Safety and Efficacy Study of AMG 820 and Pembrolizumab Combination in Select Advanced Solid Tumor Cancer

• ClinicalTrials.gov Identifier: NCT02713529
• Recruitment Status: Completed
• First Posted: March 18, 2016
• Results First Posted: June 1, 2020
• Last Update Posted: July 17, 2020
• Sponsor: Amgen
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

A multi-center Phase 1b/2 study testing the combination of AMG 820 and pembrolizumab in subjects with select advanced solid tumors.

Condition or disease	Intervention/treatment	Phase
Pancreatic Cancer; Colorectal Cancer; Non-Small Cell Lung Cancer	Biological: AMG820 and pembrolizumab	Phase 1; Phase 2

Detailed Description:

Phase 1b is AMG 820 dose determining and aimed at assessing the safety and tolerability of the selected starting dose of AMG 820 in combination with pembrolizumab. Phase 2 of the study will further evaluate safety and tolerability and additionally test whether AMG 820 can enhance the anti-tumor activity observed historically with pembrolizumab alone and/or overcome lack of response to pembrolizumab monotherapy in subjects with select solid tumors.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 117 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors
• Actual Study Start Date: April 14, 2016
• Actual Primary Completion Date: January 2, 2019
• Actual Study Completion Date: May 17, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: AMG820 and pembrolizumab; Treatment with AMG820 and pembrolizumab	Biological: AMG820 and pembrolizumab; Treatment with AMG820 and pembrolizumab

Outcome Measures

Primary Outcome Measures :

1. Participants With Dose Limiting Toxicities (DLT) [ Time Frame: The DLT evaluation period was Day 1 to Day 21 ]
   DLTs were evaluated by the Dose Level Review Team (DLRT). A DLT was defined as any grade >=3 adverse event occurring during a DLT time window (21 day period from the initial administration of AMG 820 and pembrolizumab in combination), and if judged by the investigator to be related to the administration of AMG 820 and/or pembrolizumab.
2. Participants With Treatment -Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2 ]
   TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore data are not reported for severity grade 5. Readers are referred to the 'Fatal TEAE' line in the table below for counts of participants who died during the TEAE timeframe.
3. Participants With Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment [ Time Frame: Day 1 up to 207 days for Part 1; Day 1 up to 572 days for Part 2 ]
   TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore data are not reported for severity grade 5. Readers are referred to the 'Fatal TEAE' line in the table below for counts of participants who died during the TEAE timeframe.
4. Participants With Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment [ Time Frame: Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2 ]
   TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore data are not reported for severity grade 5. Readers are referred to the 'Fatal TEAE' line in the table below for counts of participants who died during the TEAE timeframe.
5. Objective Response Rate (ORR) Per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) [ Time Frame: Baseline: Day -28; Treatment: up to Month 13.7 ]

   ORR was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI). During treatment radiographic imaging was performed at Week 10 and repeated at least every 10 weeks until disease progression.

   Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

   Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.

Secondary Outcome Measures :

1. Time to Response (TTR) Per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded [ Time Frame: Day 1 up to Month 16 (max time to censoring) ]
   Time to response was defined as the time from first dose of AMG 820 until first documented complete or partial response per irRECIST divided by 365.25 days/12.
2. Time to Progression (TTP) for Participants Who Had Progressive Disease [ Time Frame: Day 1 up to 14.4 months (max time to censoring) ]
   Time to progression was defined as the time from first dose of AMG 820 until first documented progressive disease per irRECIST divided by 365.25 days/12.
3. Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12 [ Time Frame: Day 1 up to Month 6 or Month 12 ]
   Overall survival time was calculated as the number of days from the first administration of AMG 820 to date of death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive at Month 6 and Month 12.
4. Kaplan-Meier Estimates for Progression-Free Survival (PFS) as Per irRECIST at Month 6 and Month 12 [ Time Frame: Day 1 up to Month 6 or Month 12 ]
   Progression-free survival time was calculated as the number of days from the first administration of AMG 820 to date of progressive disease or death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive and progression-free at Month 6 and Month 12.
5. AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (Tmax) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
6. AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
7. AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Last (AUClast) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
   AUClast is the area under the serum concentration-time curve from time zero to time of last quantifiable concentration.
8. AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
   AUCtau is the area under the serum concentration-time curve over the dose interval tau, with tau equal to 21 days.
9. AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
10. AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
11. AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
    Volume of distribution observed at terminal phase after intravenous dosing.
12. AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2 [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
    Drug clearance observed after intravenous dosing.
13. AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR) [ Time Frame: Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36 ]
    Accumulation ratio is AUCtau following administration in Cycle 2 / AUCtau after administration in Cycle 1

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:

• Pathologically documented, advanced colorectal, pancreatic or non-small cell lung cancer that is refractory to standard treatment, or the subjects have been intolerant to or refuse standard treatment.
• Measurable disease per RECIST 1.1 guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
• Adequate hematologic, renal, and hepatic function determined by laboratory blood and urine tests.
• Availability of recent tumor tissue within 3 months prior to enrollment, when feasible.

Exclusion Criteria:

• Has known active central nervous system metastases and/or carcinomatous meningitis.
• History of other malignancy with the past 2 years with some exceptions
• Evidence of active non-infectious pneumonitis/interstitial lung disease
• Evidence of other active autoimmune disease that has required prolonged systemic treatment in past 2 years.
• Evidence of clinically significant immunosuppression such as organ or stem cell transplantation, any severe congenital or acquired cellular and/or humoral immune deficiency, concurrent opportunistic infection.
• Receiving systemic immunostimulatory agents within 6 weeks or 5 half-lives, whichever is shorter, prior to first dose of study treatment (except ant PD-1/PD-L1 treatment if recruited into Group 4a or 4b).
• Evidence of active infection within 2 weeks prior to first dose of study treatment.
• Prior chemotherapy, radiotherapy, biological cancer therapy or major surgery within 28 days prior to enrollment
• Currently participating or has participated in a study (treatment period only) of an investigational agent or used an investigational device within 28 days of enrollment
• Received live vaccine within 28 days prior to enrollment
• Adverse event due to cancer therapy administered more than 28 days prior to enrollment that has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or better.
• Positive for human immunodeficiency virus (HIV), Hepatitis B or C
• Women planning to become pregnant or who are lactating/breastfeeding while on study through 4 months after receiving the last dose of study drug.

Contacts and Locations

Locations

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30332

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02114

Research Site

Boston, Massachusetts, United States, 02215

United States, Michigan

Research Site

Grand Rapids, Michigan, United States, 49546

United States, New York

Research Site

New York, New York, United States, 10021

United States, Pennsylvania

Research Site

Philadelphia, Pennsylvania, United States, 19111

United States, South Carolina

Research Site

Greenville, South Carolina, United States, 29605

United States, Texas

South Texas Accelerated Research Therapeutics

San Antonio, Texas, United States, 78229

Australia, New South Wales

Research Site

Camperdown, New South Wales, Australia, 2050

Australia, Victoria

Research Site

Parkville, Victoria, Australia, 3050

Belgium

Research Site

Wilrijk, Belgium, 2610

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G 2M9

Germany

Research Site

Heidelberg, Germany, 69120

Spain

Research Site

Madrid, Spain, 28040

Research Site

Madrid, Spain, 28050

Sponsors and Collaborators

Amgen

Merck Sharp & Dohme LLC

Investigators

• Study Director: MD; Amgen

  Study Documents (Full-Text)

Documents provided by Amgen:

Study Protocol  [PDF] June 15, 2018

Statistical Analysis Plan  [PDF] February 6, 2019

More Information

Additional Information:

AmgenTrials clinical trials website 

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

Razak AR, Cleary JM, Moreno V, Boyer M, Calvo Aller E, Edenfield W, Tie J, Harvey RD, Rutten A, Shah MA, Olszanski AJ, Jäger D, Lakhani N, Ryan DP, Rasmussen E, Juan G, Wong H, Soman N, Smit MD, Nagorsen D, Papadopoulos KP. Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors. J Immunother Cancer. 2020 Oct;8(2). pii: e001006. doi: 10.1136/jitc-2020-001006.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02713529
• Other Study ID Numbers: 20150195; MASTERKEY ( Other Identifier: Amgen ); 2016-001080-36 ( EudraCT Number ); KEYNOTE-347 ( Other Identifier: Merck )
• First Posted: March 18, 2016
• Results First Posted: June 1, 2020
• Last Update Posted: July 17, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• URL: https://www.amgen.com/datasharing

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

Keywords provided by Amgen:

Solid Tumor; Pancreatic Cancer; Colorectal Cancer; Non-Small Cell Lung Cancer

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Pancreatic Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents