Amivantamab With Tyrosine Kinase Inhibitors (TKI) for Advanced NSCLC With ALK, ROS1, or RET Alterations

NCT05845671 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 22-1450.cc61186372LUC2005
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 4

Brief Summary

Although non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK), c-ros oncogene 1(ROS1), and ret proto-oncogene (RET) gene fusions initially respond well to tyrosine kinase inhibitor (TKI) therapies, acquired resistance is inevitable. In many of these cases, increased activation of the erythroblastic leukemia viral oncogene homologue (ERBB) or cMet pathways appears to be a bypass signaling mechanism that allows these cancer cells to circumvent the selective pressure from TKIs. Recent data have suggested that these pathways compensate for each other in situations where one pathway is inhibited, leading to "kinase switch" drug resistance. Thus, the expected inhibition of both pathways via treatment with the amivantamab and combination TKI combination may improve overall efficacy by limiting the compensatory pathway activation.

Conditions

Lung Cancer; Non Small Cell Lung Cancer

Keywords

ALK; ROS1; RET

Outcome Measures

Primary Outcomes (3)

• Determine the MTD in adult participants with advanced NSCLC

  The MTD is defined as the dose combination with a DLT rate closest to the target DLT rate of 22%. An unevaluable patient is one who fails to complete dosing in C1 unless due to drug-related toxicities. The starting dose level will be dose level 0.

  18 months

• Determine the recommended phase 2 dose in adult participants with advanced NSCLC

  20 months

• Estimate the objective response rate (ORR) of amivantamab in combination with common TKIs used in ALK, ROS1, and RET advanced NSCLC progressing on TKIs

  To estimate the objective response rate (ORR) of amivantamab in combination with common TKIs used in ALK, ROS1, and RET advanced NSCLC progressing on TKIs. This will be done per investigator and independent central review via RECIST 1.1. and RANO guidelines (for patients with brain metastases)

  40 months

Secondary Outcomes (11)

• Collect treatment-related adverse events (TRAEs)

  40 months

• Collect treatment-emergent adverse events

  40 months

• To evaluate the overall progression free survival (PFS) in patients treated with amivantamab in combination with concurrent TKI in patients with advanced NSCLC with ALK, ROS1, and RET gene fusions

  40 months

• To evaluate the intracranial progression free survival (PFS) in patients treated with amivantamab in combination with concurrent TKI in patients with advanced NSCLC with ALK, ROS1, and RET gene fusions

  40 months

• To evaluate the extracranial progression free survival (PFS) in patients treated with amivantamab in combination with concurrent TKI in patients with advanced NSCLC with ALK, ROS1, and RET gene fusions

  40 months

Study Arms (4)

Dose Finding (Safety Lead-In) Cohort (<80 kg)

EXPERIMENTAL

To estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in adult participants with advanced NSCLC with ALK, ROS1, and RET gene fusions.

Drug: Amivantamab 1050mg

Dose Finding (Safety Lead-In) Cohort (≥80 kg)

EXPERIMENTAL

To estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in adult participants with advanced NSCLC with ALK, ROS1, and RET gene fusions.

Drug: Amivantamab 1400mg

Dose Expansion Cohort (<80 kg)

EXPERIMENTAL

To estimate the objective response rate (ORR) of amivantamab in combination with common TKIs used in ALK, ROS1, and RET advanced NSCLC progressing on TKIs.

Drug: Amivantamab (to be determined)

Dose Expansion Cohort (≥80 kg)

EXPERIMENTAL

To estimate the objective response rate (ORR) of amivantamab in combination with common TKIs used in ALK, ROS1, and RET advanced NSCLC progressing on TKIs.

Drug: Amivantamab (to be determined)

Interventions

Amivantamab 1050mg DRUG

Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET. In in vitro and in vivo studies amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

Also known as: JNJ-61186372

Dose Finding (Safety Lead-In) Cohort (<80 kg)

Amivantamab 1400mg DRUG

Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET. In in vitro and in vivo studies amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

Also known as: JNJ-61186372

Dose Finding (Safety Lead-In) Cohort (≥80 kg)

Amivantamab (to be determined) DRUG

Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET. In in vitro and in vivo studies amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Dose will be determine after the Safety Lead-In

Also known as: JNJ-61186372

Dose Expansion Cohort (<80 kg)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision to sign and date the informed consent form.
• Stated willingness to comply with all study procedures and be available for the duration of the study.
• Participant is ≥ 18 years of age.
• Participant has histologic or cytologic confirmation of locally advanced (unresectable) or metastatic NSCLC with a known (and documented) ALK, ROS1, or RET fusion based on approved diagnostic testing methods specified below. Not that NGS testing is required for all participants, but screening if any of the test below are positive.
• a. IHC: For ALK NSCLC only using the ALK D5F3 antibody b. FISH with ≥15% of 100 cells sampled constituting positivity c. NGS using a CLIA-certified test
• Participants must have clinical progression on at least one prior FDA-approved TKI. They must be on a TKI at the same dose for at least 8 weeks without radiographic progression or clinical intolerance of the TKI prior to enrolling on this study. TKIs that will be considered include (but not limited to):
• ALK fusions - alectinib, brigatinib, lorlatinib
• ROS1 fusions - entrectinib, lorlatinib
• RET fusions - selpercatinib, pralsetinib
• Participants must have at least 1 measurable lesion by RECIST v1.1 criteria using computed tomography (CT) scan or magnetic resonance imaging (MRI).
• Measurable CNS lesions ≥10mm must be captured as overall and intracranial RECIST target lesions. CNS lesions 5-9mm may be included in the intra-cranial data set alone but must be listed as non-target lesions.
• Measurable, treated brain metastases (≥ 10mm) growing after whole-brain radiotherapy (WBRT) or resection are allowed as target lesions, but lesions growing after stereotactic radiosurgery (SRS) are allowed as target lesions only if radiation necrosis or pseudoprogression is ruled out.
• Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2
• Participant has a life expectancy of greater than 12 weeks, per investigator discretion.
• Participant can ingest oral medications.

You may not qualify if:

• Participant has received an investigational drug within a 28-day period (or within 5 half-lives, whichever is shorter) before the first dose of study drug or is currently participating in another interventional clinical trial, unless in the opinion of the Sponsor-Investigator, the medication will not interfere with the study procedures or compromise subject safety.
• The participant cannot have ever received an EGFR TKI (e.g. osimertinib), EGFR- directed monoclonal antibody (e.g. cetuximab), MET TKI (e.g. capmatinib, tepotinib), MET-directed monoclonal antibody (e.g. amivantamab) or MET-directed antibody-drug conjugate (e.g. telisotuzumab vedotin) prior to study entry. For patients with ALK or ROS1 NSCLC, crizotinib cannot be used within 3 months of screening.
• Participants who have progressed on a TKI in less than 8 weeks
• The participant has evidence of neuroendocrine differentiation or small cell transformation on the screening biopsy.
• The patient has no evidence of an ALK, ROS1, and RET gene fusion as determined by molecular testing. Acquired resistance mechanisms detected through NGS (or FISH) testing for which alternative therapies exist may potentially be eligible after consultation with the PI.
• Participants with active, symptomatic, central nervous system disease defined as follows:
• Leptomeningeal disease.
• Symptomatic cord compression from metastatic disease.
• Untreated, symptomatic brain metastases
• Patients with brain metastases may be potentially eligible provided that all the following criteria are met:
• i. They are not on prednisolone 20mg equivalents daily prior to enrolling in the study.
• ii. Anticonvulsants will be permitted provided the patient has been on a stable dose for a period of 2 weeks prior to Study Day 1.
• iii. Procedural interventions (such as ventriculoperitoneal shunt) greater than 12 weeks prior to Study Day 1.
• iv. Palliative radiotherapy (either whole brain radiotherapy or stereotactic radiosurgery) ≥ 28 days prior to screening.
• Participant has active cardiovascular disease defined as the following:

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (4)

City of Hope Cancer Center

Duarte, California, 91010, United States

Location

Outpatient CTRC

Aurora, Colorado, 80045, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

amivantamab

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms

Study Officials

• Erin Schenk, MD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2023
• First Posted: May 6, 2023
• Study Start: July 17, 2023
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: January 14, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)