Clinical trial NCT03829501: A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy of Alomfilimab (KY1044) as Single Agent and in Combination With Anti-PD-L1 (Atezolizumab) in Adult Patients With Selected Advanced Malignancies
Official title: A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy of KY1044 as Single Agent and in Combination With Anti-PD-L1 (Atezolizumab) in Adult Patients With Selected Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Squamous Cell Carcinoma of Head and Neck
Non-small Cell Lung Cancer
Hepatocellular Carcinoma
Esophageal Cancer
Gastric Cancer
Melanoma
Renal Cell Carcinoma
Pancreatic Cancer
Cervical Cancer
Triple Negative Breast Cancer
Advanced Cancer
Metastatic Cancer
Lead sponsor: Kymab Limited
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2019-02-04
Enrollment: 222
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: A Phase 1/2, open label, multi-center study to evaluate the safety, efficacy and tolerability of alomfilimab as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies, who are ineligible for or there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options in each indication and therefore will be patients for whom a clinical trial is appropriate.


Eligibility criteria: Inclusion Criteria:

* Age ≥18 years (≥20 years in Taiwan)
* Histologically documented advanced/metastatic malignancies
* Phase 1 and Phase 2 participants with advanced/metastatic malignancies who have measurable disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 will be eligible if, according to the National Comprehensive Cancer Network (NCCN) guidelines, there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options. Additionally, the following specific tumor indications will be enrolled:

  1. Phase 1: Participants with advanced/metastatic malignancies, and preferred indications (non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), melanoma, cervical, esophageal, gastric, renal, pancreatic, and triple negative breast cancer)
  2. Phase 2 Alomfilimab single agent: Participants with advanced/metastatic malignancies in indications in which signs of anti-tumor activity (Complete Response (CR), Partial Response (PR) or durable stable disease (SD) with tumor shrinkage that does not qualify for PR) were seen during the dose escalation of Alomfilimab as single agent
  3. Phase 2 Alomfilimab in combination with atezolizumab: Participants with advanced/metastatic malignancies in the selected indications below, and/or indications which have shown promising activity in Phase 1:

     * NSCLC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease)
     * Gastric (anti-PD-(L)1 therapy naïve and pre-treated)
     * Recurrent and/or metastatic HNSCC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease)
     * Esophageal (anti-PD-(L)1 therapy naïve and pre-treated)
     * Cervical (anti-PD-(L)1 therapy naïve and pre-treated)
     * Indications, in which signs of anti-tumor activity has been observed in Phase 1 with Alomfilimab in combination with atezolizumab
* Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
* Life expectancy longer than 12 weeks
* Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Participants must be willing to undergo a new tumor biopsy at screening, and during therapy on the study

Exclusion Criteria:

* Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks of first dose of study treatment
* History of severe hypersensitivity reactions to other monoclonal antibodies and/or their excipients
* Known presence of neutralizing anti-atezolizumab antibodies (for patients previously treated with atezolizumab)
* Having out of range laboratory values: creatinine, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), absolute neutrophil count (ANC), platelet count, hemoglobin
* Impaired cardiac function or clinically significant cardiac disease, including any of the following:

  1. Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association \[NYHA\] Grade ≥2), uncontrolled hypertension or clinically significant arrhythmia
  2. QTcF \>470 msec on screening (electrocardiogram) ECG using Fridericia's formula (QTcF) or congenital long QT syndrome
  3. Acute myocardial infarction or unstable angina pectoris
* Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection
* Malignant disease, other than that being treated in this study
* Any medical condition that would, in the Investigator's judgment, prevent participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
* Active autoimmune disease or a documented history of autoimmune disease
* Participants previously exposed to anti-PD-(L)1 treatment who are not adequately treated for skin rash or had no replacement therapy for endocrinopathies should be excluded
* Participants with a history of drug-induced pneumonitis or current pneumonitis
* Systemic steroid therapy or any immunosuppressive therapy. Topical, inhaled, nasal, and ophthalmic steroids are not prohibited
* Use of live attenuated vaccines against infectious diseases within 4 weeks of the first dose of study treatment. SARS-CoV-2 vaccines authorized for use by the competent local regulatory health authorities for active immunization to prevent COVID 19 are allowed (unless the vaccine is live or live attenuated) and must be given in accordance with the prevailing immunization guidelines.
* Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study treatment
* Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway
* Presence of Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer therapy
* Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. To allow evaluation for response to treatment, participants enrolled in the Phase 2 part must have remaining measurable disease that has not been irradiated
* Pregnant or lactating women

Primary outcomes:
measure: Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
measure: Phase 1: Number of Participants Experiencing Dose Changes
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
measure: Phase 1: Absolute Dose Intensity
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
measure: Phase 1: Relative Dose Intensity
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
measure: Phase 1: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
timeFrame: From first dose of study treatment (Day 1) up to 21 days
measure: Phase 2: Overall Response Rate (ORR) Per RECIST 1.1
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 162 weeks
Secondary outcomes:
measure: Best Overall Response (BOR) Per RECIST 1.1
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively
measure: Progression-free Survival (PFS) Per RECIST 1.1
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively
measure: Duration of Response Per RECIST 1.1
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively
measure: ORR Per iRECIST
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively
measure: PFS Per iRECIST
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively
measure: Phase 1: ORR Per RECIST 1.1
timeFrame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 weeks
measure: Overall Survival Rate at 12 and 24 Months
timeFrame: Months 12 and 24
measure: Phase 2: Number of Participants Experiencing TEAEs
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks
measure: Phase 2: Number of Participants Experiencing Dose Changes
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks
measure: Phase 2: Absolute Dose Intensity
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks
measure: Phase 2: Relative Dose Intensity
timeFrame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks
measure: Phase 1: Maximum Concentration (Cmax) of Alomfilimab
timeFrame: Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length)
measure: Phase 1: Half-life (t1/2) of Alomfilimab
timeFrame: Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length)
measure: Number of Participants Experiencing Anti-drug Antibodies (ADA) at Anytime
timeFrame: Phase 1: pre-infusion at all cycles (up to 69 cycles) + 90 days SFUP; Phase 2: pre-infusion at all cycles (up to 28 cycles) + 90 day SFUP (21 day cycle length)
measure: Change From Baseline in Tumor-infiltrating Lymphocytes Per mm^2 at Cycle 2 Day 8
timeFrame: Baseline and Cycle 2 Day 8 (21 day cycle length)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Kymab investigational site 1109
state: California
city: New Haven
country: United States
facility: Kymab investigational site 1102
state: Connecticut
city: Orlando
country: United States
facility: Kymab investigational site 1108
state: Florida
city: Sarasota
country: United States
facility: Kymab investigational site 1104
state: Florida
city: Nashville
country: United States
facility: Kymab investigational site 1103
state: Tennessee
city: Houston
country: United States
facility: Kymab investigator site 1101
state: Texas
city: Nyíregyháza
country: Hungary
facility: Kymab investigational site 3601
state: Szabolcs-Szatmár-Bereg
city: Budapest
country: Hungary
facility: Kymab investigational site 3602
city: Meldola
country: Italy
facility: Kymab investigational site 3904
state: Forlì-Cesena
city: Candiolo
country: Italy
facility: Kymab investigational site 3906
state: Torino
city: Milano
country: Italy
facility: Kymab investigational site 3901
city: Milano
country: Italy
facility: Kymab investigational site 3903
city: Napoli
country: Italy
facility: Kymab investigational site 3902
city: Roma
country: Italy
facility: Kymab investigational site 3910
city: Turin
country: Italy
facility: Kymab investigational site 3908
city: Siedlce
country: Poland
facility: Kymab investigational site 4801
state: Mazowieckie
city: Changhua City
country: Taiwan
facility: Kymab investigational site 8806
state: Changhwa
city: Taipei
country: Taiwan
facility: Kymab investigational site 8801
city: London
country: United Kingdom
facility: Kymab investigational site 4405
city: Manchester
country: United Kingdom
facility: Kymab investigational site 4402
city: Oxford
country: United Kingdom
facility: Kymab investigational site 4404
city: Sutton
country: United Kingdom
facility: Kymab investigational site 4401
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: