Mass General - Division of Clinical Research

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

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 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 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 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.

5.2 Exclusion Criteria

A patient who meets any of the following exclusion criteria will be ineligible to
participate in this study:

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:

c. 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.

d. Systemic anticancer treatment (excluding EGFR-TKIs as described above) within 14
days prior to the first dose of study drug on C1D1.

e. Immunotherapy ≤ 28 days prior to the first dose of study drug on C1D1. f.
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.

g. 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 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.

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 QTc > 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 women; women of child-bearing potential (WOCBP) must have a
negative serum pregnancy test at within seven days prior to receiving study drug on
C1D1. WOCBP and males with partners of child-bearing potential must agree to use
adequate birth control (Section 15.3) 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), active 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.