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

Running, not enrolling · Phase 1/Phase 2

Conditions studied: Lung Cancer, Non Small Cell Lung Cancer

In brief

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.

Key facts

Study ID

NCT05845671

Run by

University of Colorado, Denver

People needed

12

Starts

2023-07-17

Expected to finish

2028-01-01

Last updated by the study team

2026-01-14

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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.
• 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
• Participant has adequate organ function as determined by the following laboratory values.
• Absolute neutrophil count (ANC)* ≥ 1,500/mm3 (≥ 1.5 x One times ten to the ninth/L) Platelets† ≥ 75,000/mm3 (≥ 75 x One times ten to the ninth/L) Hemoglobin† ≥ 9 g/dL Renal function: Serum creatinine ≤ 1.5 x upper limit normal (ULN) OR creatinine clearance ≥50 mL/min/1.73 m2 via Cockcroft-Gault Liver transaminases (ALT/AST) ≤ 3 x ULN
• 5 x ULN, if liver metastases are present on screening Bilirubin ≤ 1.5 x ULN
• 3.0 x ULN, if patient has Gilbert's disease Amylase and lipase ≤ 1.5 x ULN
• Participants cannot be receiving growth factor support using granulocyte-stimulating colony factor (G-CSF) during the screening visit.
• Participants cannot receive transfusion support up to one week prior to the screening period.
• Female participant of childbearing potential (defined as a sexually mature woman who has not undergone a hysterectomy [surgical removal of the uterus] or bilateral oophorectomy, or if ≥ 45 years old, has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must:
• Have 1 negative pregnancy test as verified by an Investigator prior to starting study therapy. This applies even if the subject practices true abstinence from heterosexual contact.

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:
• Congestive heart failure (CHF), defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF within 6 months of study Day 1.
• Symptomatic acute coronary syndrome, unstable angina, or active ischemia requiring coronary artery stenting, angioplasty, or bypass grafting within 12 weeks prior to starting investigational drug.
• Participant has evidence of current, uncontrolled, clinically significant, unstable arrhythmias. Participants receiving active anti-arrhythmic therapy are not eligible with the following exceptions:
• i. Participants with atrial fibrillation medically controlled for greater than 4 weeks prior to Study Day 1.
• ii. Participants who have medical pacemakers for control of arrhythmias. d. Participant has medically uncontrolled hypertension (defined as ≥ 160 mmHg systolic blood pressure (SBP) and ≥ 100 mmHg diastolic blood pressure (DBP).
• e. Clinically significant, acute deep vein thrombosis or pulmonary embolism within 6 months prior to first dose of study drug. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots or incidentally detected, asymptomatic, subsegmental pulmonary emboli are not considered exclusionary.
• f. History of cerebrovascular accident or transient ischemic attack within12 weeks of enrollment.
• g. QT interval corrected by Fridericia's Formula (QTcF) prolongation to > 470ms based on a 12-lead electrocardiogram.
• Participant has any history of interstitial lung disease (ILD), including drug induced ILD or radiation pneumonitis requiring treatment with prolonged steroids or other immune suppressive agents that is unresolved or resolved within the last 3 months
• Participant has clinical evidence or history of ongoing significant bowel obstruction limiting oral intake, active uncontrolled malabsorption syndromes, or any other gastrointestinal disorder or defect that would interfere with absorption, distribution, metabolism, or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.

Where it is running

• City of Hope Cancer Center — Duarte, California, United States
• Outpatient CTRC — Aurora, Colorado, United States
• University of Colorado Hospital — Aurora, Colorado, United States
• University of Michigan Rogel Cancer Center — Ann Arbor, Michigan, United States

Full record on ClinicalTrials.gov

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