Clinical trial NCT04036682: A Phase 1/2 Trial of CLN-081 in Patients With Non-Small Cell Lung Cancer
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non Small Cell Lung Cancer
EGFR Exon 20 Mutation
Keywords: NSCLC
EGFR
Exon 20 insertions
CLN-081
TAS6417
zipalertinib
Lead sponsor: Cullinan Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2019-07-30
Enrollment: 284
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: All Cohorts: The rate and severity of treatment emergent AEs.
timeFrame: 24 months
measure: All Cohorts: The rate and severity of DLTs.
timeFrame: 24 months
measure: Phase 2 Dose Expansion Cohorts: Overall response rate (ORR)
timeFrame: 24 months
measure: Module A: Pharmacokinetic (PK) parameter
timeFrame: 24 months
measure: Module A: Pharmacokinetic (PK) parameter
timeFrame: 24 months
measure: Module B and C: Confirmed overall response rate (ORR) and duration of response (DOR) by independent review committee (IRC)
timeFrame: 24 months
Secondary outcomes:
measure: Phase 1 Dose Escalation and Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: ORR by Investigator assessment
timeFrame: 24 months
measure: Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DOR (duration of response).
timeFrame: 24 months
measure: Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: DCR (disease control rate)
timeFrame: 24 months
measure: Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: PFS (progression free survival)
timeFrame: 24 months
measure: Phase 1 Dose Escalation and Dose Expansion, Phase 2a Dose Expansion, and Module B and C Cohorts: OS (overall survival)
timeFrame: 24 months
measure: All Cohorts: Assessment of maximum concentration (Cmax)
timeFrame: 24 months
measure: All Cohorts: Assessment of area under curve (AUC)
timeFrame: 24 months
measure: All Cohorts: Assessment of time to maximum concentration (tmax)
timeFrame: 24 months
measure: All Cohorts: Assessment of terminal half-life (t1/2)
timeFrame: 24 months
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center, Inc
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Irvine
country: United States
facility: City of Hope at Irvine Lennar
state: California
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System - University Hospital
state: Michigan
city: Florham Park
country: United States
facility: Summit Medical Group PA
state: New Jersey
city: Mineola
country: United States
facility: Perlmutter Cancer Center at NYU Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Portland
country: United States
facility: Providence Cancer Center
state: Oregon
city: Portland
country: United States
facility: Providence Oncology & Hematology Care Clinic-Westside
state: Oregon
city: Pittsburg
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Hong Kong
country: Hong Kong
facility: Hong Kong University - Queen Mary Hospital
city: Careggi
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Marche
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
city: Milano
country: Italy
facility: IRCCS-Istituto Europeo di Oncologia
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria Modena
city: Monza
country: Italy
facility: San Gerardo Hospital
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Niigata
country: Japan
facility: Niigata Cancer Center
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation for Cancer Research
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital (SNUBH)
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Soeul
country: Korea, Republic of
facility: Asan Medical Center (AMC)
city: Soeul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University Of Korea St. Vincent's Hospital
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute (NKI)
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Singapore
country: Singapore
facility: Singapore Clinical Research Institute
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: A Coruña
country: Spain
facility: University Hospital A Coruna
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hospital Parc Tauli
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia l'Hospitalet
city: Barcelona
country: Spain
facility: START Barcelona
city: Las Palmas
country: Spain
facility: Complejo Hospitalario Universitario Insular Materno Infantil
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon (HGUGM)
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
city: Madrid
country: Spain
facility: University Hospital Quironsalud Madrid
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Valencia
country: Spain
facility: Universitat de Valencia - Hospital Universitari i Politecnic La Fe de Valencia (Hospital La Fe Bulevar Sur)
city: Chiayi City
country: Taiwan
facility: Chang Gung Medical Foundation Chiayi Chang Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: Chung Shan Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
Study officials:
affiliation: Massachusetts General Hospital
name: Zosia Piotrowska, MD
role: STUDY_CHAIR
References:
citation: 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.