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

Sponsor

Cullinan Pearl (Other)

Overall Status

Recruiting

CT.gov ID

NCT04036682

Collaborator

(none)

Enrollment

Locations

Arms

28.5

Anticipated Duration (Months)

4.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

CLN-081-101 is a Phase 1/2a, open label, multi-center study of CLN-081 in patients with NSCLC (non small cell lung cancer) harboring EGFR (epidermal growth factor receptor) exon 20 insertion mutations, to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as to evaluate preliminary efficacy.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer EGFR Exon 20 Mutation	Drug: CLN-081	Phase 1/Phase 2

Detailed Description

This is a Phase 1/2a, open-label, multicenter, first-in-human trial to evaluate the safety and tolerability, PK, PD, and preliminary 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 three parts: Phase 1 Dose Escalation, Phase 1 Dose Expansion, and Phase 2a Dose Expansion.

The objectives of the dose escalation part are to determine the safety, tolerability, MTD, recommended Phase 2 dose (RP2D), and to evaluate the anti-tumor activity of orally administered CLN-081 monotherapy. Additional objectives are to determine the pharmacokinetic (PK) profile of CLN-081 and CLN-081's activity in patients with known central nervous system (CNS) disease.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2a, Open-Label, Multi-Center Trial to Assess Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of CLN-081 in Patients With Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations

Actual Study Start Date :

Oct 31, 2019

Anticipated Primary Completion Date :

Mar 15, 2022

Anticipated Study Completion Date :

Mar 15, 2022

Arms and Interventions

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
Experimental: Phase 1 Dose Escalation (Rolling Six) CLN-081 QD or 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
Experimental: Phase 1 Dose Expansion(s) CLN-081 BID in expansion cohorts that may be opened at doses that meet pre-specified efficacy and safety criteria in Rolling Six cohorts.	Drug: CLN-081 CLN-081 tablets Other Names: TAS6417
Experimental: Phase 2a Dose Expansion(s) CLN-081 QD or BID in expansion cohorts that may be opened at doses that meet pre-specified efficacy and safety criteria in Phase 1 Dose Escalation cohorts.	Drug: CLN-081 CLN-081 tablets Other Names: TAS6417

Outcome Measures

Primary Outcome Measures

All Cohorts: The rate and severity of treatment emergent AEs. [24 months]
All Cohorts: The rate and severity of DLTs. [24 months]
All Cohorts: Incidence of safety laboratory assessment abnormalities. [24 months]
All Cohorts: Incidence of abnormalities in vital signs. [24 months]
Phase 2a Dose Expansion Cohorts: Overall response rate (ORR) [24 months]

Secondary Outcome Measures

Phase 1 Dose Escalation and Dose Expansion Cohorts: ORR [24 months]
Phase 1 Dose Escalation and Dose Expansion Cohorts: DOR (duration of response). [24 months]
Phase 1 Dose Escalation and Dose Expansion Cohorts: DCR (disease control rate) [24 months]
Phase 1 Dose Escalation and Dose Expansion Cohorts: PFS (progression free survival) [24 months]
Phase 1 Dose Escalation and Dose Expansion Cohorts: OS (overall survival) [24 months]
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]
All Cohorts: Assessment of mean residence time (MRT) [24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed recurrent, metastatic NSCLC.
Documented EGFR exon 20 insertion mutation demonstrated by a test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory.
Prior treatment in the recurrent/metastatic disease setting including:
A platinum-based chemotherapy regimen (or other chemotherapy regimen if platinum-based chemotherapy is contra-indicated)
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.
Measurable disease by RECIST 1.1.
Age ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Ability to take pills by mouth.
Have the following laboratory values:
Serum creatinine < 1.5 × ULN or if higher than normal range, calculated creatinine clearance (CrCl) must be ≥ 50 mL/min/1.73 m2 (by Cockroft-Gault formula); actual body weight must be used for CrCl unless BMI > 30 kg/m2 then lean body weight must be used.
Total bilirubin ≤ 1.5 × ULN unless prior history of Gilbert's syndrome.
Aspartate transaminase and alanine transaminase ≤ 2.5 × ULN, or ≤ 5 × ULN if due to liver involvement by tumor.
Hemoglobin ≥ 9.0 g/dL.
Platelets ≥ 100 × 109 cells/L.
Absolute neutrophil count ≥ 1.5 ×109 cells/L.
Ability to understand and the willingness to sign a written informed consent document and comply with study procedures.

Exclusion Criteria:

Prior Exon 20 Patients Only

No Prior treatment with an EGFR exon 20 insertion-targeting drug (e.g., poziotinib, TAK788, tarloxotinib, JNJ-61186372).

Rolling Six, Phase 1 Expansion, and Phase 2a Expansion Patients Only

Prior treatment with an EGFR exon 20 insertion-targeting drug (e.g., poziotinib, TAK788, tarloxotinib, JNJ-61186372).

All Patients

Treatment with any of the following:

An EGFR tyrosine kinase inhibitors (TKIs) ≤ 8 days or 5x the terminal phase elimination half-lives, whichever is longer, prior to the first dose of study drug on C1D1
Systemic anticancer treatment (excluding EGFR-TKIs as described above) ≤ 14 days prior to the first dose of study drug on C1D1.
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 to being eligible for evaluation as target lesions.
Immunotherapy ≤ 28 days prior to the first dose of study drug on C1D1.
Major surgery (excluding placement of vascular access) ≤ 28 days of the first dose of study drug on C1D1.
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.
Have known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, treated with surgery and/or radiation, 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.
Prior therapy with CLN-081.
Known hypersensitivity to CLN-081 or any drugs similar in structure or class.
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.
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
Resting corrected QT interval (QTc) > 470 msec.
Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy.
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.
Pregnant or lactating women; women of child-bearing potential (WOCBP) must have a negative serum pregnancy test ≤ 7 days prior to receiving study drug on C1D1. WOCBP 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.
History of another primary malignancy ≤ 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.
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.
For patients with a history of hepatitis B, active infection as defined by a positive HBsAg test and detectable HBV DNA. Patients ineligible due to detectable levels of HBV DNA at baseline may be rescreened for enrollment if their HBV DNA levels become undetectable after treatment with antiviral agents, and upon agreement between the investigator and Sponsor.
For patients with a history of hepatitis C, active infection as defined by a reactive HCV antibody test and detectable HCV RNA.
Active bleeding disorders.
Is, in the Investigator's opinion, unable or unwilling to comply with the trial procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	Pacific Shores Medical Group	Long Beach	California	United States	90813
3	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
4	AdventHealth	Orlando	Florida	United States	32804
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Washington University School of Medicine	Saint Louis	Missouri	United States	63112
7	New York University Langone Health	New York	New York	United States	10016
8	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
9	Providence Cancer Center	Portland	Oregon	United States	97213
10	Medical University of South Carolina	Charleston	South Carolina	United States	29425
11	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
12	Sun Yat Sen University Cancer Center	Guangzhou	Guangdong	China	510060
13	Hong Kong University - Shenzhen Hospital	Shenzhen	Guangdong	China	518057
14	Hong Kong University - Queen Mary Hospital	Hong Kong		Hong Kong
15	The Netherlands Cancer Institute (NKI)	Amsterdam		Netherlands	1066 CX
16	Singapore Clinical Research Institute	Singapore		Singapore	138669
17	National Cancer Centre Singapore	Singapore		Singapore	169610
18	National Taiwan University Hospital	Taipei		Taiwan	10002