AMG 404 in Patients With Advanced Solid Tumors

Phase 1

Completed

Conditions: Advanced Solid Tumors

Interventions: Drug: AMG 404

Registration Number: NCT03853109

Lead Sponsor: Amgen

Brief Summary: To evaluate the safety and tolerability of AMG 404, a monoclonal antibody that binds to PD-1 and inhibits its engagement with ligands, in patients with advanced solid tumors.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 171

Inclusion Criteria

Subject has provided informed consent prior to initiation of any study specific activities/procedures.
Age greater than or equal to 18 years old at the time of signing informed consent.
Life expectancy of greater than 3 months, in the opinion of the investigator
Subject must have histologically or cytologically confirmed metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation.
Cohort 7: participant must have one of the following tumor types: melanoma, small cell lung cancer, NSCLC (PD-L1 positive), head and neck squamous cell cancer (PD-L1 positive), urothelial (PD-L1 positive), gastric or GEJ adenocarcinoma (PD-L1 positive), esophageal (squamous, PD-L1 positive), cervical (PD-L1 positive), hepatocellular carcinoma, merkel cell carcinoma, squamous cell carcinoma of the skin, renal cell carcinoma (clear cell) subtypes of sarcoma (undifferentiated pleiomorphic / malignant fibrous histiocytoma, poorly differentiated and/or dedifferentiated liposarcoma, alveolar soft tissue sarcoma, angiosarcoma), thymic carcinoma, nasopharyngeal carcinoma (EBV positive), mesothelioma
Cohort 8: participant must be MSI-H or MMR-deficient
Cohort 9: participant must have NSCLC, PD-L1 positive, TPS ≥ 50%; not have EGFR or ALK or ROS1 genomic tumor aberrations and may not have received prior systemic treatment for the advanced disease (prior neoadjuvant, adjuvant, or concurrent chemoradiation is allowed).
At least 1 measurable as defined by modified RECIST 1.1 which has not undergone biopsy within 3 months of the screening scan. This lesion cannot be biopsied at any time during the study. Note: if there is only one lesion available for biopsy and radiographic assessment, it may be permitted to be biopsied after discussion with sponsor.
Subjects with treated brain metastases are eligible provided they meet the following criteria: Definitive therapy was completed at least 2 weeks prior to enrollment. No evidence of radiographic CNS progression or CNS disease following definitive therapy and by the time of study screening. Patients manifesting progression in lesions previously treated with stereotactic radiosurgery may still be eligible if pseudoprogression can be demonstrated by appropriate means and after discussion with the medical monitor.
Any CNS disease is asymptomatic, any neurologic symptoms due to CNS disease have returned to baseline or are deemed irreversible, the patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off or on stable doses of anti-epileptic drugs for malignant CNS disease.
Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to 2.
Hematologic function, as follows without growth factor support within 2 weeks prior to study day 1: Absolute neutrophil count (ANC) greater than or equal to 1.0 x 10E9/L; Platelet count greater than or equal to 75 x 10E9/L; Hemoglobin greater than or equal to 9 g/dL (90 g/L).
Adequate renal laboratory assessments, as follows: Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation . 60 ml/min/1.73 m^2 for Cohorts 1, 2, and 4 Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal Disease) calculation >= 45 ml/min/1.73 m^2 for Cohorts 3, 6, 7, 8 and 9.
Hepatic function, as follows: Total bilirubin less than or equal to 1.5 x ULN or less than or equal to 3 x ULN for subjects with liver metastasis; AST less than or equal to 3 x ULN or less than or equal to' 5 x ULN for subjects with liver metastasis; ALT less than or equal to 3 x ULN or less than or equal to 5 x ULN for subjects with liver metastasis; Alkaline phosphatase less than or equal to 2.5 x ULN or less than or equal to 5 x ULN for subjects with liver metastasis (Note: elevated alkaline phosphatase is acceptable if it is due to non-hepatic associated pathology [eg, bone disease]).
Subjects enrolled to Cohorts 7-9 must submit tumor tissue sample. Fresh tumor biopsies may be performed if subject has a readily accessible tumor lesion and who consent to the biopsies. If fresh biopsies cannot be obtained, archival tumor samples are acceptable. Prior to enrollment it is required to determine that there is enough tumor tissue available to be sent to the central laboratory: Cohorts 7 and 9: Archival tissue collected up to 12 months prior to screening date is permitted. Biopsies collected between 12-18 months prior to screening are allowed upon discussion with the medical monitor. Subjects with EBV associated nasopharyngeal carcinoma may submit biopsy with EBV test results from within 36 months prior to screening; Cohort 8: Archival tissue with MSI-high/dMMR test results collected up to 36 months prior to screening is permitted.

Exclusion Criteria

Disease Related. Primary brain tumor, untreated or symptomatic brain metastases and leptomeningeal disease (exception: benign asymptomatic tumors are permitted).
Other Medical Conditions. History of other malignancy within the past 2 years, with the following exception[s]: Malignancy treated with curative intent and with no known active disease present for greater than or equal to 2 years before enrollment and felt to be at low risk for recurrence by the treating physician. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in situ without evidence of disease. Adequately treated breast ductal carcinoma in situ without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer. Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. Other malignancies which do not require systemic therapy, may be considered upon discussion with the medical monitor.
History of solid organ transplantation.
Major surgery within 28 days of study day 1.
Prior/Concomitant Therapy: Prior treatment with anti-programmed death 1 (PD-1), anti-PD-L1, CTLA-4 or other checkpoint inhibitor drugs
Anti-tumor therapy (radiotherapy, chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 21 days prior to study day 1. Note: Palliative radiotherapy is permitted.
Live vaccine therapy within 4 weeks prior to study drug administration.
Current treatment or within 14 days of day 1 with immunosuppressive corticosteroid defined as greater than 10 mg prednisone daily or equivalent. Corticosteroids with no or minimal systemic effect (such as topical or inhalation) are permitted. Note: Corticosteroids > 10 mg prednisone used for management of contrast allergy for study scans is allowed.
Prior/Concurrent Clinical Study Experience: Currently receiving treatment in another investigational device or drug study, or less than 21 days prior to study day 1 since ending treatment on another investigational device or drug study(ies).
Diagnostic Assessments: Evidence of interstitial lung disease or active, non-infectious pneumonitis.
History of any immune-related colitis. Infectious colitis is allowed if evidence of adequate treatment and clinical recovery exists and at least 3 months interval observed since diagnosis of colitis.
History of allergic reactions or acute hypersensitivity reaction to antibody therapies.
Positive/Non-negative test for Human Immunodeficiency Virus (HIV).
Has known active Hepatitis B (eg, hepatitis B antigen [HBsAg] reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected).
Subject currently has an active infection requiring systemic therapy.
Active or history of any autoimmune disease or immunodeficiencies. Subjects with Type I diabetes, vitiligo, psoriasis, hypo- or hyper- thyroid disease not requiring immunosuppressive treatment are permitted.
Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association greater than class II), unstable angina, or cardiac arrhythmia requiring antiarrhythmic medication.
Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, or are stable and well controlled with minimal, local, or non-invasive intervention AND there is agreement to allow by both the investigator and the Amgen Medical Monitor.
Other Exclusions: Males and females of reproductive potential who are unwilling to practice highly effective methods of birth control while on study through 6 months (females) and 8 months (males) after receiving the last dose of AMG 404.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 3	AMG 404	Cohort 3
Cohort 4	AMG 404	Cohort 4
Cohort 1	AMG 404	Cohort 1
Cohort 8	AMG 404	Cohort 8
Cohort 2	AMG 404	Cohort 2
Cohort 6	AMG 404	Cohort 6
Cohort 9	AMG 404	Cohort 9
Cohort 7	AMG 404	Cohort 7

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)	Up to Day 28	Toxicities were graded with the Common Terminology Criteria for Adverse Events CTCAE v5.0., the following toxicities were classified as DLTs: * Any treatment related grade 5 toxicity * Grade 4 neutropenia or thrombocytopenia * Febrile neutropenia * Grade 4 anemia * Grade 3 or 4 non-hematologic toxicity * Recurrent grade 2 pneumonitis * Any other toxicity requiring permanent discontinuation of AMG 404.
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)	Up to the last dose of AMG 404 + 140 days (approximately 46 months); median (min, max) exposure to AMG 404 was 3.58 (0.02, 41.7) months	A TEAE is any adverse event (AE) starting on or after the first administration of investigational product (IP) and up to and including 140 days after the last IP dose date or end of the study, whichever occurs earlier. A TEAE with unknown/missing relatedness to AMG 404 is assumed as an event is related to AMG 404. A serious adverse event (SAE) is defined as an adverse event that: is fatal, is life threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and other medically important serious event. A treatment-related AE (TRAE) is any TEAE that per investigator review has a reasonable possibility of being caused by the investigational product. In the unlikely event that the relationship is missing, the TEAE will be considered TRAE and documented in a footnote of the treatment-related summary.

Secondary Outcome Measures

Name	Time	Method
AMG 404 PK Parameter by Dose Group: Time to Achieve Cmax (Tmax) During Cycle 1 and 2	Day 1 pre-dose, end of infusion (EOI), 2h, 4h post dose; Day 2; Day 4; Day 8; Day 15 of Cycle 1 and 2 (28 day cycle length)	Tmax represents the time to reach Cmax in the blood serum.
AMG 404 Pharmacokinetic (PK) Parameter by Dose Group: Maximum Observed Serum Concentration (Cmax) During Cycle 1 and 2	Day 1 pre-dose, end of infusion (EOI), 2h, 4h post dose; Day 2; Day 4; Day 8; Day 15 of Cycle 1 and 2 (28 day cycle length)	Maximum concentration of AMG 404 in blood serum at different time points.
AMG 404 PK Parameter by Dose Group: Area Under the Serum Concentration-time Curve From Day 0 to Day 28 (AUC0-28d) During Cycle 1 and 2	Day 1 pre-dose, end of infusion (EOI), 2h, 4h post dose; Day 2; Day 4; Day 8; Day 15 of Cycle 1 and 2 (28 day cycle length)	Assessment of AMG 404 exposure over 28 days.
Disease Control Rate (DCR) Per Modified RECIST v1.1	Up to approximately 54 months	DCR was defined as the percentage of participants in whom objective response (CR or PR) or stable disease (SD) was determined as per RECIST v1.1.
Number of Participants With Anti-AMG 404 Antibodies	Day 1 pre-dose and Day 15	Transient was defined as the number of participants with negative result at the participant's last time point tested within the study period. Only participants with both baseline and post-baseline are included.
Objective Tumor Response Per Evaluation Criteria in Solid Tumours (RECIST) V1.1	Up to approximately 54 months	Objective response was defined as a tumor response assessment of either complete response (CR) (disappearance of all target lesions) or partial response (PR) (at least a 30% decrease in the sum of the diameters of target lesions) measured by positron emission tomography(PET)/computed tomography (CT), CT or magnetic resonance imaging (MRI) and assessed per RECIST v1.1. Participants who did not experience PR/CR or did not have any follow-up tumor assessments was regarded as non-responders. This endpoint was determined only for participants with measurable disease at baseline.
Progression-free Survival (PFS) Per Modified RECIST v1.1	Up to approximately 48 months	PFS was defined as the time from the first dose of IP unite the first documentation of radiological disease progression or death due to any cause, whichever occurred first in the absence of subsequent anticancer therapy.
Duration of Response (DOR) Per Modified RECIST v1.1	Up to approximately 43 months	DOR was defined as the time from the first documentation of objective response (CR or PR) until the first documentation of disease progression or death due to any cause, whichever occurred first. Only participants who achieved objective response were evaluated for DOR. DOR was censored at the last evaluable post-baseline tumor assessment date; otherwise, at the first dose of IP. Kaplan-Meier (KM) analysis was used to estimate DOR for responders, providing a median value and 80% confidence intervals (CI) where sufficient data were available. The Brookmeyer and Crowley method was used to calculate confidence intervals. For cohorts with limited responders or heavily censored data, the median DOR or CI bounds could not be calculated.
Duration of Stable Disease (DoSD) Per Modified RECIST v1.1	Up to approximately 54 months	DoSD was measured from the start of treatment until the first documentation of disease progression or death due to any cause. DoSD was calculated only in participants with the best overall response of SD, defined as neither sufficient shrinkage to qualify PR nor sufficient increase to qualify for PD. KM analysis was used to estimate the median DoSD, and CIs were calculated using the Brookmeyer and Crowley method. DoSD was censored at the last evaluable post-baseline tumor assessment date or at the first dose of IP, if no progression or death was documented.

Trial Locations

Locations (34): Narodowy Instytut Onkologii im Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy
🇵🇱
Warszawa, Poland
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
Instituto Coi
🇧🇷
Rio de Janeiro, Brazil
Universitair Ziekenhuis Antwerpen
🇧🇪
Edegem, Belgium
Uniwersyteckie Centrum Kliniczne
🇵🇱
Gdansk, Poland
Koc Universitesi Hastanesi
🇹🇷
Istanbul, Turkey
Severance Hospital Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
The Catholic University of Korea Seoul St Marys Hospital
🇰🇷
Seoul, Korea, Republic of
The Queen Elizabeth Hospital
🇦🇺
Woodville South, South Australia, Australia
Chris OBrien Lifehouse
🇦🇺
Camperdown, New South Wales, Australia
Nucleo de Oncologia da Bahia
🇧🇷
Salvador, Bahia, Brazil
Sarah Cannon Research Institute at HealthONE
🇺🇸
Denver, Colorado, United States
Sarcoma Oncology Research Center LLC
🇺🇸
Santa Monica, California, United States
University of Louisville James Graham Brown Cancer Center
🇺🇸
Louisville, Kentucky, United States
Sociedade Beneficente de Senhoras Hospital Sirio Libanes
🇧🇷
Sao Paulo, São Paulo, Brazil
National University Hospital
🇸🇬
Singapore, Singapore
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
Taipei Veterans General Hospital
🇨🇳
Taipei, Taiwan
Doktor Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi
🇹🇷
Ankara, Turkey
Sarah Cannon Research Institute UK
🇬🇧
London, United Kingdom
Ege Universitesi Ilac Gelistirme ve Farmakokinetik Arastirma Uygulama Merkezi (ARGEFAR)
🇹🇷
Izmir, Turkey
Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
National Cancer Centre Singapore
🇸🇬
Singapore, Singapore
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Hospital de Base de Sao Jose do Rio Preto
🇧🇷
São José do Rio Preto, São Paulo, Brazil
National Hospital Organization Shikoku Cancer Center
🇯🇵
Matsuyama-shi, Ehime, Japan
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
National Cancer Center Hospital East
🇯🇵
Kashiwa-shi, Chiba, Japan
Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation
🇨🇳
Taoyuan, Taiwan
Tom Baker Cancer Centre
🇨🇦
Calgary, Alberta, Canada
Wakayama Medical University Hospital
🇯🇵
Wakayama-shi, Wakayama, Japan
Hospital Universitari Vall d Hebron
🇪🇸
Barcelona, Cataluña, Spain