A Study of Targeted Agents With Atezolizumab for Patients With Recurrent or Persistent Endometrial Cancer (EndoMAP)

• ClinicalTrials.gov Identifier: NCT04486352
• Recruitment Status: Recruiting
• First Posted: July 24, 2020
• Last Update Posted: September 19, 2022
• Sponsor: Alliance Foundation Trials, LLC.
• Collaborators: Genentech, Inc.; Foundation Medicine; Pfizer
• Information provided by (Responsible Party): Alliance Foundation Trials, LLC.

Study Description

Brief Summary:

This is a Phase IB/II multi-cohort study designed to evaluate the efficacy and safety of targeted agents plus cancer immune checkpoint therapy with atezolizumab for patients with recurrent and/or persistent endometrial cancer. The main protocol provides a platform for genomic screening with homogeneous basic eligibility criteria in order to direct study subjects into biomarker-matched study cohorts consisting of testing targeted agents with atezolizumab.

Condition or disease	Intervention/treatment	Phase
Endometrial Cancer	Drug: Atezolizumab - 28 Day Cycle; Drug: Bevacizumab; Drug: Ipatasertib; Drug: Talazoparib; Drug: Trastuzumab emtansine; Drug: Tiragolumab; Drug: Atezolizumab - 21 Day Cycle	Phase 1; Phase 2

Detailed Description:

This is a Phase IB/II multi-cohort study designed to evaluate the efficacy and safety of targeted agents plus cancer immune checkpoint therapy with atezolizumab in patients with recurrent and/or persistent endometrial cancer.

This biomarker-driven study provides a platform whereby patients with persistent/recurrent endometrial cancer will be placed into study cohorts evaluating atezolizumab plus a targeted agent selected on the basis of the tumor's specific genomic profile. Prospective patients with persistent and/or recurrent endometrial cancer will be prescreened within 60 days of treatment assignment to have a tumor tissue sample submitted for next-generation sequencing (NGS) using FoundationOne® companion diagnostic (CDx) testing prior to entering screening.

Based on the FoundationOne® results, patients will be assigned to a study cohort with a targeted therapy + atezolizumab. The current study cohorts are as follows:

• Atezolizumab + Bevacizumab doublet
• Atezolizumab + Ipatasertib doublet
• Atezolizumab + Talazoparib doublet
• Atezolizumab + Trastuzumab emtansine (TDM-1) doublet
• Atezolizumab + Tiragolumab doublet

It is anticipated that 20 patients will be enrolled in each study cohort. Each study cohort will open/close independently of other study cohorts. Once a study cohort reaches 20 patients, it will be closed to further enrollment.

The study is structured to allow for additional cohorts to be added as the study progresses. These additional study cohorts may be proposed by investigators, but requires approval by the Steering Committee in order to be added to the protocol.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IB/II Multi-Cohort Study of Targeted Agents With Atezolizumab for Patients With Recurrent or Persistent Endometrial Cancer
• Actual Study Start Date: October 20, 2021
• Estimated Primary Completion Date: October 1, 2025
• Estimated Study Completion Date: October 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Atezolizumab and Bevacizumab Cohort; Following the submission of tumor tissue to Foundation Medicine for the FoundationOne® assay, patients with no specified gene signatures will be enrolled in this cohort. Twenty patients will be enrolled. Once twenty patientsare enrolled, the cohort will be closed to further enrollment. Patients in this study cohort will commence treatment as specified on Day 1 of each cycle.	Drug: Atezolizumab - 28 Day Cycle; Atezolizumab will be given to patients intravenously at a dosage of 1680 mg on day 1 of each 28-day cycle.; Other Names: Tecentriq; L01XC32; Drug: Bevacizumab; Bevacizumab will be given to patients intravenously at a dosage of 10mg per patient kilogram every 2 weeks of the 28-day cycle.; Other Names: Avastin; L01XC07
Experimental: Atezolizumab and Ipatasertib Cohort; Following the submission of tumor tissue to Foundation Medicine for the FoundationOne® assay, patients with PIK3CA/AKT1/PTEN-altered tumors will be enrolled in this cohort. Twenty patients will be enrolled. Once twenty patients are enrolled, the cohort will be closed to further enrollment. Patients in this study cohort will commence treatment as specified on Day 1 of each cycle.	Drug: Atezolizumab - 28 Day Cycle; Atezolizumab will be given to patients intravenously at a dosage of 1680 mg on day 1 of each 28-day cycle.; Other Names: Tecentriq; L01XC32; Drug: Ipatasertib; Ipatasertib will be given as an oral tablet at a dosage of 400 mg once daily for 21 days of each 28-day cycle.; Other Names: RG7440; GDC-0068
Experimental: Atezolizumab and Talazoparib Cohort; Following the submission of tumor tissue to Foundation Medicine for the FoundationOne® assay, patients with tumors that have a ≥16%genomic loss of heterozygosity (LOH) will be assigned to this cohort. Twenty patients will be enrolled. Once twenty patients are enrolled, the cohort will be closed to further enrollment. Patients in this study cohort will commence treatment as specified on Day 1 of each cycle.	Drug: Atezolizumab - 28 Day Cycle; Atezolizumab will be given to patients intravenously at a dosage of 1680 mg on day 1 of each 28-day cycle.; Other Names: Tecentriq; L01XC32; Drug: Talazoparib; Talazoparib will be given in an oral tablet at a dosage of 1 mg once daily for each day of the 28-day cycle.; Other Names: Talzenna; L01XX60
Experimental: Atezolizumab and Trastuzumab emtansine (TDM-1) Cohort; Following the submission of tumor tissue to Foundation Medicine for the FoundationOne® assay, patients with tumors that with an amplification of ERBB2/HER2 will be assigned to this cohort. Twenty patients will be enrolled. Once twenty patients are enrolled, the cohort will be closed to further enrollment. Patients in this study cohort will commence treatment as specified on Day 1 of each cycle.	Drug: Trastuzumab emtansine; Trastuzumab emtansine be given to patients intravenously at a dosage of 3.6 mg per patient kilogra, on day 1 of each 21-day cycle.; Other Names: T-DM1; Kadcyla; Drug: Atezolizumab - 21 Day Cycle; Atezolizumab will be given to patients intravenously at a dosage of 1200 mg on day 1 of each 21-day cycle.; Other Names: Tecentriq; L01XC32
Experimental: Atezolizumab and Tiragolumab Cohort; Following the submission of tumor tissue to Foundation Medicine for the FoundationOne® assay, patients with tumor type MSI-H and/or tTMB >=10 mut/mb will be assigned to this cohort. Twenty patients will be enrolled initially. Once twenty patients are enrolled, the cohort may be expanded if a positive signal is shown. Patients in this study cohort will commence treatment as specified on Day 1 of each cycle.	Drug: Atezolizumab - 28 Day Cycle; Atezolizumab will be given to patients intravenously at a dosage of 1680 mg on day 1 of each 28-day cycle.; Other Names: Tecentriq; L01XC32; Drug: Tiragolumab; Tiragolumab will be given to patients intravenously at a dosage of 840 mg on day 1 of each 28-day cycle.

Outcome Measures

Primary Outcome Measures :

1. Investigator-assessed overall response rate (ORR) of each biomarker cohort [ Time Frame: 48 Months ]
   Overall response rate for each biomarker cohort is defined as the proportion of patients achieving a complete (CR) or partial (PR) response on two consecutive occasions at least 4 weeks apart, as determined by the investigator from tumor assessments per RECIST v1.1.

Secondary Outcome Measures :

1. Relative proportion of patients in each biomarker cohort who remain progression-free for at least 6 months compared to that from historical control studies [ Time Frame: 6 Months per cohort ]
   PFS rate at 6 months is defined as the proportion of patients who have not experienced disease progression or death from any cause at 6 months, as determined by the investigator according to RECIST v1.1
2. Investigator assessed disease-control rate of each biomarker cohort [ Time Frame: 48 Months ]
   Disease-control rate is defined as the proportion of patients achieving either stable disease, complete response, or partial response.
3. Duration of response for patients in each biomarker cohort who achieve a complete or partial response. [ Time Frame: 48 Months ]
   Duration of response is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
4. Overall survival (OS) rates of patients in each biomarker cohort after 24 months [ Time Frame: 24 Months per cohort ]
   24-month overall survival rate is defined as the proportion of patients who have not experienced death from any cause at 24 months.

Other Outcome Measures:

1. Safety of each biomarker cohort: adverse events [ Time Frame: 48 Months ]
   The incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), as well as summaries of changes in clinically relevant laboratory test results, changes in vital signs, and study treatment exposures for each biomarker cohort

Eligibility Criteria

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

Criteria

Key Inclusion Criteria:

• Recurrent or persistent endometrial carcinoma which has progressed or recurred after at least 1, but no more than 2, prior lines of therapy. Prior hormonal therapies (e.g., tamoxifen, aromatase inhibitors) will not count toward the prior regimen limit. Chemotherapy given in conjunction with radiotherapy as a radiosensitizer will be counted as a systemic therapeutic regimen.
• Measurable disease per RECIST 1.1
• Formalin-fixed, paraffin-embedded tumor tissue, a specimen as proximal to the current recurrence as possible, must be submitted to the Central Lab for molecular testing (FoundationOne CDxTM)
• Life expectancy > 12 weeks
• Recovery from effects of recent radiotherapy, surgery, or chemotherapy

Key Exclusion Criteria:

• Endometrial tumors with the following histologies: squamous carcinomas, sarcomas
• Other invasive malignancies within the last 5 years, except for non-melanoma skin cancer with no evidence of disease within the past 5 years AND localized breast cancer with previous adjuvant chemotherapy treatment for breast cancer completed > 5 years ago
• Synchronous primary invasive ovarian or cervical cancer
• Have an active or history of autoimmune disease or immune deficiency
• Have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis based on a screening chest computed tomography (CT) scan
• Active tuberculosis
• Severe infections within 4 weeks
• Have received therapeutic oral or IV antibiotic medication within 2 weeks, except prophylactic antibiotic medication
• Have significant cardiovascular disease
• Are administered treatment with a live attenuated vaccine within 4 weeks, or anticipation of need for such a vaccine during the course of the study
• Have prior allogeneic bone marrow transplantation or solid organ transplant
• Prior treatment with T-cell costimulating or immune checkpoint blockade therapies including, but not limited to, CD137 agonists, anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapeutic antibodies
• History of treatment with systemic immunostimulatory agents (including but not limited to interferons, interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment
• History of treatment with systemic immunosuppressive medications within 2 weeks except acute, low-dose, systemic immunosuppressant medications, corticosteroids for chronic obstructive pulmonary disease and asthma, or mineralocorticoids and low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency
• Have a history or clinical evidence of any untreated CNS disease, seizures not controlled with standard medical therapy, or history of cerebrovascular accident (stroke), transient ischemic attack or subarachnoid hemorrhage within 6 months

Contacts and Locations

Contacts

Contact: Quality Management and Compliance; 617-732-8727; ClinicalTrials.Queries@alliancefoundationtrials.org

Locations

United States, California

City of Hope Comprehensive Cancer Center; Recruiting

Duarte, California, United States, 91010

Contact: Daphne Stewart

Principal Investigator: Daphne Stewart, MD, MS

University of San Francisco Medical Center; Not yet recruiting

San Francisco, California, United States, 94143

Contact: Edwin Alvarez, MD

Principal Investigator: Edwin Alvarez, MD

United States, District of Columbia

Medstar Georgetown Cancer Institute; Recruiting

Washington, District of Columbia, United States, 20007

Contact: Ebony Hoskins, MD

United States, Florida

Mount Sinai Comprehensive Cancer Center; Recruiting

Miami Beach, Florida, United States, 33140

Contact: Brian Slomovitz, MD

Principal Investigator: Brian Slomovitz, MD

United States, Illinois

University of Chicago; Recruiting

Chicago, Illinois, United States, 60637

Contact: John Moroney, MD

Principal Investigator: John Moroney, MD

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02125

Contact: Joyce Liu, MD, MPH

Principal Investigator: Joyce Liu, MD, MPH

United States, Minnesota

University of Minnesota; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Britt Erickson, MD

United States, Missouri

Washington University School of Medicine Siteman Cancer Center; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Premal Thaker, MD, MS

Principal Investigator: Premal Thaker, MD, MS

United States, Nebraska

Nebraska Methodist Hospital; Recruiting

Omaha, Nebraska, United States, 68114

Contact: Brent Tierney, MD

United States, New Jersey

Englewood Health; Recruiting

Englewood, New Jersey, United States, 07631

Contact: Nimesh Nagarsheth, MD

Principal Investigator: Nimesh Nagarsheth, MD

Atlantic Health Systems/Morristown Medical Center; Recruiting

Morristown, New Jersey, United States, 07960

Contact: Nana Tchabo, MD

Principal Investigator: Nana Tchabo, MD

United States, New York

Roswell Park; Recruiting

Buffalo, New York, United States, 14263

Contact: Peter Frederick, MD

Weill Cornell Medicine; Recruiting

New York, New York, United States, 10065

Contact: Evelyn Cantillo, MD, MPH

Principal Investigator: Evelyn Cantillo, MD, MPH

United States, North Carolina

Duke University Cancer Center; Recruiting

Durham, North Carolina, United States, 27710

Contact: Angeles Alvarez Secord, MD

Principal Investigator: Angeles Alvarez Secord, MD

United States, Oregon

Providence Portland Cancer Institute; Recruiting

Portland, Oregon, United States, 97213

Contact: Christopher Darus, MD

United States, Pennsylvania

University of Pittsburgh Medical Center; Recruiting

Pittsburgh, Pennsylvania, United States, 15261

Contact: Alexander B. Olawaiye, MD

Sponsors and Collaborators

Alliance Foundation Trials, LLC.

Genentech, Inc.

Foundation Medicine

Pfizer

More Information

Additional Information:

CTCAE Version 5.0 

Publications:

Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, Rotmensch J, Barnes MN, Hanjani P, Leslie KK. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011 Jun 1;29(16):2259-65. doi: 10.1200/JCO.2010.32.6397. Epub 2011 May 2.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

Rous J, Rems J, Cermak Z. [Extraction of peripherally located bronchial foreign bodies using a x-ray picture amplifier with a television loop]. Cesk Otolaryngol. 1975 Dec;24(6):335-41. No abstract available. Czech.

Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. doi: 10.1016/S0140-6736(16)00561-4. Epub 2016 Mar 4.

Schwartz LH, Seymour L, Litiere S, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, Hayes W, Hodi FS, Hoekstra OS, Huang EP, Lin N, Liu Y, Therasse P, Wolchok JD, de Vries E. RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group. Eur J Cancer. 2016 Jul;62:138-45. doi: 10.1016/j.ejca.2016.03.082. Epub 2016 May 26.

Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. doi: 10.1016/S0140-6736(19)30723-8. Epub 2019 May 9.

Colle R, Cohen R, Cochereau D, Duval A, Lascols O, Lopez-Trabada D, Afchain P, Trouilloud I, Parc Y, Lefevre JH, Flejou JF, Svrcek M, Andre T. Immunotherapy and patients treated for cancer with microsatellite instability. Bull Cancer. 2017 Jan;104(1):42-51. doi: 10.1016/j.bulcan.2016.11.006. Epub 2016 Dec 13.

Westin SN, Sill MW, Coleman RL, Waggoner S, Moore KN, Mathews CA, Martin LP, Modesitt SC, Lee S, Ju Z, Mills GB, Schilder RJ, Fracasso PM, Birrer MJ, Aghajanian C. Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study. Gynecol Oncol. 2019 Dec;155(3):420-428. doi: 10.1016/j.ygyno.2019.09.024. Epub 2019 Oct 15.

LoRusso PM. Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. J Clin Oncol. 2016 Nov 1;34(31):3803-3815. doi: 10.1200/JCO.2014.59.0018. Epub 2016 Sep 30.

Correction: A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors. Cancer Discov. 2018 Nov;8(11):1490. doi: 10.1158/2159-8290.CD-18-1114. No abstract available.

Xue G, Zippelius A, Wicki A, Mandala M, Tang F, Massi D, Hemmings BA. Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy. J Natl Cancer Inst. 2015 Jun 11;107(7):djv171. doi: 10.1093/jnci/djv171. Print 2015 Jul.

Cancer Genome Atlas Research Network; Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113. Erratum In: Nature. 2013 Aug 8;500(7461):242.

Miyasaka A, Oda K, Ikeda Y, Wada-Hiraike O, Kashiyama T, Enomoto A, Hosoya N, Koso T, Fukuda T, Inaba K, Sone K, Uehara Y, Kurikawa R, Nagasaka K, Matsumoto Y, Arimoto T, Nakagawa S, Kuramoto H, Miyagawa K, Yano T, Kawana K, Osuga Y, Fujii T. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. BMC Cancer. 2014 Mar 13;14:179. doi: 10.1186/1471-2407-14-179.

Gockley AA, Kolin DL, Awtrey CS, Lindeman NI, Matulonis UA, Konstantinopoulos PA. Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor. Gynecol Oncol. 2018 Aug;150(2):219-226. doi: 10.1016/j.ygyno.2018.05.028. Epub 2018 Jun 22.

Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, Hsu JL, Yu WH, Du Y, Lee HH, Li CW, Chou CK, Lim SO, Chang SS, Litton J, Arun B, Hortobagyi GN, Hung MC. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res. 2017 Jul 15;23(14):3711-3720. doi: 10.1158/1078-0432.CCR-16-3215. Epub 2017 Feb 6.

Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, Garber JE, Chowdhury D, Wu CJ, D'Andrea AD, Matulonis UA, Konstantinopoulos PA. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016 Mar 22;7(12):13587-98. doi: 10.18632/oncotarget.7277.

• Responsible Party: Alliance Foundation Trials, LLC.
• ClinicalTrials.gov Identifier: NCT04486352
• Other Study ID Numbers: AFT-50
• First Posted: July 24, 2020
• Last Update Posted: September 19, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Endometrial Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Bevacizumab; Trastuzumab; Ado-Trastuzumab Emtansine; Atezolizumab; Maytansine; Talazoparib; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Immunologic Factors; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors