Phase 1/2 Study of CLN-081 in Patients with Lung Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cullinan Pearl Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Mar 2020 → ongoing

Decision date (initial)

2024-09-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Cullinan Pearl Corp., USA

External identifiers

EU CT number

2024-516532-97-00

EudraCT number

2019-002409-23

ClinicalTrials.gov

NCT04036682

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

1. Phase I :
*Assess safety, tolerability and define maximum tolerated dose (MTD) of orally administered CLN-081.
2. Phase 2a - Dose Expansion:
*Evaluate objective response rate (ORR) and define recommended phase 2 dose (RP2D) of orally administered CLN-081.
3. Module A
* Investigate PK profile of single doses of CLN-081 with or without a high fat meal in patients with solid tumors.
4. Module B, Part 1:
* Define safety, tolerability and PK profile of CLN-081 administered as repeat doses BID with food to patients with locally-advanced or metastatic NSCLC harboring EGFR ex20ins mutations.
*Investigate effect of food on CLN-081 tolerability BID.
5. Module B, Part 2:
* Evaluate ORR and duration of response (DOR) by ICR of orally administered CLN-081 at RP2D.
6. Module C:
* Evaluate ORR and DOR by ICR of orally administered CLN-081 BID in patients whose disease has progressed after prior treatment with an agent for the treatment of EGFR ex20ins mutant NSCLC.

Secondary objectives 5

1. 1. Phase I: a) Assess anti-tumor activity; b) Characterize select PK parameters
2. 2. Phase 2a: a) Evaluate DOR, DCR; b) PFS, OS c) Confirm safety and tolerability; d) Characterize select PK parameters and relationships to response
3. 3. Module A: a) Assess safety of single doses of CLN-081 with or without food
4. 4. Module B, Part 1: a) Evaluate ORR by ICR; b) Investigate antitumor activity of CLN-081 BID given with food
5. 5. Module B, Part 2 (CLN-081 RP2D) and 6. Module C: a) Evaluate ORR and DOR by Investigator assessment; b) Evaluate DCR, PFS and OS; c) Confirm safety and tolerability; d) Characterize select PK parameters and relationships with response

Conditions and MedDRA coding

Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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. 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. 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. 4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (except for patients enrolled on Module A).
5. 5. Age ≥ 18 years.
6. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. 7. Ability to take pills by mouth.
8. 8. Have 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) 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. 9. For Module A patients only: patients must have a negative coronavirus disease 2019 (COVID-19) polymerase chain reaction test prior to enrolment.
10. 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. 11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria 25

1. 1. R6, 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.
2. 10. All 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.
3. 11. All 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.
4. 12. All Patients: Prior therapy with CLN-081.
5. 13. All Patients: Known hypersensitivity to CLN-081 or any drugs similar in structure or class.
6. 14. All 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.
7. 15. All 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.
8. 16. All Patients: Resting QTcF > 470 msec.
9. 17. All 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.
10. 18. All 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.
11. 19. All 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.
12. 2. Module A Patients Only: Conditions that compromise esophageal or gastrointestinal (GI) function.
13. 20. All 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.
14. 21. All 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.
15. 22. All 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.
16. 23. All Patients: For patients with a history of hepatitis C, active infection as defined by a reactive HCV antibody test and detectable HCV RNA.
17. 24. All Patients: Active bleeding disorders.
18. 25. All Patients: The patient is, in the Investigator's opinion, unable or unwilling to comply with the trial procedure.
19. 3. Module A Patients Only: Recurrent diarrhea, nausea, or vomiting.
20. 4. Module 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.
21. 5. Module A Patients Only: Any allergies to the composition of the high fat meal.
22. 6. Module A Patients Only: Patients who use tobacco products.
23. 7. All Patients: History of COVID-19-related pneumonitis requiring hospitalization.
24. 8. All Patients: History of COVID-19 infection within 4 weeks prior to enrolment, or clinically significant pulmonary symptoms related to prior COVID-19 pneumonitis.
25. 9. All Patients: Treatment with any of the following: a) An 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) 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. 1. Phase 1: The rate and severity of treatment emergent AEs (TEAEs), SAEs, incidence of safety laboratory assessment abnormalities
2. 2. Phase 2a: ORR by investigator assessment per RECIST v1.1
3. 3. Module A: CLN-081 PK
4. 4. Module B, Part 1: *The rate and severity of TEAEs, DLTs, SAEs, incidence of safety laboratory assessment abnormalities; *CLN-081 PK
5. 5. Module B, Part 2 and 6. Module C: * ORR by independent central review assessment per RECIST v1.1; * Tumor response characteristics including DOR by independent central review

Secondary endpoints 6

1. 1. Phase 1: a) ORR by Investigator assessment per RECIST v1.1 b) DOR, DCR, PFS, and OS by investigator assessment c) CLN-081 PK
2. 2. Phase 2a: a) DOR, DCR, PFS, time to tumor response, and OS based on investigator assessment b) The rate and severity of TEAEs, SAEs, incidence of safety laboratory assessment abnormalities c) CLN-081 PK
3. 3. Module A: a) The rate and severity of TEAEs, SAEs, incidence of safety laboratory assessment abnormalities
4. 4. Module 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
5. 5. Module B, Part 2: a) ORR 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
6. 6. Module C: a) ORR 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cullinan Pearl Corp.

Sponsor organisation

Cullinan Pearl Corp.

Address

1 Main Street Suite 520

City

Cambridge

Postcode

02142-1531

Country

United States

Scientific contact point

Organisation

Cullinan Pearl Corp.

Contact name

Study Responsible Physician

Public contact point

Organisation

Cullinan Pearl Corp.

Contact name

Study Responsible Physician

Third parties 4

Locations

3 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications