A Phase 1/2 Trial of CLN-081 in Patients with Non-Small Cell Lung Cancer (REZILIENT1)

A Phase 1/2, Open-Label, Multi-Center Trial to Assess Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of CLN-081 in Patients with Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations Who Have Previously Received Platinum-Based Systemic Chemotherapy

CLN-081-001 is a Phase 1/2, open label, multi-center study of CLN-081 in patients with non-small cell lung cancer (NSCLC) harboring EGFR (epidermal growth factor receptor) exon 20 insertion mutations, to characterize the safety, determine the recommended Phase 2 dose (RP2D), and evaluate efficacy.

Study Overview

• Status: Active, not recruiting
• Conditions: Non Small Cell Lung Cancer; EGFR Exon 20 Mutation
• Intervention / Treatment: Drug: CLN-081

Detailed Description

This is a Phase 1/2, open-label, multicenter, first-in-human trial to evaluate the safety and tolerability, PK, PD, and efficacy of CLN-081 in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

This trial is divided into multiple parts: Phase 1 Dose Escalation, Phase 2a Dose Expansion, Module A, Module B, and Module C.

The objectives of the dose escalation and dose expansion parts are to determine the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary anti-tumor activity of orally administered CLN-081 monotherapy.

The objective of Module A is to preliminarily assess the effect of food on the PK profile of CLN-081.

The objective of Module B is to further characterize the safety and efficacy of CLN-081 monotherapy in patients with EGFR exon 20 insertion mutation NSCLC who have received prior systemic anti-cancer treatment for locally advanced or metastatic disease.

The objective of Module C is to explore the safety, tolerability, and efficacy of CLN-081 monotherapy in patients with EGFR exon 20 insertion mutation NSCLC who have received prior treatment with an agent approved for EGFR exon 20 insertion mutant NSCLC

CLN-081 will be dosed twice daily (BID).

