Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors

• ClinicalTrials.gov Identifier: NCT03330405
• Recruitment Status: Completed
• First Posted: November 6, 2017
• Last Update Posted: January 20, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

Condition or disease	Intervention/treatment	Phase
Avelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors	Drug: Avelumab Phase 1b; Drug: Talazoparib Phase 1b; Drug: Avelumab Phase 2; Drug: Talazoparib Phase 2	Phase 2

Detailed Description:

Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against programmed death ligand 1 (PD L1). Avelumab selectively binds to PD L1 and competitively blocks its interaction with programmed death receptor 1 (PD 1), thereby interfering with this key immune checkpoint inhibition pathway. Avelumab is currently being investigated as single agent and in combination with other anti cancer therapies in patients with locally advanced or metastatic solid tumors and various hematological malignancies.

Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.

Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 226 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI TUMOR ACTIVITY OF AVELUMAB IN COMBINATION WITH THE POLY(ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
• Actual Study Start Date: October 19, 2017
• Actual Primary Completion Date: February 22, 2022
• Actual Study Completion Date: January 4, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Level 0 Phase 1b; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 1b; Avelumab; Other Name: MSB0010718C; Drug: Talazoparib Phase 1b; Talazoparib; Other Name: MDV3800, BMN 673
Experimental: Dose Level -1 Phase 1b; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 1b; Avelumab; Other Name: MSB0010718C; Drug: Talazoparib Phase 1b; Talazoparib; Other Name: MDV3800, BMN 673
Experimental: Dose Level -2 Phase 1b; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 1b; Avelumab; Other Name: MSB0010718C; Drug: Talazoparib Phase 1b; Talazoparib; Other Name: MDV3800, BMN 673
Experimental: A1. NSCLC Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: A2. NSCLC PD-L1 Resistant DDR+ Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: B1. TNBC Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: B2. HR+BC DDR Defect +Assay Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: C1. Ovarian CA Recurrent Plat-Sensitive Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: C2.Ovarian CA Recurrent Plat-Sensitive BRCA defect Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: D.Urothelial CA Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: E1. CRPC Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: E2. CRPC DDR Defect +Assay Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673
Experimental: F: Advanced Solid Tumors with BRCA or ATM defect Phase 2; Drug: Avelumab Drug: Talazoparib	Drug: Avelumab Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MSB0010718C; Drug: Talazoparib Phase 2; The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.; Other Name: MDV3800, BMN 673

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: Cycle 1 Days 1-28 (28 days from date of first dose of study treatment) ]
   Phase 1b: DLT during the DLT evaluation period (Cycle 1)
2. Overall Response (OR) [ Time Frame: From date of first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to approximately 24 months ]
   Phase 2: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with metastatic CRPC

Secondary Outcome Measures :

1. Serum concentrations of avelumab [ Time Frame: Day 1 Cycles 1-4, 6, 9, 12, 18, 24 and Day 15 Cycle 1 ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
2. Anti drug antibody (ADA) levels of avelumab [ Time Frame: Day 1 Cycles 1-4, 6,9,12,18, 24 and Day 15 Cycle 1 ]
   Immunogenicity assessment of avelumab
3. OR [ Time Frame: From the start of treatment until disease progression/recurrence up to approximately 24 months ]
   Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in patients with metastatic CRPC.
4. PSA Tumor Marker [ Time Frame: Baseline, Day1 of each cycle (each cycle is 28 days), and End of Treatment ( up to approximately 24 months) ]
   PSA response greater than or equal to 50% for patients with metastatic CRPC.
5. CA-125 Tumor Marker [ Time Frame: Baseline, Day1 of each cycle (each cycle is 28 days), and End of Treatment (up to approximately 24 months) ]
   CA-125 response for patients with ovarian cancer.
6. Biomarker PD-L1 [ Time Frame: Baseline ]
   PD-L1 expression level in baseline tumor tissue.
7. Genomic [ Time Frame: Baseline ]
   Genomic scarring and the presence of defects in select genes, considered critical to effective DDR, in baseline tumor tissue.
8. Serum concentrations of avelumab [ Time Frame: Day 1 Cycles 1-4, 6,9,12,18, 24 and Day 15 Cycle 1 ]
   Pharmacokinetic parameters: maximum concentrations (Cmax)
9. Plasma concentrations of talazoparib [ Time Frame: Day 1 Cycles 1-4 and Day 15 Cycle 1 ]
   Pharmacokinetic parameters: pre-dose/trough concentrations (Ctrough)
10. Plasma concentration of talazoparib [ Time Frame: Day 1 Cycles 1-4 and Day 15 Cycle 1 ]
    Pharmacokinetic parameters: post-dose concentrations
11. Neutralizing antibodies (Nab) levels against avelumab. [ Time Frame: Day 1 Cycles 1-4, 6, 9, 12, 18, 24 and Day 15 Cycle 1 ]
    Immunogenicity assessment of avelumab
12. Time to Tumor Response (TTR) [ Time Frame: Baseline up to approximately 24 months ]
    Time to Tumor Response (TTR) is defined for patients with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response.
13. Duration of response (DR) [ Time Frame: Baseline up to approximately 24 months ]
    Duration of Response (DR) is defined for patients with confirmed objective response (complete response [CR] or partial response [PR]) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
14. Progression-Free Survival (PFS) [ Time Frame: Baseline up to approximately 24 months ]
    Progression Free Survival (PFS) is defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurs first.
15. Prostate-Specific Antigen (PSA) response [ Time Frame: Baseline up to approximately 24 months ]
    PSA response is defined as the proportion of patients with confirmed PSA decline greater than or equal to 50% compared to baseline.
16. Overall Survival (OS) [ Time Frame: Baseline up to approximately 24 months ]
    OS is defined as the time from the first dose of study treatment to the date of death.
17. Biomarker Tumor Mutational Burden [ Time Frame: Baseline ]
    Tumor mutational burden in baseline tumor tissue

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent in adult patients with: NSCLC, TNBC, HR+ breast cancer, recurrent platinum sensitive ovarian cancer, UC, CRPC, and other advanced solid tumors with a BRCA or ATM gene defect
• Mandatory primary or metastatic tumor biopsy. If archival tumor tissue is available from a biopsy/surgery the tumor tissue may be submitted without repeating a tumor biopsy during the screening period.
• Minimum age in Japan is 20 years.
• ECOG performance status 0 or 1.
• Resolved acute effects of prior therapy
• Adequate bone marrow, renal, and liver function.
• Negative serum pregnancy test at screening.
• Pregnant, breastfeeding females or female patients able to have children must agree to use highly effective method of contraception throughout the study and for at least 30 days after the last dose of avelumab and for at least 7 months after the last dose of talazoparib; fertile male patients must use a condom during treatment and for at least 4 months after the last dose of talazoparib.
• Signed and dated informed consent.

Exclusion Criteria:

• Prior treatment with a PARP inhibitor.
• Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, OX 40, GITR, LAG 3, IDO, TDO,TIM 3, CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. Prior treatment with Sipuleucel-T for patients with mCRPC is allowed. For cohort A2 NSCLC patients prior treatment with anti-PD-1/L1 is allowed
• Prior anti-cancer therapy within 2 weeks prior to study enrollment. Prior radiation therapy within 2 weeks prior to enrollment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 2 days prior to study enrollment and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
• Major surgery within 4 weeks prior to study enrollment.
• Current use of immunosuppressive medication at the time of study enrollment.
• Known prior or suspected hypersensitivity to investigational products.
• Known history of immune mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.
• Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
• Prior organ transplantation including allogenic stem-cell transplantation.
• Vaccination within 4 weeks of study enrollment and while on trial is prohibited except for administration of inactivated vaccines.
• Diagnosis of Myelodysplastic Syndrome.
• Patients with known brain metastases requiring steroids.
• Participation in other studies involving investigational drug(s) within 4 weeks prior to study participation and/or during study participation.
• Persisting toxicity related to prior therapy >Grade 1
• Known HIV or AIDs-related illness.
• Positive HBV or HCV test indicating acute or chronic infection.
• Active infection requiring systemic therapy.
• Clinically significant cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months prior to study entry; unstable angina, congestive heart failure or a serious cardiac arrhythmia requiring medication.
• Current or anticipated use within 7 days prior to first dose of study drug, or anticipated use during the study of a strong P-gp inhibitor.
• Other acute or chronic medical or psychiatric conditions.

Contacts and Locations

Locations

United States, Arkansas

Highlands Oncology Group

Fayetteville, Arkansas, United States, 72703

Highlands Oncology Group

Rogers, Arkansas, United States, 72758

Highlands Oncology Group

Springdale, Arkansas, United States, 72762

United States, California

Tower Hematology Oncology Medical Group

Beverly Hills, California, United States, 90211

Keck Hospital of USC

Los Angeles, California, United States, 90033

LAC+USC Medical Center

Los Angeles, California, United States, 90033

USC/Norris Comprehensive Cancer Center/Investigational Drug Services

Los Angeles, California, United States, 90033

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

Hoag Memorial Hospital Presbyterian

Newport Beach, California, United States, 92663

Freidenrich Center for Translational Research (CTRU)

Palo Alto, California, United States, 94304

Stanford Cancer Institute

Stanford, California, United States, 94305

Stanford Hospital and Clinics

Stanford, California, United States, 94305

Stanford Women's Cancer Center

Stanford, California, United States, 94305

United States, District of Columbia

Georgetown University Medical Center

Washington, District of Columbia, United States, 20007

United States, Massachusetts

Massachusetts General Hospital (MGH)

Boston, Massachusetts, United States, 02114

Massachusetts General Hospital Attn: Svetlana Rashkova

Boston, Massachusetts, United States, 02114

Brigham & Women's Hospital

Boston, Massachusetts, United States, 02115

Dana Farber Cancer Institute, Attn: Vasilika Koci, PharmD

Boston, Massachusetts, United States, 02215

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Minnesota

University Of Minesota Health: Clinics And Surgery Center

Minneapolis, Minnesota, United States, 55455

University of Minesota Medical Center, Fairview IDS Pharmacy

Minneapolis, Minnesota, United States, 55455

University of Minnesota Medical Center, Fairview

Minneapolis, Minnesota, United States, 55455

United States, New York

Roswell Park Cancer Center Institute

Buffalo, New York, United States, 14263

NYU Investigational Pharmacy

New York, New York, United States, 10016

NYU Langone Medical Center

New York, New York, United States, 10016

NYU Laura and Isaac Perlmutter Cancer Center

New York, New York, United States, 10016

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Mount Sinai Hospital- Pharmacy department

New York, New York, United States, 10029

United States, Ohio

Cleveland Clinic Taussig Cancer Center Investigational Pharmacy

Cleveland, Ohio, United States, 44106

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Australia, New South Wales

Macquarie University

North Ryde, New South Wales, Australia, 2109

Northern Cancer Institute

St. Leonards, New South Wales, Australia, 2065

Australia, Queensland

Mater Misericordiae Ltd

Brisbane, Queensland, Australia, 4101

Australia, Western Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia, 6150

Belgium

Institut Jules Bordet

Brussels, Belgium, 1000

Cliniques Universitaires Saint-Luc

Bruxelles, Belgium, 1200

Grand Hôpital de Charleroi - Site Notre-Dame

Charleroi, Belgium, 6000

Canada, Alberta

Cross Cancer Institute

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G 2M9

Denmark

Phase 1 Unit, Department of Oncology, Section 5073.

Copenhagen, Denmark, 2100

The Experimental Cancer Therapy Unit

Herlev, Denmark, 2730

Hungary

Orszagos Onkologiai Intezet

Budapest, Hungary, H-1122

CRU Hungary Kft.

Miskolc, Hungary, 3529

Pecsi Tudomanyegyetem

Pecs, Hungary, H-7624

Korea, Republic of

Gachon University Gil Medical Center

Incheon, Korea, Republic of, 21565

Seoul National University Hospital

Seoul, Korea, Republic of, 03080

Asan Medical Center

Seoul, Korea, Republic of, 05505

Russian Federation

Medical Radiological Research Center n.a. A.F. Tsyba -

Obninsk, Kaluga Region, Russian Federation, 249036

Medical Radiological Research Center n.a. A.F. Tsyba

Obninsk, Kaluga Region, Russian Federation, 249036

GBUZ

Chelyabinsk, Russian Federation, 454087

FSBI "National Medical Research Centre of Oncology n.a.

Moscow, Russian Federation, 115478

Budget Healthcare Institution of Omsk Region "Clinical Oncology Dispensary"

Omsk, Russian Federation, 644013

State budgetary institution of healthcare of Yaroslavl region "Clinical oncology hospital"

Yaroslavl, Russian Federation, 150054

United Kingdom

University College London Hospitals NHS Foundation Trust

London, Other, United Kingdom, W1T 7HA

University Hospitals of Leicester NHS Trust

Leicester, United Kingdom, LE1 5WW

Freeman Hospital, The Sir Bobby Robson Cancer Trials

Newcastle Upon Tyne, United Kingdom, NE7 7DN

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yap TA, Bardia A, Dvorkin M, Galsky MD, Beck JT, Wise DR, Karyakin O, Rubovszky G, Kislov N, Rohrberg K, Joy AA, Telli ML, Schram AM, Conte U, Chappey C, Stewart R, Stypinski D, Michelon E, Cesari R, Konstantinopoulos PA. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2023 Jan 1;9(1):40-50. doi: 10.1001/jamaoncol.2022.5228.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03330405
• Other Study ID Numbers: B9991025; 2017-001509-33 ( EudraCT Number ); JAVELIN PARP MEDLEY ( Other Identifier: Alias Study Number )
• First Posted: November 6, 2017
• Last Update Posted: January 20, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

NSCLC, TNBC, hormone receptor positive (HR+) breast cancer, recurrent epithelial ovarian cancer, UC, and castration resistant prostate cancer (CRPC).

Additional relevant MeSH terms:

Neoplasms; Avelumab; Talazoparib; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action