **S1900C**. Assignment to **S1900C** is determined by the **LUNGMAP** protocol genomic profiling using the FoundationOne assay.  
Biomarker eligibility for **S1900C** is based on the identification of a pathogenic somatic mutation in STK11 or *STK11* bi-allelic loss on tumor.
b. Patients must have histologically or cytologically confirmed Stage IV or recurrent non-squamous, mixed squamous/non-squamous (e.g., adeno-squamous carcinoma), or non-small cell lung cancer not otherwise specified (NSCLC NOS).  
Patients with pure squamous cell carcinoma are not eligible.  
c. Patients with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to substudy registration.
d. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to sub-study registration.  
e. Patients with known human immunodeficiency virus (HIV) infection are eligible, provided they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to sub-study registration.  
f. Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK  
  
gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy.  
5.2 Prior/Concurrent Therapy Criteria
a. Patients must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for Stage III, IV or recurrent disease. Any number of additional, non-platinum-based chemotherapy or targeted therapy regimens for recurrent or metastatic disease are allowed.  
1. Patients may not have received more than one line of anti-PD-1 or antiPD-L1 therapy in the Stage IV or recurrent setting. Anti-PD-1 or anti-PDL1 therapy may have been given alone or in combination with platinumbased chemotherapy, an anti-CTLA4 therapy, or other immunemodulatory therapy. Patients must have experienced disease progression>42 days following initiation (Cycle 1 Day 1) of the anti-PD-1 or anti-PD-L1 containing regimen.  
2. Patients, must have received prior platinum-based chemotherapy and experienced disease progression >42 days following initiation (Cycle 1 Day 1) of platinum based chemotherapy. Note: Patients may have received this in combination with anti-PD-1 or anti-PD-L1.  
3. Patients who received anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for Stage III disease as their only line of antiPD-1 or anti-PD-L1 therapy, are eligible if they experienced disease progression less than (<) 365 days from the date of initiation of anti-PD-1 or anti-PD-L1 therapy.
b. Patients who received prior adjuvant platinum-based therapy post-surgical resection for Stage I-III disease (i.e. the patient has not received platinum-based chemotherapy for Stage IV or recurrent disease) must have had disease progression during or after platinum-based chemotherapy that occurred less than
(<) 365 days from the last date that the patient received that therapy.  
c. Patients must be able to swallow capsules whole.  
d. Patients must not have had prior exposure to any agent with a PARP inhibitor (e.g.,
veliparib, olaparib, rucaparib, niraparib, talazoparib) as its primary pharmacology.  
e. Patients must not be taking, nor plan to take while on protocol treatment strong Pgp inhibitors, P-gp inducers, or strong breast cancer resistance protein (BCRP)
inhibitors. Please refer section 3.1 c. for detailed information.  
f. Patients must have progressed (in the opinion of the treating physician) following their most recent line of therapy.
g. Patients must not have received prior systemic immunotherapy within 28 days prior  
  
to sub-study registration and must not have received any prior systemic therapy
(including 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. Patients must not have received any radiation therapy within 14 days prior to sub-study registration. (See 5.3b for criteria regarding therapy for CNS metastases).  
h. Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
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5.3 clinical/laboratory criteria

a. Patients must have measurable disease (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 sub-study registration. See Sections 15.5 and Appendix 18.2 for guidelines and submission instructions for required central radiology review. CT and MRI scans must be submitted for central review via TRIAD.  
b. 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 prior to sub-study registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study registration.  
c. Patient must not have had a major surgery within 14 days prior to sub-study registration. Patient must have fully recovered from the effects of prior surgery in the opinion of the treating investigator.
d. 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).  
e. Patients must have a serum creatinine ≤ the IULN or calculated creatinine clearance ≥ 60 mL/min using the following Cockroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study registration:
Calculated Creatinine Clearance = (140 - age) X (weight in kg) †
72 x serum creatinine* Multiply this number by 0.85 if the patient is a female. † 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 0.7 mg/ dL. Creatinine Calculator:  
 https://crawb.crab.org/TXWB/CreatinineClearanceCalculator.aspx  
f. Patients' most recent Zubrod performance status must be 0-1 (Section 10.4)
documented within 28 days prior to sub-study registration.
g. 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 (Appendix 18.1).  
h. Pre-study history and physical exam must be obtained within 28 days prior to substudy registration.  
i. 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.
j. 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.  
k. Patients must not have a history of prior organ transplantation, including allogeneic stem-cell transplantation.
l. Patients must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to sub-study registration. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.  
m. Patients must not have active autoimmune disease that requires systemic steroids
(equivalent of >10 mg of prednisone) or immunosuppressive agents within 14 days prior to sub-study registration (for example disease-modifying anti-rheumatic drugs). Exceptions include: patients with controlled type 1 diabetes mellitus, controlled hypo- or hyperthyroidism, vitiligo, resolved childhood asthma/atopy, or psoriasis not requiring immunosuppressive therapy.  
n. Patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of talazoparib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or active peptic ulcer disease). Note: peptic ulcer is considered non-active if clinically stable for 1 month.  
o. Patients must not have active small or large intestine inflammation such as Crohn's disease or ulcerative colitis within 12 months prior to sub-study registration.  
p. Patients must not have known prior or suspected hypersensitivity to monoclonal  
  
