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

Phase 2TerminatedNCT03829501

Kymab Limited222 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

222

Conditions

Squamous Cell Carcinoma of Head and Neck Non-small Cell Lung Cancer Hepatocellular Carcinoma Esophageal Cancer Gastric Cancer

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (22)

Kymab investigational site 1109

Duarte, California, United States

Kymab investigational site 1102

New Haven, Connecticut, United States

Kymab investigational site 1108

Orlando, Florida, United States

Kymab investigational site 1104

Sarasota, Florida, United States

Kymab investigational site 1103

Nashville, Tennessee, United States

Kymab investigator site 1101

Houston, Texas, United States

Kymab investigational site 3601

Nyíregyháza, Szabolcs-Szatmár-Bereg, Hungary

Kymab investigational site 3602

Budapest, Hungary

Kymab investigational site 3904

Meldola, Forlì-Cesena, Italy

Kymab investigational site 3906

Candiolo, Torino, Italy

...and 12 more locations

Outcomes

Primary Outcomes

Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a participant administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. An serious AE (SAE) was any AE that: * resulted in death; * was life-threatening; * resulted in inpatient hospitalization or prolongation of existing hospitalization; * resulted in a persistent or significant disability/incapacity; * resulted in congenital anomaly/birth defect in the offspring of a participant who received IMPs; * constituted an important medical event. Clinically significant changes in laboratory parameters, vital signs and electrocardiogram results were reported as AEs. A TEAE was defined as an AE observed after starting administration of the specific treatment.

Time frame: 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

Phase 1: Number of Participants Experiencing Dose Changes

Dose changes were defined as infusion interruption and dose reduction.

Time frame: 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

Phase 1: Absolute Dose Intensity

Absolute dose intensity was calculated as cumulative dose received (mg) / study treatment duration (weeks).

Time frame: 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

Phase 1: Relative Dose Intensity

Relative dose intensity was calculated as the cumulative dose received (mg) / initial planned cumulative dose (mg). Initial planned cumulative dose was calculated as the starting dose multiplied by the scheduled number of administrations within the study treatment duration.

Time frame: 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

Phase 1: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)

A DLT was defined as a clinically relevant AE or abnormal laboratory value of Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) ≥ Grade 3 assessed as unrelated to disease, PD, inter-current illness or concomitant medications, which occurs within the first cycle (21 days) of treatment with alomfilimab as single agent or in combination with atezolizumab during the dose escalation part of the study.

Time frame: From first dose of study treatment (Day 1) up to 21 days

Phase 2: Overall Response Rate (ORR) Per RECIST 1.1

ORR was the percentage of participants with a measurable disease at baseline and with a confirmed response of complete response (CR) or partial response (PR) according to RECIST v1.1 as the best response. The response is confirmed by a later scan conducted at least 4 weeks after the initial response is observed. The 95% confidence interval (CI) was calculated using the exact binomial method (Clopper-Pearson). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Time frame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 162 weeks

Secondary Outcomes

Best Overall Response (BOR) Per RECIST 1.1

BOR for each participant was defined as the best confirmed response per RECIST 1.1 among all responses recorded from start of treatment until PD, initiation of new anti-cancer therapy, death, or analysis cut-off date, whichever comes first, with responses of: CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. Not evaluable (NE).

Time frame: 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

Progression-free Survival (PFS) Per RECIST 1.1

PFS was calculated as (first documented PD or death due to any cause - first dose date of study drug +1)/30.4375. Participants who were not observed to have progressed or died were censored at the date of the last tumor assessment. Participants who missed two or more sequential assessments were censored at the date of the last tumor assessment before the missed assessments. Participants who started new anti-cancer therapy prior to documented PD were censored at the date of the last tumor assessment prior to the start of the new therapy. Participants who did not have any tumor assessments were censored with a duration of 1 day. PFS was obtained via Kaplan Meier estimation using the Brookmeyer-Crowley method. PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

Time frame: 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

Duration of Response Per RECIST 1.1

Duration of response was calculated as (date of the first documentation of PD or to death due to any cause in the absence of PD - date of the first documentation of unconfirmed objective response \[CR or PR\] + 1\]/30.4375. Participants who were not observed to have progressed or died were censored at the date of the last tumor assessment. Participants who missed two or more sequential assessments were censored at the date of the last tumor assessment before the missed assessments. Participants who started new anti-cancer therapy prior to documented PD were censored at the date of the last tumor assessment prior to the start of the new therapy. Participants with no disease assessment (or only had assessments with response = NE) after first study treatment or have baseline or post-baseline assessments where the RECIST criteria could not be applied had their duration of response time censored. Duration of response was obtained via Kaplan Meier estimation.

ORR Per iRECIST

RECIST 1.1 has been modified to take into consideration the unique response kinetics which have been observed with immunotherapy in some patients where responses to immune therapies may occur after progression has been assessed. ORR was the percentage of participants with a measurable disease at baseline and with a confirmed response of complete immune-response (iCR) or partial immune-response (iPR) according to iRECIST as the best response. The 95% CI was calculated using the exact binomial method (Clopper-Pearson). iCR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). iPR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Time frame: 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

PFS Per iRECIST

PFS was calculated as (first documented iPD or death due to any cause - first dose date of study drug +1)/30.4375. Participants who were not observed to have progressed or died were censored at the date of the last tumor assessment. Participants who missed two or more sequential assessments were censored at the date of the last tumor assessment before the missed assessments. Participants who started new anti-cancer therapy prior to documented PD were censored at the date of the last tumor assessment prior to the start of the new therapy. Participants who did not have any tumor assessments were censored with a duration of 1 day. PFS was obtained via Kaplan Meier estimation using the Brookmeyer-Crowley method. iPD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.

Time frame: 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

Phase 1: ORR Per RECIST 1.1

ORR was the percentage of participants with a measurable disease at baseline and with a confirmed response of CR or PR according to RECIST v1.1 as the best response. The response is confirmed by a later scan conducted at least 4 weeks after the initial response is observed. The 95% CI was calculated using the exact binomial method (Clopper-Pearson). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.

Time frame: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 weeks

Overall Survival Rate at 12 and 24 Months

Overall Survival rate was defined as the proportion of participants that had known survival status. Overall survival rate was obtained via Kaplan Meier estimation using the complimentary log-log transformation method.

Time frame: Months 12 and 24

Phase 2: Number of Participants Experiencing TEAEs

An AE was any untoward medical occurrence in a participant administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. An SAE was any AE that: * resulted in death; * was life-threatening; * resulted in inpatient hospitalization or prolongation of existing hospitalization; * resulted in a persistent or significant disability/incapacity; * resulted in congenital anomaly/birth defect in the offspring of a participant who received IMPs; * constituted an important medical event. Clinically significant changes in laboratory parameters, vital signs and electrocardiogram results were reported as AEs. A TEAE was defined as an AE observed after starting administration of the specific treatment.

Time frame: 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

Phase 2: Number of Participants Experiencing Dose Changes

Dose changes were defined as infusion interruption and dose reduction.

Time frame: 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

Phase 2: Absolute Dose Intensity

Absolute dose intensity was calculated as cumulative dose received (mg) / study treatment duration (weeks).

Time frame: 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

Phase 2: Relative Dose Intensity

Time frame: 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

Phase 1: Maximum Concentration (Cmax) of Alomfilimab

The serum pharmacokinetics (PK) of alomfilimab were characterized using non-compartmental analysis (NCA). Nominal times of sample collections were used for the NCA. All below limit of quantification (BLQ) values were set to 0 units.

Time frame: Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length)

Phase 1: Half-life (t1/2) of Alomfilimab

The serum PK of alomfilimab were characterized using NCA. Nominal times of sample collections were used for the NCA. All BLQ values were set to 0 units.

Time frame: Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length)

Number of Participants Experiencing Anti-drug Antibodies (ADA) at Anytime

Detection of ADA was assessed from blood samples taken during the study using validated bioanalytical methods. The number of participants who developed detectable anti-alomfilimab or anti-atezolizumab antibodies during any cycle or the safety follow-up period (SFUP) was calculated.

Time frame: 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)

Change From Baseline in Tumor-infiltrating Lymphocytes Per mm^2 at Cycle 2 Day 8

Biological samples (e.g., archived and fresh tumor samples or blood samples) were collected for analysis of responsive biomarkers. The summary of change in the following markers were calculated: * FOXP3-ICOS double-positive cells per mm\^2 in the Tumor * CD8-positive cells per mm\^2 in the tumor * CD8-positive cells per mm\^2 in the invasive margin.

Time frame: Baseline and Cycle 2 Day 8 (21 day cycle length)

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

Overview

Conditions

Interventions

Eligibility

Locations (22)

Outcomes

Primary Outcomes

Secondary Outcomes