CLN-081 for Non-small cell lung cancer with EGFR exon 20 insertion mutations

Inclusion criteria

• {"criterion_text":"- 1.\tHistologically or cytologically confirmed locally advanced or metastatic NSCLC (all patients). For module A only, histologically or cytologically confirmed solid tumor with the exception of esophageal, gastric, pancreatic, hepatobiliary, or small bowel carcinomas, or history of gastric resection.\n- 10.\tFor 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.\n- 11.\tAbility to understand and the willingness to sign a written informed consent document.\n- 2.\tDocumented EGFR exon 20 insertion (ex20ins) mutation demonstrated by a validated test (per protocol) and performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory (all patients other than Module A Food Effect PK Assessment Module).\n- 3.\tPrior treatment in the recurrent/metastatic disease setting including: a)\tA platinum-based chemotherapy regiment (or other chemotherapy regimen if platinum-based chemotherapy is contra-indicated). b) 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. c) No prior therapy is required for patients enrolled on Module A. d) Prior therapy with an agent approved by the local regulatory authorities for the treatment of EGFR ex20ins mutant NSCLC (Module C only).\n- 4.\tMeasurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (except for patients enrolled on Module A).\n- 5.\tAge ≥ 18 years.\n- 6.\tEastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n- 7.\tAbility to take pills by mouth.\n- 8.\tHave the following laboratory values: a) 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). b)\tTotal bilirubin ≤ 1.5 × ULN unless prior history of Gilbert's syndrome. c)\tAST and ALT ≤ 2.5 × ULN, or ≤ 5 × ULN if due to liver involvement by tumor. d)\tHemoglobin ≥ 9.0 g/dL in the absence of transfusion ≤ 14 days prior to the first dose of study drug on C1D1. e)\tPlatelets ≥ 100 × 10E9 cells/L in the absence of transfusion <14 days prior to the first dose of study drug on Cycle 1 Day 1 (C1D1). f)\tAbsolute neutrophil count ≥ 1.5 ×10E9 cells/L.\n- 9.\tFor Module A patients only: patients must have a negative coronavirus disease 2019 (COVID-19) polymerase chain reaction test prior to enrolment."}

Exclusion criteria

• {"criterion_text":"- 1.\tR6, Phase 1 Expansion, Phase 2a, Module A and Module B Patients Only: Prior treatment with an EGFR ex20ins-targeting drug (see protocol for examples). Note: enrolment of patients treated previously with EGFR ex20ins-targeting drugs allowed selectively during accelerated titration dose escalation and Module C only.\n- 18.\tAll Patients: 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.\n- 19.\tAll Patients: Pregnant or lactating females; 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 throughout their participation and for six months following the last dose of study treatment.\n- 2.\tModule A Patients Only: Conditions that compromise esophageal or gastrointestinal (GI) function.\n- 20.\tAll Patients: 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.\n- 21.\tAll Patients: Uncontrolled intercurrent illness including, but not limited to, uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including 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.\n- 22.\tAll Patients: For patients with a history of HBV, negative PCR test is required. Patients with active HBV infection. 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.\n- 23.\tAll Patients: For patients with a history of hepatitis C, active infection as defined by a reactive HCV antibody test and detectable HCV RNA.\n- 24.\tAll Patients: Active bleeding disorders.\n- 25.\tAll Patients: The patient is, in the Investigator's opinion, unable or unwilling to comply with the trial procedure.\n- 3.\tModule A Patients Only: Recurrent diarrhea, nausea, or vomiting.\n- 10.\tAll Patients: 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 enrol after agreement between the Investigator and Sponsor.\n- 4.\tModule A Patients Only: Unable to refrain from or anticipates use of any drug, including prescription and non-prescription medications (see protocol for further details) for the periods defined in the protocol.\n- 5.\tModule A Patients Only: Any allergies to the composition of the high fat meal.\n- 6.\tModule A Patients Only: Patients who use tobacco products.\n- 7.\tAll Patients: History of COVID-19-related pneumonitis requiring hospitalization.\n- 8.\tAll Patients: History of COVID-19 infection within 4 weeks prior to enrolment, or clinically significant pulmonary symptoms related to prior COVID-19 pneumonitis.\n- 9.\tAll Patients: Treatment with any of the following: a)\tAn EGFR TKIs ≤ 8 days or 5 x the terminal phase elimination half-lives, whichever is longer, prior to first dose of study drug on C1D1. b)\tSystemic anticancer treatment (excluding EGFR-TKIs as described above) within 14 days prior to the first dose of study drug on C1D1. c)\tImmunotherapy ≤ 28 days prior to the first dose of study drug on C1D1. d)\tRadiotherapy ≤ 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. e)\tMajor surgery (excluding placement of vascular access) ≤ 28 days of the first dose of study drug on C1D1.\n- 11.\tAll Patients: 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.\n- 12.\tAll Patients: Prior therapy with CLN-081.\n- 13.\tAll Patients: Known hypersensitivity to CLN-081 or any drugs similar in structure or class.\n- 14.\tAll Patients: Past medical history of interstitial lung disease, drug-induced interstitial lung disease, treatment-related pneumonitis, or any evidence of clinically active interstitial lung disease.\n- 15.\tAll Patients: Cardiac conditions as follows: Patient has a history of CHF Class III/IV according to the NYHA Functional Classification or serious cardiac arrhythmias requiring treatment.\n- 16.\tAll Patients: Resting QTcF > 470 msec.\n- 17.\tAll Patients: Patient is unable to take drugs orally due to disorders or diseases that may affect GI function, including but not limited to inflammatory bowel diseases or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy."}

Primary endpoints

• {"endpoint_text":"- 1.\tPhase 1: The rate and severity of treatment emergent AEs (TEAEs), SAEs, incidence of safety laboratory assessment abnormalities","definition_or_measurement_approach":"Assessment of rate and severity of TEAEs and SAEs and incidence of safety laboratory assessment abnormalities (safety laboratory monitoring as specified in protocol)."}
• {"endpoint_text":"- 2.\tPhase 2a: ORR by investigator assessment per RECIST v1.1","definition_or_measurement_approach":"Objective response rate assessed by investigator according to RECIST v1.1."}
• {"endpoint_text":"- 3.\tModule A: CLN-081 PK","definition_or_measurement_approach":"Pharmacokinetic profiling of CLN-081 (single-dose PK assessment, with and without high fat meal as specified)."}
• {"endpoint_text":"- 4.\tModule B, Part 1: *The rate and severity of TEAEs, DLTs, SAEs, incidence of safety laboratory assessment abnormalities; *CLN-081 PK","definition_or_measurement_approach":"Safety assessments (TEAEs, dose-limiting toxicities, SAEs, laboratory abnormalities) and PK characterization during repeat-dose (BID) administration."}
• {"endpoint_text":"- 5.\tModule B, Part 2 and 6. Module C: *\tORR by independent central review assessment per RECIST v1.1; *\tTumor response characteristics including DOR by independent central review","definition_or_measurement_approach":"ORR and tumor response characteristics (including duration of response) assessed by independent central review per RECIST v1.1."}

Secondary endpoints

• {"endpoint_text":"- 1.\tPhase 1: a)\tORR by Investigator assessment per RECIST v1.1 b)\tDOR, DCR, PFS, and OS by investigator assessment c)\tCLN-081 PK","definition_or_measurement_approach":"Investigator-assessed ORR (RECIST v1.1), duration of response, disease control rate, progression-free survival, overall survival, and PK parameters."}
• {"endpoint_text":"- 2.\tPhase 2a: a)\tDOR, DCR, PFS, time to tumor response, and OS based on investigator assessment b)\tThe rate and severity of TEAEs, SAEs, incidence of safety laboratory assessment abnormalities c)\tCLN-081 PK","definition_or_measurement_approach":"Investigator-assessed tumor response metrics (DOR, DCR, PFS, time to response, OS), safety (TEAEs/SAEs/labs), and PK."}
• {"endpoint_text":"- 3.\tModule A: a)\tThe rate and severity of TEAEs, SAEs, incidence of safety laboratory assessment abnormalities","definition_or_measurement_approach":"Safety assessment of single-dose administration (TEAEs/SAEs/laboratory abnormalities)."}
• {"endpoint_text":"- 4.\tModule B, Part 1: a) ORR based on independent central review assessment per RECIST v1.1 b) Tumor response characteristics including DOR, DCR, PFS, and time to tumor response based on local investigator assessment and OS","definition_or_measurement_approach":"ORR by independent central review (RECIST v1.1); tumor response characteristics by investigator and central review; OS measured."}
• {"endpoint_text":"- 5.\tModule B, Part 2: a)\tORR and DOR by Investigator assessment b) DCR, median PFS, rate of PFS and OS at 6, 12 and 24 months based on independent central review and investigator assessment and OS c) The rate and severity of TEAEs, DLTs, SAEs, incidence of safety laboratory assessment abnormalities d) CLN-081 PK","definition_or_measurement_approach":"Investigator and central review assessments of ORR, DOR, DCR, median PFS and timepoint PFS/OS rates; safety (TEAEs/DLTs/SAEs/labs); PK."}
• {"endpoint_text":"- 6. Module C: a)\tORR and DOR by Investigator assessment per RECIST v1.1 b) Tumor response characteristics including DCR, PFS, and time to tumor response assessed by independent central review and investigator assessment and OS c) The rate and severity of TEAEs, DLTs, SAEs, incidence of safety laboratory assessment abnormalities d) CLN-081 PK","definition_or_measurement_approach":"Investigator and central review assessments of ORR, DOR, DCR, PFS, time to response and OS; safety and PK assessments."}

Netherlands

Earliest CTIS Part Ii Submission Date

16-08-2024

Latest Decision Or Authorization Date

23-09-2024

Processing Time Days

38

Number Of Sites

2

Number Of Participants

27

Italy

Earliest CTIS Part Ii Submission Date

16-08-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

45

Number Of Sites

5

Number Of Participants

14

Spain

Earliest CTIS Part Ii Submission Date

16-08-2024

Latest Decision Or Authorization Date

10-10-2024

Processing Time Days

55

Number Of Sites

13

Number Of Participants

22

Primary sponsor

Full Name

Cullinan Pearl Corp.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Medical Imaging

Responsibilities

Collection and management of imaging data

Name

Icon Laboratory Services Inc.

Responsibilities

Sample storage/ shipping

Name

Icon Clinical Research Limited

Responsibilities

Multiple sponsor duties supporting the trial (codes listed in CTIS); sample storage/shipping

Name

Icon Development Solutions LLC

Responsibilities

PK and PD analysis

Third parties

• {"country":"United States","full_name":"Icon Medical Imaging","duties_or_roles":"Collection and management of imaging data","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Icon Laboratory Services Inc.","duties_or_roles":"Sample storage/ shipping","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Multiple sponsor duties (codes provided in CTIS); includes sample storage/shipping (value listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Development Solutions LLC","duties_or_roles":"PK and PD analysis","organisation_type":"Pharmaceutical company"}