Clinical trial NCT02609776: Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer
Official title: A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of JNJ-61186372, a Human Bispecific EGFR and cMet Antibody, in Subjects With Advanced Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Non-Small-Cell Lung Cancer
Keywords: Non-Small-Cell Lung Cancer
Amivantamab
First-in-Human
Human Bispecific Epidermal Growth Factor Receptor (EGFR)
c-Mesenchymal-Epithelial Transition (cMet) Antibody
JNJ372
Exon 20
Exon 20 insertion
Tyrosine Kinase Inhibitor (TKI) Resistant
TKI Resistance
EGFR C797s
Met Amplification
Met + EGFR bispecific
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-11-20
Enrollment: 751
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of Amivantamab as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (Amivantamab in combination with standard of care carboplatin and pemetrexed) in 21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).

Detailed description: This open label (all participants know the identity of the study drug), multicenter (more than one study site), first-in-human study consists of 2 parts. Part 1 is a Amivantamab Monotherapy and Combination Dose Escalations and Part 2 Amivantamab Monotherapy and Combination Dose Expansions. In Part 1, participants with evaluable NSCLC will be enrolled into cohorts at increasing dose levels of Amivantamab monotherapy, the RP2CD of the Amivantamab and lazertinib combination which will be administered in 28 day treatment cycles, and RP2q3W of Amivantamab in combination with standard of care carboplatin and pemetrexed (chemotherapy combination) which will be administered in 21 day treatment cycles. The dose will be escalated until the maximum tolerated dose (MTD, or maximum administered dose \[MAD\], if no MTD is found) is reached. Part 1 will follow a traditional 3+3 design. At each dose level, 3 participants will complete Cycle 1. If no dose limiting toxicity (DLT) occurs in these 3 participants, then escalation will continue in a new cohort of 3 participants. Data from Part 1 will be used to determine one or more RP2D regimen(s). In Part 2, participants with documented epidermal growth factor receptor (EGFR) mutations and measurable disease, whose disease has progressed after previous treatment will be enrolled and receive Amivantamab at the RP2D determined in Part 1 as a monotherapy at the RP2D regimen(s), or in combination with lazertinib at the RP2CD regimen. For both parts, the study consists of following periods: an optional pre-Screening period; a Screening period (up to 28 days prior to the first dose of study drug); a Treatment period (first dose of study drug until 30(+7) days after the last dose of study drug or prior to starting any subsequent anti-cancer treatment, whichever comes first); and a Follow Up period (approximately 6 months). All participants will be followed for survival in the post-treatment follow-up period until the end of study and safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Participant must have histologically or cytologically confirmed non-small cell lung cancer (NSCLC) that is metastatic or unresectable. Participants must have either progressed after prior standard of care therapy (Cohorts C and hepatocyte growth factor receptor gene \[MET\]-1: epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKI\]; Cohort D: platinum-based chemotherapy; MET-2: per regional standard of care; Cohorts wild-type adenocarcinoma (WT-Ad) and wild-type squamous cell carcinoma (WT-Sq): platinum-containing chemotherapy and programmed death- 1/ ligand-1 (PD-1/L1) therapy, either as a combined regimen or as separate lines of therapy) for metastatic disease, or be ineligible for, or have refused all other currently available therapeutic options. In cases where participants refuse currently available therapeutic options, this must be documented in the study records. For Part 1 Chemotherapy Combination Cohort only: Participants must have histologically or cytologically confirmed NSCLC that is metastatic or unresectable and be eligible for treatment with combination carboplatin and pemetrexed, in accordance with standard of care, and be willing to receive additional investigational therapy with Amivantamab
* For Part 1 Combination Dose Escalation with lazertinib only: Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment naïve for metastatic disease, without access to third generation TKI in the front-line setting, or (b) have progressed after front-line treatment with first (erlotinib or gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or (c) have been treated with a third generation TKI (e.g., osimertinib) in either the front line or second-line setting, and are not eligible for enrollment in either Cohort C or MET-1. For Part 1 Chemotherapy Combination Cohort: Participants may be diagnosed with EGFR mutated or EGFR wild type NSCLC. For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2). Documentation of primary activating EGFR or cMet mutation eligibility by CLIA-certified laboratory (or equivalent) testing is required. For Part 2 Cohorts WT-Ad and WT-Sq: Participants must have wild-type EGFR, anaplastic lymphoma kinase (ALK), and absence of MET Exon 14 skipping mutation as tested by the Food and Drug Administration (FDA) approved test or a CLIA-certified laboratory (or equivalent). The pathology report or equivalent must be in the medical record for verification. Where testing for EGFR and ALK are not part of standard of care for participants with squamous cell carcinoma histology, documentation of the absence of these mutations is not necessary for enrollment into the WT-Sq cohort
* For Part 1: Participant must have evaluable disease. For Part 2: Participant must have measurable disease according to Response Criteria in Solid Tumors (RECIST) v1.1
* For Part 2: Cohorts A and B: Participants EGFR mutated disease must have most recently progressed following treatment with a marketed EGFR inhibitor. Exception: In participants diagnosed with mutations associated with de novo EGFR inhibitor resistance (for example, Exon 20 insertions), only previous treatment with combination platinum-based chemotherapy is required. Cohort C: Participants with primary EGFR mutated disease, with a documented EGFR alteration (example, C797S) mediating resistance to previous treatment with a third generation EGFR TKI (for example, osimertinib), in participants with primary Exon 20ins disease, the documented EGFR alteration may arise following treatment with a TKI with known activity against Exon 20ins disease (for example, poziotinib). Cohort D: participants must have been previously diagnosed with an EGFR Exon 20 insertion and have not been previously treated with a TKI with known activity against Exon 20ins disease (example, poziotinib). Cohort MET-1: Participants with documented primary EGFR mutated disease and documented MET amplification or MET mutation after progression on any EGFR TKI. Participants with disease characterized by both MET amplification and EGFR resistance mutations to prior third generation EGFR TKI will be preferentially enrolled into Cohort C. Participants may have received or have been intolerant to prior platinum-based chemotherapy. Cohort MET-2: Participants with documented primary MET Exon 14 skipping mutation non-small cell lung cancer (NSCLC). Cohort E (combination Amivantamab and lazertinib): Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and have progressed after first or second-line treatment with a third generation TKI (e.g., osimertinib). Cohort WT-Ad: Participant must have been diagnosed with NSCLC of adenocarcinoma histology, with positive EGFR and/or MET expression as detected on a validated immunohistochemistry (IHC) assay performed by the central laboratory and have progressed on prior platinum containing chemotherapy and PD-1/L1 therapy, either as a combined regimen or as a separate line of therapy. Eligibility may be determined through IHC analysis of either archival (pre-screening) or mandatory fresh tumor tissue collected during the Screening period. Cohort WT-Sq: Participant must have been diagnosed with NSCLC of squamous cell carcinoma histology, with positive EGFR and/or MET expression as detected on a validated IHC assay performed by the central laboratory and have progressed on prior platinum-containing chemotherapy and PD-1/L1 therapy, either as a combined regimen or as a separate line of therapy. Eligibility may be determined through IHC analysis of either archival (pre-screening) or mandatory fresh tumor tissue collected during the Screening
* Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

* Participant has uncontrolled inter-current illness, including but not limited to poorly controlled hypertension, or diabetes, ongoing or active infection, (that is, has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. Participants with medical conditions requiring chronic continuous oxygen therapy are excluded. For Part 1 Chemotherapy Combination Cohort only: additionally, participants with active bleeding diathesis
* Participant has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives whichever is longer, before the first administration of study drug. For agents with long half-lives, the maximum required time since last dose is 4 weeks. Toxicities from previous anti-cancer therapies should have resolved to baseline levels or to Grade 1 or less, (except for alopecia \[any grade\], Grade less than or equal to \[\<=\] 2 peripheral neuropathy, and Grade less than \[\<\] 2 hypothyroidism stable on hormone replacement). For Part 1 Combination Dose Escalation: Any previous treatment with systemic anti-cancer immunotherapy, including but not limited to anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents. For Part 1 Chemotherapy Combination Cohort only: Any previous treatment with systemic anti-cancer immunotherapy in the past 3 months or localized radiotherapy to lung within the past 6 months. For Part 2 only: Cohorts A and B: Prior treatment with chemotherapy for metastatic disease is not allowed unless the tumor mutation carries de-novo resistance to EGFR TKI (example, Exon 20 insertions). Cohort C and MET-1: Prior treatment with more than 2 lines of cytotoxic chemotherapy for metastatic disease (maintenance therapy is not included). Cohort D: Previous treatment with an EGFR TKI with activity against EGFR Exon 20 insertions (such as poziotinib). Cohort E (combination Amivantamab and lazertinib): Any previous treatment in the metastatic setting with other than a first, second, or third generation EGFR TKI. Cohorts WT-Ad and WT-Sq: more than three lines of prior systemic therapy in the metastatic setting
* Participants with untreated brain metastases. Participants with definitively, locally-treated metastases that are clinically stable and asymptomatic for at least 2 weeks and who are off or receiving low-dose corticosteroid treatment (\<=10 mg prednisone or equivalent) for at least 2 weeks prior to study treatment are eligible. Exception: participants with asymptomatic, untreated brain metastases, each less than 1 cm in diameter, may be eligible for Amivantamab and lazertinib combination therapy in the Part 1 Combination Dose Escalation or Part 2 Combination Expansion Cohort E
* Participant has a history of malignancy other than the disease under study within 3 years before Screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with or minimal risk of recurrence within a year from Screening)
* Participant has not fully recovered from major surgery or significant traumatic injury prior the first dose of study drug or expects to have major surgery during the study period or within 6 months after the last dose of study drug
* Participant has, or will have, any of the following: a. An invasive operative procedure with entry into a body cavity, within 4 weeks or without complete recovery before Cycle 1 Day 1. Thoracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to Cycle 1 Day 1, as long as the participant has adequately recovered from the procedure prior to the first dose of study drug in the clinical judgement of the investigator; b. Significant traumatic injury within 3 weeks before the start of Cycle 1 Day 1 (all wounds must be fully healed prior to Day 1); c. Any medical condition that requires intact wound healing capacity and is expected to endanger subject safety if wound healing capacity would be severely reduced during administration of the investigational agent; d. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study drug

Primary outcomes:
measure: Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: Up to Day 28
measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious AEs
timeFrame: Screening up to follow-up (30 [+7] days after the last dose)
measure: Part 2: Overall Response Rate (ORR)
timeFrame: Up to End of Treatment Follow (EOT) Up Period (30 [+7] days after the last dose)
measure: Part 2: Duration of Response (DOR)
timeFrame: Up to EOT Follow Up Period (30 [+7] days after the last dose)
measure: Part 2: Percentage of Participants With Clinical Benefit
timeFrame: Up to EOT Follow Up Period (30 [+7] days after the last dose)
measure: Trough Serum Concentration (Ctrough) of Amivantamab
timeFrame: Up to EOT (30 days after last dose)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab
timeFrame: Up to EOT (30 days after last dose)
Secondary outcomes:
measure: Maximum Serum Concentration (Cmax) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through end of infusion (EOT) or Follow Up (approximately 16 months) (each cycle is of 28 days)
measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Area Under the Serum Concentration-Time Curve From t1 to t2 Time (AUC[t1-t2]) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Trough Serum Concentration (Ctrough) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Maximum Serum Concentration (Cmax) of Lazertinib
timeFrame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of Lazertinib
timeFrame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
measure: Trough Serum Concentration (Ctrough) of Lazertinib
timeFrame: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)
measure: Accumulation ratio (R) of Amivantamab
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Number of Participants With Anti-Drug Antibodies (ADA)
timeFrame: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)
measure: Progression-Free Survival (PFS)
timeFrame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)
measure: Time to Treatment Failure (TTF)
timeFrame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)
measure: Overall Survival (OS)
timeFrame: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)
Other outcomes:
Locations:
city: Duarte
country: United States
state: California
city: La Jolla
country: United States
state: California
city: Orange
country: United States
state: California
city: Santa Monica
country: United States
state: California
city: West Hollywood
country: United States
state: California
city: Tampa
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Bethesda
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: Rochester
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Houston
country: United States
state: Texas
city: Fairfax
country: United States
state: Virginia
city: Camperdown
country: Australia
city: Heidelberg
country: Australia
city: Kogarah
country: Australia
city: Murdoch
country: Australia
city: Woolloongabba
country: Australia
city: Toronto
country: Canada
state: Ontario
city: Beijing
country: China
city: Changchun
country: China
city: Changsha
country: China
city: Chengdu
country: China
city: Chongqing
country: China
city: Guangzhou
country: China
city: Hangzhou
country: China
city: Hefei
country: China
city: Nanchang
country: China
city: Nanjing
country: China
city: Wuhan
country: China
city: Zhengzhou
country: China
city: Bordeaux
country: France
city: Dijon
country: France
city: Lyon Cedex 8
country: France
city: Marseille
country: France
city: Paris
country: France
city: Saint-Herblain Cedex
country: France
city: Villejuif Cedex
country: France
city: Chuo Ku
country: Japan
city: Hyogo
country: Japan
city: Kashiwa
country: Japan
city: Kurume
country: Japan
city: Nagoya Shi
country: Japan
city: Niigata
country: Japan
city: Osaka
country: Japan
city: Tokyo
country: Japan
city: Wakayama
country: Japan
city: Yonago
country: Japan
city: Cheongju-si
country: Korea, Republic of
city: Goyang si
country: Korea, Republic of
city: Incheon
country: Korea, Republic of
city: Seongnam-si
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: A Coruna
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Santander
country: Spain
city: Seville
country: Spain
city: Kaohsiung
country: Taiwan
city: Taichung
country: Taiwan
city: Taipei City
country: Taiwan
city: Taipei
country: Taiwan
city: Manchester
country: United Kingdom
city: Newcastle upon Tyne
country: United Kingdom
city: Sutton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Jatkoe T, Wang S, Odegaard JI, Velasco Roth AM, Osgood D, Martinez G, Lucas P, Curtin JC, Karkera J. Clinical Validation of Companion Diagnostics for the Selection of Patients with Non-Small Cell Lung Cancer Tumors Harboring Epidermal Growth Factor Receptor Exon 20 Insertion Mutations for Treatment with Amivantamab. J Mol Diagn. 2022 Nov;24(11):1181-1188. doi: 10.1016/j.jmoldx.2022.07.003. Epub 2022 Aug 10.
citation: Park K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, Viteri S, Han JY, Kim SW, Lee CK, Sabari JK, Spira AI, Yang TY, Kim DW, Lee KH, Sanborn RE, Trigo J, Goto K, Lee JS, Yang JC, Govindan R, Bauml JM, Garrido P, Krebs MG, Reckamp KL, Xie J, Curtin JC, Haddish-Berhane N, Roshak A, Millington D, Lorenzini P, Thayu M, Knoblauch RE, Cho BC. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402. doi: 10.1200/JCO.21.00662. Epub 2021 Aug 2.
citation: Kohler J, Janne PA. Amivantamab: Treating EGFR Exon 20-Mutant Cancers With Bispecific Antibody-Mediated Receptor Degradation. J Clin Oncol. 2021 Oct 20;39(30):3403-3406. doi: 10.1200/JCO.21.01494. Epub 2021 Aug 2. No abstract available.