Amivantamab With Tyrosine Kinase Inhibitor (TKI)

Sponsor

University of Colorado, Denver (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05845671

Collaborator

Janssen Research & Development, LLC (Industry)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Although non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), and rearranged during transfection (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 (epidermal growth factor receptor (ERBB) or mesenchymal-epithelial transition (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.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Non Small Cell Lung Cancer	Drug: Amivantamab 1050mg Drug: Amivantamab 1400mg Drug: Amivantamab (to be determined) Drug: Amivantamab (to be determined)	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 / 2, Open Label, Study of Amivantamab (JNJ-61186372) Among Participants With Advanced NSCLC Harboring ALK, ROS1, and RET Gene Fusions in Combination With Tyrosine Kinase Inhibitors

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2027

Anticipated Study Completion Date :

Jan 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Finding (Safety Lead-In) Cohort (<80 kg) 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 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. Other Names: JNJ-61186372
Experimental: Dose Finding (Safety Lead-In) Cohort (≥80 kg) 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 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. Other Names: JNJ-61186372
Experimental: Dose Expansion Cohort (<80 kg) 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) 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 Other Names: JNJ-61186372
Experimental: Dose Expansion Cohort (≥80 kg) 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) 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 Other Names: JNJ-61186372

Outcome Measures

Primary Outcome Measures

Determine the MTD in adult participants with advanced NSCLC [18 months]
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.
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 [40 months]
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)

Secondary Outcome Measures

Collect treatment-related adverse events (TRAEs) [40 months]
All graded AEs (using CTCAE 5.0 criteria)
Collect treatment-emergent adverse events [40 months]
All graded AEs (using CTCAE 5.0 criteria)
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]
To evaluate the overall disease control rate (DCR) among 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 disease control rate (DCR) among 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 disease control rate (DCR) among 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 overall duration of response (DOR) among responders 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 duration of response (DOR) among responders 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 duration of response (DOR) among responders in patients treated with amivantamab in combination with concurrent TKI in patients with advanced NSCLC with ALK, ROS1, and RET gene fusions [40 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 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 TKI. They must be on a TKI at the same dose for at least 3 months 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. b. 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.
Participant has received the final dose of any of the following treatments/procedures*† with the specified minimum intervals before the first dose of study drug (unless in the opinion of the Sponsor-Investigator, the medication will not interfere with the study or compromise participant safety).

Chemotherapy‡ 21 days Antibody-drug conjugate (ADC) 28 days Immune checkpoint inhibitors (ICI) 28 days Locally ablative radiotherapy§ 28 days Palliative radiotherapy§ 14 days Major surgery 28 days

*The patient cannot have received an EGFR TKI (e.g. osimertinib, afatinib), EGFR-directed monoclonal antibody (e.g. cetuximab), MET-inhibitor (e.g., tepotinib, capmatinib, telisotuzumab vedotin, etc.) at any point prior to study entry. For patients with ALK and ROS1 NSCLC, crizotinib cannot be used within 3 months of screening.

† Patients will be allowed to remain on their prior TKI without need for a washout therapy.

‡ Chemotherapy washout period will be 21 days or 5 half-lives, whichever is longer. As patients are required to be on a stable dose of TKI for 3 months prior to study entry, this criterion would rarely (if ever) apply to any participant in this study.

§ Locally ablative therapy will be considered as any form of radiotherapy with the intent of providing ablative doses for oligoprogressive lesions while on TKI therapy. Palliative radiotherapy will be considered as any form of radiotherapy with the intent of alleviating symptomatic lesions.

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Colorado Research Center	Aurora	Colorado	United States	80045
2	Outpatient CTRC	Aurora	Colorado	United States	80045
3	UCHealth Metro Denver	Aurora	Colorado	United States	80045