antibodies (Grade ≥3).
q. Patients must not have any history of anaphylaxis or uncontrolled asthma.  
Uncontrolled asthma is defined as a patient having any one of the following criteria:  
1. Poor symptom control: ACQ consistently >1.5 or ACT <20 (or "not well controlled" by NAEPP or GINA guidelines over the 3 months or evaluation).  
2. Frequent severe exacerbations: 2 or more bursts of systemic CSs (>3 days each) in the previous year.  
3. Serious exacerbations: at least one hospitalization, Intensive Care Unit stay or mechanical ventilation in the previous year.  
4. Airflow limitation: FEV1<80% predicted (in the presence of reduced FEV1/FVC defined as less than the normal lower limit) following a withhold of both short- and long-acting bronchodilators.
r. Patients must not have experienced any immune related adverse event ( including but not limited to pneumonitis), that led to permanent discontinuation of prior immunotherapy and/or required prolonged high dose of steroids (defined as>10mg daily prednisone or equivalent for more than 56 days (8 weeks)).  
s. Patients must not have evidence of active infection requiring systemic therapy.  
t. Patients must not have received any live attenuated vaccinations within 28 days prior to sub-study registration.
u. 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. Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to sub-study registration).  
5.4 Specimen Submission Criteria
a. Patients must agree to have blood specimens submitted for circulating tumor DNA
(ctDNA) as outlined in Section 15.3.  
b. Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens as described in Section 15.4.  
5.5 Regulatory Criteria a. 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.  
b. As a part of the OPEN registration process (**LUNGMAP** Section 13.2 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.  
c. 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). For patients with impaired decision making capabilities, legally authorized representatives may sign and give informed consent on behalf of study patient in accordance with applicable federal, local, and CIRB regulations.
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7.0 treatment plan

For treatment or dose modification questions, please contact Dr. Ferdinandos Skoulidis and Dr.  
Jennifer Marie Suga at S1900CMedicalQuery@swog.org. For dosing principles or questions, please consult the SWOG Policy \#38 "Dosing Principles for Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.
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7.1 precautions

See Section 3.0 and Appendix 18.5 for drug interactions and precautions. Patients must not receive any live attenuated vaccinations during protocol treatment.  
7.2 Pre-Medication and Supportive Care a. Pre-medication associated with standard drug administration and supportive care
(including anti-diarrheas, antibiotics, diuretics or other medications) may be given as indicated by the current American Society of Clinical Oncology (ASCO) guidelines.  
b. In order to mitigate infusion-related reactions, a premedication with an antihistamine and with acetaminophen 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg acetaminophen IV or oral). Premedication should be administered for subsequent avelumab infusions based upon clinical judgment and presence/severity of prior infusion reactions. This may be modified based on local treatment standards and guidelines, as appropriate.  
c. Small volume, low dose palliative radiotherapy (≤ 20 Gy) for painful bone metastases is permitted, provided that no target lesions are encompassed, and the patient does not have progression as defined in Section 10.0. Delaying the next dose of protocol therapy by up to two weeks is permitted.  
7.3 Disease Assessment
See Section 9.0 for disease assessment timepoints. Submit scans as outlined in Section 14.0 and Section 15.0.
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disease assessment during treatment

CT or MRI (the same method used at pre-study to meet the eligibility criteria in Section 5.3)
must be performed on week 6 (± 7 day window), week 12 (± 7 day window), and then every 8 weeks (± 7 day window) thereafter regardless of treatment delays, until discontinuation of protocol treatment. The 6 weeks should start from sub-study registration. If the patient remains on protocol treatment after progression due to clinical benefit in the opinion of the treating investigator (per Section 7.6), scans must continue per protocol schedule until treatment is discontinued.  
Pre-study Brain CT/MRI is required per Section 5.3. If patient has brain metastases at baseline, scans must use the same modality as baseline and be repeated at week 12 (± 7 days) and every 8 weeks (± 7 days) thereafter while on treatment. Disease Assessment During Off Protocol Treatment, Prior to Progression After off protocol treatment prior to progression, disease assessments should continue every 12 weeks (± 7 day window) until progression.  
If patient has brain metastases at baseline, continue brain CT or MRI scans (same modality as baseline) after off protocol treatment prior to progression, as clinically indicated. For alignment with the protocol and good clinical practice, recommended frequency of brain scans after off protocol treatment (and prior to progression) is at least every 12 weeks, unless more frequent scans are clinically appropriate.
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7.4 treatment - s1900c

| Agent                                | Dose     | Route   | Schedule *   |
|--------------------------------------|----------|---------|--------------|
| Talazoparib                          | 1000 mcg | PO      | Daily        |
| Avelumab                             | 800 mg   | IV over | Days 1 & 15  |
| 60 mins                              |          |         |              |
| * Note: One cycle = 28 calendar days |          |         |              |  
Setting: Avelumab should be administered in a setting that allows for access to and administration of therapy for anaphylaxis, such as the ability to implement immediate resuscitation measures. Steroids, epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for immediate access. Sites must have a plan to contact emergency services to provide prompt advanced life support including intubation.  
Observation period: Following avelumab infusions, patients must be observed for 30 minutes post-infusion for potential infusion-related reactions.
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patient instructions

Patients should be advised that talazoparib is a toxic substance and that patients and their caregivers should always use gloves when handling capsules.  
Patients should be instructed to swallow talazoparib capsules whole and not to chew them prior to swallowing. Talazoparib can be taken with or without food. No capsule should be ingested if it is broken, cracked, or otherwise not intact. Patients should be encouraged to take their dose at approximately the same time each day (preferably in the morning).  
Patients who miss a day's dose entirely must be instructed NOT to "make it up" the next day.  
If more than 12 hours has elapsed from usual dose time (e.g. 10am), patient should consider that day skipped, and he/she should resume treatment the next day at the usual time.  
Patients who vomit any time after taking a dose must be instructed NOT to "make it up,"  
 and to resume treatment the next day as prescribed. Patients who inadvertently take one extra dose during a day must be instructed to skip the next day's dose.  
Note: On days the patient is in-clinic, there are no study dosing order of study drugs.  
7.5 Drug Compliance Documentation
Drug compliance will be recorded by patients in the Patient Diary (see Appendix 18.4).  
Institutional CRAs will review and ascertain patient adherence with protocol therapy at the end of treatment for each cycle. The Patient Diary should be kept in the patient's research chart. All sites *must* use the Patient Diary provided. CIRB requires that the provided Patient Diary be utilized for this study.  
7.6 Criteria for Removal from Protocol Treatment a. Progression of disease or symptomatic deterioration (as defined in Sections 10.2d and 10.2e). However, the patient may continue protocol treatment as long as the patient is continuing to clinically benefit from treatment in the opinion of the treating investigator. Patients should still be removed from protocol treatment for criteria below.
Upon progression, the Request for New Sub-Study Assignment Form may be submitted under the patient's screening protocol (**LUNGMAP**) to receive a new sub-study assignment (see Section 14.4i).  
b. Unacceptable toxicity.  
c. Treatment delay for any reason is > 28 days except for patients receiving steroid therapy for an immune related adverse event (as noted in Section 8.0). If patient is receiving steroid therapy for an immune related adverse event (irAE), the maximum dose delay could be 84 days to allow tapering of the steroid dose to ≤
10 mg prednisone or equivalent.  
d. The patients may withdraw from protocol treatment at any time for any reason.  
7.7 Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented in the Off Protocol Treatment Notice.  
7.8 Follow-Up Period
All patients will be followed until death or 3 years after sub-study registration, whichever occurs first.  
Note: Patients who enroll on a new sub-study following progression must continue followup on this sub-study, in addition to follow-up on the new sub-study.
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8.0 toxicities to be monitored

This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events)  
 Version 5.0 for toxicity and Serious Adverse Event reporting. A copy of the CTCAE Version 5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy of the CTCAE Version 5.0.  
8.2 General Considerations
a. Missed doses are to be omitted rather than made up.  
b. If multiple toxicities are experienced, dose modifications will be based on the toxicity requiring the largest dose reduction.  
c. Once talazoparib dose is reduced, patients will continue at the new dose. No talazoparib dose re-escalations are allowed.  
d. A maximum of three dose reductions are allowed.  
e. The maximum dose delay for any reason is 28 days, with the exception that if patient is receiving steroid therapy for an immune related adverse event (irAE), the maximum dose delay could be 84 days to allow tapering of the steroid dose to ≤
10 mg prednisone or equivalent.  
f. The assessment for discontinuation of talazoparib should be made separately from the assessment made for discontinuation of avelumab.  
g. Although there is overlap among the discontinuation criteria, if discontinuation criteria are met for avelumab but not for talazoparib, treatment with talazoparib may continue if avelumab is discontinued, at the discretion of the treating physician. In the event that criteria are met subsequently for resumption of avelumab while treatment with talazoparib is ongoing, avelumab should be reintroduced on the first day of the next scheduled cycle of therapy. The above criteria would also apply if discontinuation criteria are met for talazoparib but not for avelumab.
If a patient receiving combination therapy meets criteria for discontinuation and the investigator is unable to determine whether the event is related to both or one study drug, the patient should discontinue both drugs.  
See Section 7.4 for patient instructions.  
8.3 Dose Interruptions - Avelumab Dose modifications should be made based on the observed toxicity, as summarized in the tables below.  
a. Treatment Modification for Symptoms of Infusion-Related Reactions  
  
| NCI-CTCAE Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Treatment Modification for Avelumab                                                                                                                                                                                   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 - mild Mild transient reaction; infusion interruption not indicated;  intervention not indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Decrease avelumab infusion rate by 50%  and monitor closely for any worsening.                                                                                                                                        |
| Grade 2 - moderate Therapy or infusion interruption indicated but responds  promptly to symptomatic treatment (for example,  antihistamines, NSAIDs, narcotics, IV fluids);  prophylactic medications indicated for  24 h.                                                                                                                                                                                                                                                                                                                                                   | Temporarily discontinue avelumab infusion. Resume infusion at 50% of previous rate  once infusion-related reaction has resolved  or decreased to at least Grade 1 in severity  and monitor closely for any worsening. |
| Grade 3 or Grade 4 - severe or life-threatening Grade 3: Prolonged (for example, not rapidly responsive  to symptomatic medication and/or brief interruption of  infusion); recurrence of symptoms following initial  improvement; hospitalization indicated for clinical  sequelae. Grade 4: Life-threatening consequences; urgent  intervention indicated.                                                                                                                                                                                                                  | Stop avelumab infusion immediately and  disconnect infusion tubing from the patient. Patients must be withdrawn immediately  from avelumab treatment and must not  receive any further avelumab treatment.            |
| - If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it  must remain decreased for the next scheduled infusion. If no infusion reaction is observed in the next  scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based  on investigator's medical judgment. - If hypersensitivity reaction occurs, the patient must be treated according to the best available medical  practice.  IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse |                                                                                                                                                                                                                       |  
b. Management of Immune-mediated Adverse Reactions  
| Gastrointestinal irAEs                                                                                                             |                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Severity of                                                                                                                        |                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                   |
| Diarrhea/Colitis                                                                                                                   | Initial Management                                                                                                                                                                                                                                                                                       | Follow-up Management                                                                                                                                                              |
| Grade 1                                                                                                                            | Continue avelumab therapy                                                                                                                                                                                                                                                                                | Close monitoring for worsening                                                                                                                                                    |
| Symptomatic treatment (e.g. loperamide)                                                                                            | symptoms Educate patient to report worsening  immediately If worsens: Treat as Grade 2, 3 or 4.                                                                                                                                                                                                          |                                                                                                                                                                                   |
| Grade 2                                                                                                                            | Withhold avelumab therapy                                                                                                                                                                                                                                                                                | If improves to Grade ≤ 1:                                                                                                                                                         |
| Symptomatic treatment                                                                                                              | Resume avelumab therapy If persists > 5-7 days or recurs: Treat as Grade 3 or 4.                                                                                                                                                                                                                         |                                                                                                                                                                                   |
| Grade 3 to 4                                                                                                                       | Withhold avelumab for Grade 3. Permanently discontinue avelumab for  Grade 4 or recurrent Grade 3.                                                                                                                                                                                                       | If improves:  Continue steroids until Grade ≤ 1, then  taper < 10 mg per day over at least 1  month; resume avelumab therapy  following steroids taper (for initial Grade  3). ** |
| 1 to 2 mg/kg/day prednisone IV or  equivalent Add prophylactic antibiotics for opportunistic  infections  Consider lower endoscopy | If worsens, persists > 3 to 5 days, or  recurs after improvement: Add infliximab 5mg/kg (if no  contraindication). Note: infliximab  should not be used in cases of  perforation or sepsis.  Permanently discontinue avelumab for  Grade 4 diarrhea or colitis or recurrent  Grade 3 diarrhea or colitis |                                                                                                                                                                                   |  
| Version Date 4/7/21                |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                       |
|------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Dermatological irAEs               |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                       |
| Grade of Rash                      | Initial Management                                                                                                                                                                                                                                              | Follow-up Management                                                                                                                                                                                                                                                                                                                                                                  |
| Grade 1 to 2                       | Continue avelumab therapy Symptomatic  therapy (for example, antihistamines, topical  steroids)                                                                                                                                                                 | If persists > 1 to 2 weeks or recurs:  Withhold avelumab therapy  Consider skin biopsy  Consider 0.5-1.0 mg/kg/day prednisone  or equivalent. Once improving, taper  steroids < 10 mg per day over at least 1  month, consider prophylactic antibiotics  for opportunistic infections, and resume  avelumab therapy following steroids  taper. ** If worsens:  Treat as Grade 3 to 4. |
| Grade 3 to 4                       | Withhold avelumab for Grade 3. Permanently discontinue for Grade 4 or  recurrent Grade 3.  Consider skin biopsy  Dermatology consult  1 to 2 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for opportunistic  infections                      | If improves to Grade ≤ 1:  Taper steroids < 10 mg per day over at  least 1 month; resume avelumab  therapy following steroids taper (for  initial Grade 3). **                                                                                                                                                                                                                        |
| Pulmonary irAEs                    |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                       |
| Grade of                           |                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                       |
| Pneumonitis                        | Initial Management                                                                                                                                                                                                                                              | Follow-up Management                                                                                                                                                                                                                                                                                                                                                                  |
| Grade 1 Radiographic  changes only | Consider withholding avelumab therapy  Monitor for symptoms every 2 to 3 days  Consider Pulmonary and Infectious Disease  consults                                                                                                                              | Clinically re-assess at least every 2 weeks and resume at the discretion of  the treating investigator If worsens:  Treat as Grade 2 or Grade 3 to 4.                                                                                                                                                                                                                                 |
| Grade 2                            | Withhold avelumab therapy Pulmonary and Infectious Disease consults Monitor symptoms daily; consider  hospitalization  1 to 2 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for opportunistic  infections  Consider bronchoscopy, lung biopsy | Re-assess every 1 to 3 days  If improves:  When symptoms return to Grade ≤ 1,  taper steroids < 10 mg per day over at  least 1 month, and then resume  avelumab therapy following steroids  taper ** If not improving after 2 weeks or  worsening:  Treat as Grade 3 to 4.                                                                                                            |  
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|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3 to 4                                                                                                                                                    | Permanently discontinue avelumab therapy. Hospitalize. Pulmonary and Infectious Disease consults. 1 to 2 mg/kg/day prednisone or equivalent  Add prophylactic antibiotics for opportunistic  infections  Consider bronchoscopy, lung biopsy                                                                                        | If improves to Grade ≤ 1:  Taper steroids < 10 mg per day over at  least 1 month ** If not improving after 48 hours or  worsening:  Add additional immunosuppression (for  example, infliximab, cyclophosphamide,  IV immunoglobulin, or mycophenolate  mofetil)                                               |
| Hepatic irAEs                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                |
| Grade of Liver  Test Elevation                                                                                                                                  | Initial Management                                                                                                                                                                                                                                                                                                                 | Follow-up Management                                                                                                                                                                                                                                                                                           |
| Grade 1                                                                                                                                                         | Continue avelumab therapy                                                                                                                                                                                                                                                                                                          | Continue liver function monitoring  If worsens:  Treat as Grade 2 or 3 to 4.                                                                                                                                                                                                                                   |
| Grade 2                                                                                                                                                         | Withhold avelumab therapy Increase frequency of monitoring to every 3  days.                                                                                                                                                                                                                                                       | If returns to Grade ≤ 1: Resume routine monitoring; resume  avelumab therapy after corticosteroid  taper. ** If elevation persists > 5 to 7 days or  worsens:  Treat as Grade 3 to 4.                                                                                                                          |
| Administer corticosteroids (initial dose of 1  to 2 mg/kg/day prednisone or equivalent,  followed by a corticosteroid taper) for Grade  2 or greater hepatitis. |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                |
| Grade 3 to 4                                                                                                                                                    | Permanently discontinue avelumab therapy  Increase frequency of monitoring to every 1  to 2 days  1 to 2 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for opportunistic  infections  Consult gastroenterologist/ hepatologist Consider obtaining MRI/CT scan of liver and  liver biopsy if clinically warranted | If returns to Grade ≤ 1:  Taper steroids < 10 mg per day over at  least 1 month ** If does not improve in > 3 to 5 days,  worsens or rebounds:  Add mycophenolate mofetil 1 gram (g)  twice daily  If no response within an additional 3 to  5 days, consider other  immunosuppressants per local  guidelines. |
| Renal irAEs                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                |
| Grade of  Creatinine  Increased                                                                                                                                 | Initial Management                                                                                                                                                                                                                                                                                                                 | Follow-up Management                                                                                                                                                                                                                                                                                           |
| Continue renal function monitoring                                                                                                                              |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                |
| Grade 1                                                                                                                                                         | Continue avelumab therapy                                                                                                                                                                                                                                                                                                          | If worsens: Treat as Grade 2 to 3 or 4.                                                                                                                                                                                                                                                                        |  
| Version Date 4/7/21                                                                                                                                                                       |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| If returns to Grade ≤1: Taper steroids < 10 mg per day over at least 1 month, and resume  avelumab therapy following  steroids taper. ** If worsens:  Treat as Grade 4.                   |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                   |
| Grade 2 to 3                                                                                                                                                                              | Withhold avelumab therapy Increase frequency of monitoring to every 3 days 1 to 2 mg/kg/day prednisone or equivalent. Add prophylactic antibiotics for opportunistic  infections Consider renal biopsy                         | If returns to Grade ≤1: Taper steroids < 10 mg per day over at least 1 month. **                                                                                                                                                                                                                  |
| Grade 4                                                                                                                                                                                   | Permanently discontinue avelumab therapy Monitor creatinine daily 1 to 2 mg/kg/day prednisone or equivalent. Add prophylactic antibiotics for opportunistic  infections Consider renal biopsy Nephrology consult Cardiac irAEs |                                                                                                                                                                                                                                                                                                   |
| Myocarditis                                                                                                                                                                               | Initial Management                                                                                                                                                                                                             | Follow-up Management                                                                                                                                                                                                                                                                              |
| New onset of cardiac signs or  symptoms and / or new  laboratory cardiac biomarker  elevations (e.g. troponin, CK-MB,  BNP) or cardiac imaging  abnormalities suggestive of  myocarditis. | Withhold avelumab therapy. Hospitalize. In the presence of life-threatening cardiac decompensation, consider  transfer to a facility experienced in  advanced heart failure and  arrhythmia management. Cardiology consult to establish  etiology and rule-out immunemediated myocarditis.  Guideline based supportive  treatment as per cardiology  consult.*                                                                                                                                                                                                                                | If symptoms improve and  immune-mediated etiology is  ruled out, re-start avelumab  therapy. If symptoms do not  improve/worsen, viral  myocarditis is excluded, and  immune-mediated etiology is  suspected or confirmed  following cardiology consult,  manage as immune-mediated  myocarditis. |
| Consider myocardial biopsy if  recommended per cardiology  consult.                                                                                                                       |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                   |
| Immune-mediated myocarditis                                                                                                                                                               | Permanently discontinue avelumab. Guideline based supportive  treatment as appropriate as per  cardiology consult.* 1 to 2 mg/kg/day prednisone or  equivalent                                                                 | Once improving, taper steroids < 10 mg per day over at least 1  month. ** If no improvement or  worsening, consider additional                                                                                                                                                                    |  
Page 41 Version Date 4/7/21 Add prophylactic antibiotics for opportunistic infections.  
immunosuppressants (e.g. azathioprine, cyclosporine A).  
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines  
AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001  
| AHA guidelines website:  http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 Endocrine irAEs Endocrine Disorder Initial Management Follow-up Management Grade 1 or Grade 2 endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus) Continue avelumab therapy Endocrinology consult if needed Continue hormone  replacement/suppression and  monitoring of endocrine  function as appropriate. Start thyroid hormone  replacement therapy (for  hypothyroidism), anti-thyroid  treatment (for hyperthyroidism),  corticosteroids (for adrenal  insufficiency) or insulin (for Type I  diabetes mellitus) as appropriate.  Rule-out secondary  endocrinopathies (i.e.  hypopituitarism / hypophysitis) Grade 3 or Grade 4 endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus) Withhold avelumab therapy Consider hospitalization Endocrinology consult Resume avelumab once  symptoms and/or laboratory  tests improve to Grade ≤ 1 (with  or without hormone  replacement/suppression). Start thyroid hormone  replacement therapy (for  hypothyroidism), anti-thyroid  treatment (for hyperthyroidism),  corticosteroids (for adrenal  insufficiency) or insulin (for type I  diabetes mellitus) as appropriate.  Continue hormone  replacement/suppression and  monitoring of endocrine  function as appropriate.  Rule-out secondary  endocrinopathies (i.e.  hypopituitarism / hypophysitis) Hypopituitarism/Hypophysitis  If secondary thyroid and/or  (secondary endocrinopathies) adrenal insufficiency is confirmed  (i.e. subnormal serum FT4 with  inappropriately low TSH and/or  low serum cortisol with  inappropriately low ACTH): Resume avelumab once  symptoms and hormone tests  improve to Grade ≤ 1 (with or  without hormone replacement). In addition, for hypophysitis with  abnormal MRI, resume  avelumab only once shrinkage  of the pituitary gland on MRI/CT  scan is documented.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Version Date 4/7/21                                                                                                                                                                                                                    |                                                                   |                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|--------------------------------------------------------------------|
| -                                                                                                                                                                                                                                      | Refer to endocrinologist for  dynamic testing as indicated  and measurement of other  hormones (FSH, LH, GH/IGF1, PRL, testosterone in men,  estrogens in women)                                                                   |                                                                    |
| -                                                                                                                                                                                                                                      | Hormone  replacement/suppressive  therapy as appropriate          |                                                                    |
| -                                                                                                                                                                                                                                      | Perform pituitary MRI and  visual field examination as  indicated | Continue hormone  replacement/suppression  therapy as appropriate. |
| If hypophysitis confirmed: - Continue avelumab if mild  symptoms with normal MRI.  Repeat the MRI in 1 month - Withhold avelumab if  moderate, severe or lifethreatening symptoms of  hypophysitis and/or abnormal  MRI. Consider hospitalization.  Initiate corticosteroids (1 to 2  mg/kg/day prednisone or  equivalent) followed by  corticosteroids taper during at  least 1 month. ** - Add prophylactic antibiotics  for opportunistic infections.                                                                                                                                                                                                                                        |                                                                   |                                                                    |
| Other irAEs (not described above)                                                                                                                                                                                                      |                                                                   |                                                                    |
| Grade of other irAEs                                                                                                                                                                                                                   | Initial Management                                                | Follow-up Management                                               |
| Stevens Johnson Syndrome  (SJS)/toxic epidermal necrolysis  (TEN), rhabdomyolysis,  myasthenia gravis, histiocytic  necrotizing lymphadenitis,  demyelination, vasculitis,  hemolytic anemia, hypophysitis,  iritis, and encephalitis) | Permanently discontinue  avelumab.                                |                                                                    |
| Grade 2 or Grade 3 clinical signs  or symptoms suggestive of a  potential irAE                                                                                                                                                         | Withhold avelumab therapy                                         | If irAE is ruled out, manage as                                    |
| pending clinical investigation                                                                                                                                                                                                         | appropriate according to the  diagnosis and consider restarting avelumab therapy If irAE is confirmed, treat as  Grade 2 or 3 irAE.                                                                   |                                                                    |
| Grade 2 irAE or first                                                                                                                                                                                                                  | Withhold avelumab therapy                                         |                                                                    |
| occurrence of Grade 3 irAE                                                                                                                                                                                                             | 1 to 2 mg/kg/day prednisone or  equivalent                        | If improves to Grade ≤ 1:                                          |  
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| Taper steroids < 10 mg per day over at least 1 month and  resume avelumab therapy  following steroids taper. **                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                      |                                                                                     |
| Recurrence of same Grade 3                                                                                                                                                                                                                                                                                                                                                            | Permanently discontinue                                                                                                                                                                                                                              |                                                                                     |
| irAEs                                                                                                                                                                                                                                                                                                                                                                                 | avelumab therapy 1 to 2 mg/kg/day prednisone or equivalent Add prophylactic antibiotics for  opportunistic infections  Specialty consult as appropriate Add prophylactic antibiotics for  opportunistic infections  Specialty consult as appropriate | If improves to Grade ≤ 1:  Taper steroids < 10 mg per day over at least 1 month. ** |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                               | Permanently discontinue  avelumab therapy 1 to 2 mg/kg/day prednisone or equivalent and/or  other immunosuppressant as  needed Add prophylactic antibiotics for  opportunistic infections  Specialty consult.                                        | If improves to Grade ≤ 1:  Taper steroids < 10 mg per day over at least 1 month **  |
| ** Requirement for 10 mg per  day or greater prednisone or  equivalent for more than 12  weeks for reasons other than  hormonal replacement for  adrenal insufficiency                                                                                                                                                                                                                | Permanently discontinue  avelumab therapy Specialty consult                                                                                                                                                                                          |                                                                                     |
| Persistent Grade 2 or 3 irAE  lasting 12 weeks or longer Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase;  AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed  tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; |                                                                                                                                                                                                                                                      |                                                                                     |  
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.  
8.4 Dose Modifications - Talazoparib Dose modifications should be made based on the observed toxicity, as summarized in the tables below. For any grade 4 toxicity, please contact Dr. Ferdinandos Skoulidis and Dr.  
Jennifer Marie Suga at S1900CMedicalQuery@swog.org.  
| DRUG        | DOSE LEVEL   | DOSE         |
|-------------|--------------|--------------|
| Talazoparib | Full         | 1000 mcg/day |
| -1 Level    | 750 mcg/day  |              |
| -2 Level    | 500 mcg/day  |              |
| -3 Level    | 250 mcg/day  |              |
| -4 Level    | Discontinue  |              |  
  
  
| Table 1: Renal Impairment Dose Modifications   |                                                                                                          |
|------------------------------------------------|----------------------------------------------------------------------------------------------------------|
| Toxicity                                       | Dose Modification                                                                                        |
| Grade ≥ 3                                      | Hold protocol treatment until resolution to < Grade 2, treatment may  then resume at the next lower dose |  
Talazoparib should be discontinued permanently if ALL of the following 4 criteria are met (i.e., potential severe DILI/Hy's Law case):  
| Note: No dose modifications are required for any grade lymphopenia.   |                                                                                                           |
|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|
| Toxicity                                                              | Dose Modification                                                                                         |
| Hemoglobin Grade ≥ 3                                                  | Hold protocol treatment until resolution to < Grade 2, treatment  may then resume at the next lower dose. |
| Platelet count Grade ≥ 3                                              | Hold protocol treatment until resolution to ˂ Grade 2, treatment  may then resume at the next lower dose. |
| Neutrophil count Grade ≥ 3                                            | Hold protocol treatment until resolution to ˂ Grade 2, treatment  may then resume at the next lower dose. |  
| Table 3: Liver Test Abnormalities That Require Dose Modifications   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                 |
|---------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Baseline AST or  ALT Value                                          | Elevation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Dose Modification and Toxicity Management                                                                                                                       |
| ≤ 3 × ULN                                                           | > 5 × ULN to ≤ 8 ×                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Hold protocol treatment pending investigation into alternative  causes of drug-induced liver injury (DILI). The patient should be                               |
| ULN                                                                 | followed for possible DILI. Resuming treatment, at one dose level  reduction if no prior dose reduction otherwise resume at same dose, may be considered if an alternative cause for the impaired liver tests  (i.e., ALT, AST, total bilirubin) is discovered and the laboratory  abnormalities resolve to < Grade 1. The decision to resume treatment should be discussed and agreed  on unanimously by the patient, treating investigator, and Study  Chair. Following rechallenge, patients should be closely monitored  for signs and symptoms of hepatitis, and/or abnormal liver test  results. If signs or symptoms recur with rechallenge, talazoparib should be permanently discontinued and removed from protocol  treatment. |                                                                                                                                                                 |
| > 3 to ≤ 5 × ULN                                                    | > 8 × ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                 |
| Baseline Total                                                      | Elevation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                 |
| Bilirubin Value ≤ 1.5 × ULN                                         | > 3 × ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | If an alternative cause for the impaired liver tests cannot be found,  permanently discontinue and remove from protocol treatment. See Table 4 for evaluations. |  
1. AST or ALT increases to ≥ 3 × ULN (> 5 × ULN if baseline ALT/AST is > 3 and
≤ 5 × ULN)
2. Total bilirubin increases to > 2 × ULN and/or INR > 1.5 3. Alkaline phosphatase (ALP) value does not reach 2 × ULN 4. No alternative cause explains the combination of the above laboratory abnormalities; important alternative causes include, but are not limited to:
- Hepatobiliary tract disease
- Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, parvovirus)
- Congestive heart failure, hypotension, or any cause of hypoxia to the liver causing ischemia
- Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants, and mushrooms
- Alcoholic hepatitis
- Non-alcoholic steatohepatitis (NASH)
- Autoimmune hepatitis
- Wilson's disease and hemochromatosis
- Alpha-one antitrypsin deficiency
If an alternative cause for hepatotoxicity is identified or if the liver test abnormalities do not reach the specified severity, it is recommended, but not required that talazoparib be withheld or permanently discontinued, as appropriate for the safety of the patient based on the patient population and/or severity of the hepatotoxicity or event. All patients in whom talazoparib is withheld (either conditionally or permanently) due to a potential DILI are to undergo a period of "close observation" until the liver test abnormalities return to baseline or normal values. The evaluations listed in Table 4 are recommend, but not required to be performed.
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table 4 liver monitoring after

