A Phase 1/2 Study of TAS3351 in Patients with Advanced Non-Small Cell Lung Cancer and EGFR Mutations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

21 May 2024 → 18 Apr 2025

Decision date (initial)

2023-07-10

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Taiho Oncology, Inc.

External identifiers

EU CT number

2022-502595-23-00

ClinicalTrials.gov

NCT05765734

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety

Phase 1 Dose Escalation
• To investigate safety and determine the recommended Phase 2 dose (RP2D) and dosing schedule of TAS3351

Phase 1 Dose Expansion
• To explore the efficacy of TAS3351

Phase 2
• To assess the efficacy of TAS3351

Secondary objectives 3

1. Phase 1 Dose Escalation • To evaluate the antitumor activity of TAS3351 • To characterize the pharmacokinetics (PK) of TAS3351 and its active metabolite (TAS-05- 14317) in plasma
2. Phase 1 Dose Expansion • To confirm the safety and tolerability of TAS3351 at the RP2D and dosing schedule • To further explore the anti-tumor efficacy of TAS3351
3. Phase 2 • To further assess the efficacy of TAS3351 • To evaluate the safety and tolerability of TAS3351 • To evaluate patient reported outcomes (PROs)

Conditions and MedDRA coding

Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring an acquired C797S epidermal growth factor receptor (EGFR) mutation.

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Provide written informed consent
2. 10. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test prior to administration of the first dose of study treatment. Female patients are not considered to be of child-bearing potential if they are post-menopausal (no menses for 12 months without an alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
3. 11. Both males and females of reproductive potential must agree to use highly effective birth control throughout the study and at least for: - 6 months after the last dose of study treatment for females - 3 months after the last dose of study treatment for males or longer, based on local requirements
4. 2. ≥18 years of age (or meets the country’s regulatory definition for legal adult age, whichever is greater)
5. 3. Histologically or cytologically confirmed, locally advanced, non-resectable or metastatic NSCLC
6. 4. Has received the following prior treatment and no more than 2 lines of prior cytotoxic chemotherapy for locally advanced or metastatic disease setting: a. Part A1 (Phase 1 Dose Escalation): Standard of care (SOC) that is available to the patient, unless contraindicated, intolerable to the patient, or declined by the patient b. Part A2: Progression on third-generation EGFR TKI (eg, osimertinib, lazertinib) and having received or not eligible for platinum-based chemotherapies or other targeted approved therapies in case of off-target alterations. c. Parts B and C: Progression on third-generation EGFR TKI (eg, osimertinib, lazertinib)
7. 5. Has the following EGFRmt status as determined by a CLIA certified (US), locally certified (outside of the US), or the study central laboratory based on tumor tissue or plasma cfDNA: a. Part A1 (Phase 1 Dose Escalation): Any EGFRmt b. Parts A2, B, and C: Any sensitizing EGFRmt and a confirmed C797S EGFRmt (Note: no T790M EGFRmt required)
8. 6. Has tumor tissue available collected after progression on the most recent systemic EGFR TKI treatment in a quantity sufficient to allow for analysis of EGFRmt status by the Sponsor’s central laboratory (optional for Part A1 only). Please refer to the Laboratory Manual for details.
9. 7. Has measurable disease per RECIST v1.1 (optional for patients in Part A1)
10. 8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
11. 9. Adequate organ function as defined by the following criteria: a. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L b. Platelet count ≥ 100,000/mm^3 (≥ 100 × 10^9/L); last transfusion of blood products must be ≥2 weeks prior to start of study treatment. c. Hemoglobin ≥ 9.0 g/dL d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5.0 × ULN e. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert’s syndrome f. Creatinine clearance (CrCl) (calculated or measured value): ≥50 mL/min. For calculated CrCl, use the Cockcroft-Gault formula g. Potassium blood levels ≥3.0 mmol/L
12. In addition to the above, patients in France must meet the following criterion: 12. Affiliated with a social security system or be a beneficiary of an equivalent system of patient care as applicable by local regulations in France.

Exclusion criteria 12

1. 1. Currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study
2. 10. Pregnant female or breastfeeding female
3. 11. Any other clinically significant acute or chronic medical or psychiatric condition that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results based on Investigator discretion
4. 2. Has received prior treatment with any of the following within the specific time frame prior to the first dose of study treatment: a. Major surgery/surgical therapy for any cause within 4 weeks; the patient must have recovered adequately from the toxicity and/or complications of the intervention prior to starting study treatment b. Chemotherapy, biologic therapy, targeted therapy, immunotherapy, or investigational agents within 5 half-lives or within 4 weeks (whichever is shorter) prior to the first dose of study treatment. Patient must have recovered from toxicities of the prior therapy based on the Investigator’s judgement prior to starting study treatment c. No prior treatment with: (i). Part A1 (Phase 1 Dose Escalation): Systemic immunotherapy (eg, PD- 1/PD-L1 antibody) (ii). Parts A2, B, and C: Any EGFR C797S mutation-targeting agent (eg, BLU-945) d. Radiotherapy prior to the start of study treatment within: (i). 2 weeks for radiation therapy of non-thoracic regions (7 days for palliative radiation of single lesions) (ii). 3 months for radiation therapy including thoracic region. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
5. 3. Have any unresolved clinically relevant toxicity of Grade ≥ 2 from previous anti-cancer treatment, except for alopecia, skin pigmentation, and Grade 2, prior platinum-therapy related neuropathy. Patients with chronic, but stable Grade 2 toxicities may be allowed to enroll if the Investigator and Sponsor agree.
6. 4. Any strong and moderate inhibitors/inducers of cytochrome P450 (CYP) 3A two weeks prior to start of therapy. If a patient is receiving strong inhibitors/inducers of CYP3A (see Appendix A), these medications and substances must be discontinued ≥2 weeks prior to the first dose of study treatment.
7. 5. Has the following CNS metastases disease status: a. Part A1 (Phase 1 Dose Escalation): Known untreated central nervous system (CNS) metastases, or history of uncontrolled seizures, or leptomeningeal disease. b. Parts A2, B, and C: Spinal cord compression, symptomatic and unstable CNS metastases, requiring steroids over the last 4 weeks prior to enrollment.
8. 6. Impaired cardiac function or clinically significant cardiac disease, including any of the following: a. Baseline QT interval > 470 msec (for women) and > 450 msec (for men) corrected for heart rate using Fridericia’s formula (QTcF, verified on repeat measurements) b. History of QTc prolongation or predisposition for QTc prolongation (clinically relevant electrolyte abnormalities, cardiac disorder, bradycardia, etc.), or family history of sudden cardiac death or QT prolongation (long QT syndrome) c. Regular use of medications known to prolong QTc interval or to be arrhythmogenic (such as ondansetron, erythromycin, droperidol) within 2 weeks of the first dose of TAS3351. A list of these medications can be found at: http://crediblemeds.org. d. History or presence of clinically important abnormalities in rhythm or conduction in resting ECG (eg, sinus arrest, second- or third-degree atrioventricular block (first degree atrioventricular block not excluded), serious uncontrolled ventricular arrhythmias), or severe myocardial infarction within 6 months of screening.
9. 7. General health condition of the patient is not suitable for the study including: a. Disease or condition that significantly affects gastrointestinal absorption of the study treatment b. Clinically relevant active infection (ie, known HBC, HCV, HIV) or other uncontrolled medical condition c. History of interstitial lung disease/pneumonitis, drug-induced lung disease/pneumonitis d. Known additional malignancy that is progressing or requires active treatment, with the exception of patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or antitumor assessment of the investigational regimen. Exceptions must be discussed with the Sponsor prior to patient enrollment
10. 8. Known hypersensitivity to the ingredients of TAS3351
11. 9. Unable to swallow whole tablets
12. 12. Vulnerable patients who are: a. Deprived of their liberty by a judicial or administrative decision. b. Receiving psychiatric care c. Admitted to a health or social institution for purposes other than research. d. Under legal protection (ie, guardianship, curatorship, and safeguard of justice) e. Unable to express their consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase 1 Dose Escalation • Safety, including (but not limited to) AEs graded by CTCAE v5.0, and incidence of dose limiting toxicities (DLTs). As supplementary data, preliminary antitumor activity and PK/PD results will be considered.
2. Phase 1 Dose Expansion • ORR per RECIST v1.1 by independent central review (ICR)
3. Phase 2 • ORR per RECIST v1.1 by ICR

Secondary endpoints 3

1. Phase 1 Dose Escalation • Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator • Duration of response (DoR), disease control rate (DCR), and time on treatment • Progression free survival and OS (Patients in part A2 only) • PK parameters including but not limited to maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC), and terminal elimination halflife (T½)
2. Phase 1 Dose Expansion • AEs, including SAEs, clinical laboratory tests, vital signs, and 12-lead ECGs graded according to CTCAE v5.0 • DoR, PFS, and DCR by ICR • ORR, DoR, PFS, and DCR by Investigator assessment. • Overall survival (OS)
3. Phase 2 • DoR, PFS, and DCR by ICR • ORR, DoR, PFS, and DCR by Investigator assessment • Overall survival (OS) • AEs, including SAEs, clinical laboratory tests, vital signs, and 12-lead ECGs graded according to CTCAE v5.0 • EORTC QLQ-C30 and EQ-5D-5L

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 101

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Trial Information Desk

Third parties 10

Locations

5 EU/EEA countries · 7 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 50 files

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

Application history

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