• Study Type: Interventional
• Enrollment (Estimated): 284
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Hong Kong University - Queen Mary Hospital
• Italy
  • Careggi, Italy
    • Azienda Ospedaliero Universitaria Careggi
  • Marche, Italy
    • Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I
  • Meldola, Italy
    • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
  • Milano, Italy
    • IRCCS-Istituto Europeo di Oncologia
  • Modena, Italy
    • Azienda Ospedaliero Universitaria Modena
  • Monza, Italy
    • San Gerardo Hospital
  • Ravenna, Italy
    • Ospedale Santa Maria Delle Croci
• Japan
  • Chiba, Japan
    • National Cancer Center Hospital East
  • Niigata, Japan
    • Niigata Cancer Center
  • Osaka, Japan
    • Osaka City General Hospital
  • Osaka, Japan
    • Osaka International Cancer Institute
  • Shizuoka, Japan
    • Shizuoka Cancer Center
  • Tokyo, Japan
    • National Cancer Center Hospital
  • Tokyo, Japan
    • The Cancer Institute Hospital of Japanese Foundation for Cancer Research
• Korea, Republic of
  • Goyang-si, Korea, Republic of
    • National Cancer Center
  • Gyeonggi-do, Korea, Republic of
    • Seoul National University Bundang Hospital (SNUBH)
  • Incheon, Korea, Republic of
    • Inha University Hospital
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Soeul, Korea, Republic of
    • Korea University Guro Hospital
  • Soeul, Korea, Republic of
    • Asan Medical Center (AMC)
  • Suwon-si, Korea, Republic of
    • Ajou University Hospital
  • Suwon-si, Korea, Republic of
    • The Catholic University of Korea St. Vincent's Hospital
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • The Netherlands Cancer Institute (NKI)
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre Singapore
  • Singapore, Singapore, 138669
    • Singapore Clinical Research Institute
• Spain
  • A Coruña, Spain
    • University Hospital A Coruña
  • Barcelona, Spain
    • Hospital Clínic I Provincial de Barcelona
  • Barcelona, Spain
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain
    • Institut Català d'Oncologia L'Hospitalet
  • Barcelona, Spain
    • Hospital Parc Tauli
  • Barcelona, Spain
    • START Barcelona
  • Las Palmas, Spain
    • Complejo Hospitalario Universitario Insular Materno Infantil
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro de Majadahonda
  • Madrid, Spain
    • Hospital General Universitario Gregorio Maranon (HGUGM)
  • Madrid, Spain
    • University Hospital Quironsalud Madrid
  • Málaga, Spain
    • Hospital Regional Universitario de Malaga
  • Pamplona, Spain
    • Clinica Universidad de Navarra
  • Valencia, Spain
    • Universitat de Valencia - Hospital Universitari i Politecnic La Fe de Valencia (Hospital La Fe Bulevar Sur)
• Taiwan
  • Chiayi City, Taiwan
    • Chang Gung Medical Foundation Chiayi Chang Gung Memorial Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Taichung, Taiwan
    • Chung Shan Medical University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan
    • Taipei Medical University Hospital
• United States
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center, Inc
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Irvine, California, United States, 92618
      • City of Hope at Irvine Lennar
    • Long Beach, California, United States, 90813
      • Pacific Shores Medical Group
  • Florida
    • Orlando, Florida, United States, 32804
      • AdventHealth
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System - University Hospital
  • New Jersey
    • Florham Park, New Jersey, United States, 07932
      • Summit Medical Group PA
  • New York
    • Mineola, New York, United States, 11501
      • Perlmutter Cancer Center at NYU Langone Hospital - Long Island
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Health
  • Ohio
    • Canton, Ohio, United States, 44701
      • Gabrail Cancer Center Research
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Cancer Center
    • Portland, Oregon, United States, 97225
      • Providence Oncology & Hematology Care Clinic-Westside
  • Pennsylvania
    • Pittsburg, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Histologically or cytologically confirmed locally advanced or metastatic NSCLC (all patients).
2. Documented EGFR ex20ins mutation demonstrated by a validated test listed in Section 9.7 and performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory (all patients other than Module A Food Effect PK Assessment Module). Institutions that don't have access to these tests should contact the sponsor for assistance.

3. Prior treatment in the recurrent/metastatic disease setting including:

   1. A platinum-based chemotherapy regiment (or other chemotherapy regimen if platinum-based chemotherapy is contra-indicated)
   2. Any other approved standard therapy that is available to the patient, unless this therapy is contraindicated, intolerable to the patient, or is declined by the patient. In the case of a patient declining such therapy, documentation that the patient has been informed and declined should be documented in the medical record.
   3. No prior therapy is required for patients enrolled on Module A.
   4. Prior therapy with an agent approved by the local regulatory authorities for the treatment of EGFR ex20ins mutant NSCLC (Module C only).
4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (except for patients enrolled on Module A).
5. Age ≥ 18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Ability to take pills by mouth.

8. Have the following laboratory values:

   1. Serum creatinine < 1.5 × upper limit of normal (ULN) or calculated creatinine clearance (CrCl) must be ≥ 50 mL/min/1.73 m2 (if calculated by Cockroft-Gault formula, the actual body weight must be used for CrCl unless body mass index [BMI] >30 kg/m2 then lean body weight must be used).
   2. Total bilirubin ≤ 1.5 × ULN unless prior history of Gilbert's syndrome.
   3. AST and ALT ≤ 2.5 × ULN, or ≤ 5 × ULN if due to liver involvement by tumor.
   4. Hemoglobin ≥ 9.0 g/dL in the absence of transfusion ≤ 14 days prior to the first dose of study drug on C1D1.
   5. Platelets ≥ 100 × 109 cells/L in the absence of transfusion <14 days prior to the first dose of study drug on Cycle 1 Day 1 (C1D1).
   6. Absolute neutrophil count ≥ 1.5 ×109 cells/L.
9. For Module A patients only: patients must have a negative coronavirus disease 2019 (COVID-19) polymerase chain reaction test prior to enrolment.
10. For Module B and Module C patients only: verification of suitable archived tumor tissue available at the participating center for biomarker analysis. A fresh biopsy is required if an archived sample is not available.
11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

R6, Phase 1 Expansion, Phase 2a, Module A and Module B Patients Only

1. Prior treatment with an EGFR ex20ins -targeting drug (eg, including, but not limited to poziotinib, mobocertinib, amivantamab, DZD9008, BDTX-189).

   Note: enrolment of patients treated previously with EGFR ex20ins-targeting drugs allowed selectively during accelerated titration dose escalation and Module C only.

   Module A Food Effect PK Assessment Module patients only

2. Conditions that compromise esophageal or gastrointestinal (GI) function, including esophageal, gastric, pancreatic, hepatobiliary, or small bowel carcinomas, or history of gastric resection.
3. Recurrent diarrhea, nausea, or vomiting.

4. Unable to refrain from or anticipates the use of:

   1. Any drug, including prescription and non-prescription medications, including drugs that change gastrointestinal motility (eg, loperamide) or gastric pH (eg, antacids, H2 antagonists, proton pump inhibitors), herbal remedies, or vitamin supplements within 14 days prior to the first dosing on Day 1 to follow-up.
   2. Any drugs known to be inhibitors or inducers of CYP3A enzymes and/or P-glycoprotein (P-gp), including St. John's Wort and grape fruit juice, within 28 days prior to the first dosing and throughout the PK assessment.
5. Any allergies to the composition of the high fat meal.

6. Patients who use tobacco products.

   All Patients

7. History of COVID-19-related pneumonitis requiring hospitalization.
8. History of COVID-19 infection within 4 weeks prior to enrolment, or clinically significant pulmonary symptoms related to prior COVID-19 pneumonitis.

9. Treatment with any of the following:

   1. An EGFR TKI ≤ 8 days or 5 × the terminal phase t1/2, whichever is longer, prior to the first dose of study drug on C1D1.
   2. Systemic anticancer treatment (excluding EGFR-TKIs as described above) within 14 days prior to the first dose of study drug on C1D1.
   3. Immunotherapy ≤ 28 days prior to the first dose of study drug on C1D1.
   4. Radiotherapy < 28 days and palliative radiation ≤ 14 days prior to the first dose of study drug on C1D1. If irradiated, lesions must have demonstrated clear-cut progression prior to being eligible for evaluation as target lesions.
   5. Major surgery (excluding placement of vascular access) ≤ 28 days of the first dose of study drug on C1D1.
10. Have any unresolved toxicity of Grade ≥ 2 from previous anti-cancer treatment, except for alopecia and skin pigmentation. Patients with chronic but stable Grade 2 toxicities may be allowed to enroll after agreement between the Investigator and Sponsor.
11. Have known or suspected leptomeningeal metastasis. Have known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, treated with surgery and/or radiation (if clinically indicated), and has been stable without requiring escalating corticosteroids or anti-convulsant medications for at least four weeks prior to the first dose of study drug on C1D1.
12. Prior therapy with CLN-081.
13. Known hypersensitivity to CLN-081 or any drugs similar in structure or class.
14. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, treatment-related pneumonitis, or any evidence of clinically active interstitial lung disease.
15. Cardiac conditions as follows: Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment.
16. Resting QTcF > 470 msec.
17. Patient is unable to take drugs po due to disorders or diseases that may affect GI function, including but not limited to inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy.
18. Have any condition or illness that, in the opinion of the Investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug.
19. Pregnant or lactating females; females of child-bearing potential (FOCBP) must have a negative serum pregnancy test at within seven days prior to receiving study drug on C1D1. FOCBP and males with partners of child-bearing potential must agree to use adequate birth control (Section 16.3) throughout their participation and for six months following the last dose of study treatment.
20. History of another primary malignancy within 2 years prior to starting study drug on C1D1, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ.
21. Uncontrolled intercurrent illness including, but not limited to, uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including human immunodeficiency virus (HIV) and active clinical tuberculosis), or renal transplant; ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirements.
22. For patients with a history of hepatitis B (HBV), negative PCR test is required. Patients with active hepatitis B (HBV) infection [as defined by a positive hepatitis B serum antigen (HBsAg) test and detectable HBV deoxyribonucleic acid (DNA)]. Patients ineligible due to detectable levels of HBV DNA at baseline may be rescreened for enrolment if their HBV DNA levels become undetectable after treatment with antiviral agents, and upon agreement between the Investigator and Sponsor.
23. For patients with a history of hepatitis C, active infection as defined by a reactive hepatitis C virus (HCV) antibody test and detectable HCV ribonucleic acid (RNA).
24. Active bleeding disorders.
25. The patient is, in the Investigator's opinion, unable or unwilling to comply with the trial procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Escalation (Accelerated Titration); CLN-081 BID in single patient dose escalation cohorts enrolling NSCLC patients with EGFR exon 20 insertion mutations that either have received or never received prior EGFR TKIs.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib
Experimental: Phase 1 Dose Escalation (Rolling Six); CLN-081 BID in Rolling Six dose escalation cohorts enrolling NSCLC patients with EGFR exon 20 insertion mutations.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib
Experimental: Module A Food Affect; Single-dose CLN-081 150 mg with and without high fat food intake.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib
Experimental: Module B; CLN-081 BID in NSCLC patients with EGFR exon 20 insertion mutations that have received prior systemic therapy for locally advanced or metastatic disease.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib
Experimental: Module C; CLN-081 BID to patients with EGFR exon 20 insertion mutant NSCLC after prior therapy with an agent approved for the treatment of ex20ins mutant NSCLC.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib
Experimental: Phase 2a Dose Expansion(s); CLN-081 BID in expansion cohorts that may be opened at doses that meet pre-specified efficacy and safety criteria.	Drug: CLN-081; CLN-081 tablets; Other Names: TAS6417; zipalertinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Cohorts: The rate and severity of treatment emergent AEs.		24 months
All Cohorts: The rate and severity of DLTs.		24 months
Phase 2 Dose Expansion Cohorts: Overall response rate (ORR)		24 months
Module A: Pharmacokinetic (PK) parameter	Maximum Plasma Concentration [Cmax]	24 months
Module A: Pharmacokinetic (PK) parameter	Area Under Curve [AUC]	24 months
Module B and C: Confirmed overall response rate (ORR) and duration of response (DOR) by independent review committee (IRC)		24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
All Cohorts: Assessment of maximum concentration (Cmax)	24 months
All Cohorts: Assessment of area under curve (AUC)	24 months
All Cohorts: Assessment of time to maximum concentration (tmax)	24 months
All Cohorts: Assessment of terminal half-life (t1/2)	24 months
Phase 1 Dose Escalation and Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: ORR by Investigator assessment	24 months
Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DOR (duration of response).	24 months
Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DCR (disease control rate)	24 months
Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: PFS (progression free survival)	24 months
Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: OS (overall survival)	24 months

Collaborators and Investigators

• Sponsor: Cullinan Therapeutics Inc.
• Investigators: Study Chair: Zosia Piotrowska, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Ye L, Chen X, Zhou F. EGFR-mutant NSCLC: emerging novel drugs. Curr Opin Oncol. 2021 Jan;33(1):87-94. doi: 10.1097/CCO.0000000000000701.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2019
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: July 23, 2019
• First Submitted That Met QC Criteria: July 25, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; EGFR; Exon 20 insertions; CLN-081; TAS6417; zipalertinib
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: CLN-081-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No