| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations |
| Niet-kleincellige longkanker met EGFR-exon 20-invoegingsmutaties |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I
• Assess safety, tolerability and define maximum tolerated dose (MTD) of orally administered CLN-081
Phase 2a - Dose Expansion
• Evaluate objective response rate (ORR) and define recommended
phase 2 dose (RP2D) of orally administered CLN-081
Module A
• Investigate PK profile of single doses of 150 mg of CLN-081 with or without a high fat meal in patients with solid tumors
Module B, Part 1
• Define safety, tolerability and PK profile of CLN-081 administered as repeat doses of 150 mg BID with food to patients with locally-advanced
or metastatic NSCLC harboring EGFR ex20ins mutations
• Investigate effect of food on CLN-081 tolerability at 150 mg BID
Module B, Part 2
• Evaluate ORR and duration of response (DOR) by ICR of orally
administered CLN-081 at RP2D
Module C
• Evaluate ORR and DOR by ICR of orally administered CLN-081 100 mg BID in patients whose disease has progressed after prior treatment with an agent for the treatment of EGFR ex20ins mutant NSCLC |
|
| E.2.2 | Secondary objectives of the trial |
Phase I
• Assess anti-tumor activity
• Characterize select PK parameters
Phase 2a
• Evaluate DOR, DCR
• Determine median PFS, median OS, landmark PFS, landmark OS
• Confirm safety and tolerability
• Characterize select PK parameters and relationships to response
Module A
• Assess safety of single doses of 150 mg of CLN-081 with or without food
Module B, Part 1
• Evaluate ORR by ICR of repeat doses of 150 mg BID
• Investigate antitumor activity of CLN-081 150 mg BID given with food
• Evaluate concordance between local and central biomarker determination via CDx assay.
Module B, Part 2 (CLN-081 RP2D) and Module C (CLN-081 100 mg BID)
• Evaluate ORR and DOR by Investigator assessment
• Evaluate DCR, median PFS and OS, landmark PFS and OS rates by ICR and investigator
• Confirm safety and tolerability
• Characterize select PK parameters and relationships with response
• Evaluate concordance between local and central biomarker determination via CDx assay. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically 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.
2. Documented 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).
3. Prior treatment in the recurrent/metastatic disease setting including:
a. A 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).
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:
a. Serum creatinine < 1.5 × upper limit of normal (ULN) or if higher than
normal range, 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. Total bilirubin ≤ 1.5 × ULN unless prior history of Gilbert's syndrome.
c. AST and ALT ≤ 2.5 × ULN, or ≤ 5 × ULN if due to liver involvement by
tumor.
d. Hemoglobin ≥ 9.0 g/dL in the absence of transfusion ≤ 14 days prior
to the first dose of study drug on C1D1.
e. Platelets ≥ 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. Absolute neutrophil count ≥ 1.5 ×10E9 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. |
|
| E.4 | Principal exclusion criteria |
R6, Phase 1 Expansion, Phase 2a, Module A and Module B Patients Only
1. 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.
Module A Patients Only
2. Conditions that compromise esophageal or gastrointestinal (GI)
function.
3. Recurrent diarrhea, nausea, or vomiting.
4. Unable to refrain from or anticipates use of any drug, including
prescription and non-prescription medications (see protocol) for the periods defined in the protocol.
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:
a. An EGFR TKIs ≤ 8 days or 5 x the terminal phase elimination halflives,
whichever is longer, prior to first dose of study drug on C1D1
b. Systemic anticancer treatment (excluding EGFR-TKIs as described
above) within 14 days prior to the first dose of study drug on C1D1.
c. Immunotherapy ≤ 28 days prior to the first dose of study drug on
C1D1.
d. 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.
e. 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 enrol 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 CHF Class
III/IV according to the NYHA Functional Classification or serious cardiac arrhythmias requiring treatment.
16. Resting QTcF > 470 msec.
17. 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.
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; 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.
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 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 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.
23. For patients with a history of hepatitis C, active infection as defined
by a reactive HCV antibody test and detectable HCV RNA.
24. Active bleeding disorders.
25. The patient is, in the Investigator's opinion, unable or unwilling to
comply with the trial procedure |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1
• The rate and severity of treatment emergent AEs (TEAEs), SAEs, incidence of safety laboratory assessment abnormalities
Phase 2a
• ORR by investigator assessment per RECIST v1.1
Module A
• CLN-081 PK
Module B, Part 1
• The rate and severity of TEAEs, DLTs, SAEs, incidence of safety
laboratory assessment abnormalities
• CLN-081 PK
Module B, Part 2 and Module C
• ORR by independent central review assessment per RECIST v1.1
• Tumor response characteristics including DOR by independent central review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study (refer to the protocol for further information) |
|
| E.5.2 | Secondary end point(s) |
Phase 1
• ORR by Investigator assessment per RECIST v1.1
• DOR, DCR, PFS, and OS by investigator assessment
• CLN-081 PK
Phase 2a
• DOR, DCR, PFS, time to tumor response, and OS based on investigator
assessment
• The rate and severity of TEAEs, SAEs, incidence of safety laboratory
assessment abnormalities
• CLN-081 PK
Module A
• The rate and severity of TEAEs, SAEs, incidence of safety laboratory
assessment abnormalities
Module B, Part 1
• ORR based on independent central review assessment per RECIST v1.1
• Tumor response characteristics including DOR, DCR, PFS, and time to tumor response based on local investigator assessment and OS
• Concordance between local and central determination of EGFR ex20ins mutational status via CDx assay
Module B, Part 2
• ORR and DOR by Investigator assessment
• DCR, median PFS, rate of PFS and OS at 6, 12 and 24 months based on
independent central review and investigator assessment and OS
• The rate and severity of TEAEs, DLTs, SAEs, incidence of safety
laboratory assessment abnormalities
• CLN-081 PK
• Concordance between local and central determination of EGFR ex20ins mutational status via CDx assay
Module C
• ORR and DOR by Investigator assessment per RECIST v1.1
• Tumor response characteristics including DCR, PFS, and time to tumor response assessed by independent central review and investigator
assessment and OS
• The rate and severity of TEAEs, DLTs, SAEs, incidence of safety
laboratory assessment abnormalities
• CLN-081 PK
• Concordance between local and central determination of EGFR ex20ins |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study (refer to the protocol for further information) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1/2 study (Phase I enrolment complete) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Hong Kong |
| Taiwan |
| Japan |
| Korea, Republic of |
| United States |
| Italy |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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