| Results                                                                                                                    | Frequency for Repeating Liver (AST, ALT, Bilirubin  [Total and Direct]) and INR Tests   |
|----------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| After the initial liver test abnormality                                                                                   | Within 24 hours                                                                         |
| If AST or ALT ≥ 3 × ULN (> 5 × ULN if baseline  ALT/AST is > 3 and ≤ 5 × ULN), and total bilirubin >  2 × ULN or INR > 1.5 | Every 24 hours until laboratory abnormalities improve                                   |
| If ALT or AST ≥ 3 × ULN (> 5 × ULN if baseline  ALT/AST is > 3 and ≤ 5 × ULN) and total bilirubin  and/or INR are normal   | Every 48 to 72 hours until laboratory abnormalities  improve                            |
| If the liver test abnormalities improve AND the patient                                                                    | Frequency may decrease                                                                  |
| is asymptomatic                                                                                                            |                                                                                         |  
As DILI is a diagnosis of exclusion, it is important to initiate investigation of  
  
alternative causes for abnormal liver tests; this may include consultation with a hepatologist. The Study Chair should be contacted for questions regarding adequate follow-up tests.
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8.5 dose modification contacts

For treatment or dose modification questions, please contact Dr. Ferdinandos Skoulidis and Dr. Jennifer Marie Suga at S1900CMedicalQuery@swog.org. For dosing principles or questions, please consult the SWOG Policy \#38 "Dosing Principles for Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.
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8.6 adverse event reporting requirements

TheRave® Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEPAERS) integration enables evaluation of post-baseline Adverse Events (AE) entered in Rave to determine whether they require expedited reporting and facilitates entry in CTEPAERS for those AEs requiring expedited reporting.  
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, which is available for entry at each treatment or reporting period, and used to collect AEs that start during the period or persist from the previous reporting period. CRA will enter AEs that occur prior to the start of treatment on a baseline form that is not included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must begin and end on the baseline Adverse Events form and should not be included on the standard Adverse Events form that is available at treatment unless there has been an increase in grade.  
Prior to sending AEs through the rule's evaluation process, site staff should verify the following on the Adverse Event form in Rave:
- The reporting period (course/cycle) is correct; and
- AEs are recorded and complete (no missing fields) and the form is query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA modifies an AE, it must be re-submitted for rules evaluation. Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation by completing the Expedited Reporting Evaluation form. Both NCI and protocolspecific reporting rules evaluate the AEs submitted for expedited reporting. A report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting requirements. The CRA completes the report by accessing CTEP-AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form.  
In the rare occurrence, that Internet connectivity is lost; a 24-hour notification is to be made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour notification that was phoned in must be entered immediately into CTEP-AERS using the direct link from Medidata Rave.  
Additional information about the CTEP-AERS integration is available on the CTSU website:
- Study specific documents: Protocols > Documents> Education and Promotion; and
- Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU
Operations Information> User Guides & Help Topics.  
NCI requirements for SAE reporting are available on the CTEP website:
- NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid elines.pdf.  
If you have questions about this process, please contact the SAE Program Manager 210-  
 614-8808 or email adr@swog.org.  
The CTEP-AERS electronic reporting system "Help" feature has detailed instructions in the section "Submitting Reports for RAVE Users".  
8.7 Serious Adverse Event Reporting Requirements
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a. definition and purpose

Definition: Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. (FDA,
21 CFR 312.32). See Table 8.6 for definition of a Serious Adverse Event (SAE)
and reporting requirements.  
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. (Directions for routine reporting are provided in Section 14.0.) Additionally, certain adverse events must be reported in an expedited manner to allow for more timely monitoring of patient safety and care. The following guidelines prescribe expedited adverse event reporting for this protocol.
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b. reporting method

This study requires that expedited adverse events be reported to SWOG
Operations Office using the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  
NOTE: For this study, all adverse events requiring expedited reporting must initially be reported on the Adverse Event Form in the appropriate Treatment Cycle folder in Medidata Rave. The CTEP-AERS report must then be initiated directly from the Adverse Event Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-AERS website.
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c. when to report an

Some adverse events require 24-hour notification (refer to Table 8.6) via CTEPAERS.  
In the rare event when internet connectivity is disrupted a 24-hour notification is made to SWOG by telephone at 210-614-8808 or by email adr@swog.org. An electronic report MUST be submitted immediately upon re-establishment of internet connection.  
When the adverse event requires expedited reporting, submit the report via CTEPARS within the number of calendar days of learning of the event specified in Table 8.6
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d. other recipients of adverse

The SWOG Operations Office will forward reports and documentation to the appropriate regulatory agencies and drug companies as required.  
Adverse events determined to be reportable to the Institutional Review Board  
  
responsible for oversight of the patient must be reported according to local policy and procedures.