A Phase 1/2 Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer

Non Small Cell Lung Cancer Clinical Trial

— REZILIENT1  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04036682
• Other study ID #: CLN-081-001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 31, 2019
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2024
• Source: Cullinan Therapeutics Inc.
• Contact: Shengting Li, MD, PhD
• Phone: 617-410-4650
• Email: ClinOps[@]cullinanoncology.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 284
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• EGFR Exon 20 Mutation
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• CLN-081
CLN-081 tablets

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Cullinan Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All Cohorts: The rate and severity of treatment emergent AEs.		24 months
Primary	All Cohorts: The rate and severity of DLTs.		24 months
Primary	Phase 2 Dose Expansion Cohorts: Overall response rate (ORR)		24 months
Primary	Module A: Pharmacokinetic (PK) parameter	Maximum Plasma Concentration [Cmax]	24 months
Primary	Module A: Pharmacokinetic (PK) parameter	Area Under Curve [AUC]	24 months
Primary	Module B and C: Confirmed overall response rate (ORR) and duration of response (DOR) by independent review committee (IRC)		24 months
Secondary	Phase 1 Dose Escalation and Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: ORR by Investigator assessment		24 months
Secondary	Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DOR (duration of response).		24 months
Secondary	Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DCR (disease control rate)		24 months
Secondary	Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: PFS (progression free survival)		24 months
Secondary	Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: OS (overall survival)		24 months
Secondary	All Cohorts: Assessment of maximum concentration (Cmax)		24 months
Secondary	All Cohorts: Assessment of area under curve (AUC)		24 months
Secondary	All Cohorts: Assessment of time to maximum concentration (tmax)		24 months
Secondary	All Cohorts: Assessment of terminal half-life (t1/2)		24 months