2-((S)-4-((S)-7-(3-AMINO-2-FLUORO-5-METHYL-6-(TRIFLUOROMETHYL)PHENYL)-2-(((2R,7AS)-2-FLUOROTETRAHYDRO-1H-PYRROLIZIN-7A(5H)-YL)METHOXY)-7,8-DIHYDRO-5H-PYRANO(4,3-D)PYRIMIDIN-4-YL)-1-(2-FLUOROACRYLOYL)PIPERAZIN-2-YL)ACETONITRILE for Advanced solid tumor with KRAS p.G12C mutation

Inclusion criteria

• {"criterion_text":"- Subject must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor which is progressing.\n- Subject must have documented KRAS p.G12C mutation identified within the last 5 years by a local test on tumor tissue or blood. (Note: For subjects with unknown KRAS mutation status, central laboratory testing on tumor tissue can be offered if available in respective region or country).Local KRAS p.G12C testing must be performed using a verified and well-validated test in line with local regulations, performed at a Clinical Laboratory Improvement Amendments certified or a College of American Pathologists accredited laboratory for the United States sites. An equivalent accredited laboratory or following local clinical practice is required for sites outside the US United States and local testing methods must clearly identify KRAS p.G12C mutations distinctively from other KRAS mutations. Note: For subjects in Part 3a, subjects should have known PD-L1 expression per Dako 22C3, or willing to provide tissue samples for central testing. For all parts, if not specified, subjects should have no known second KRAS driver mutations (including G12A, G12V, G12R, G13C, G12D, G12S, H95, Y96, Q61, and R68).\n- Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as defined by at least 1 lesion that can be accurately measured at baseline as ≥10 mm at the longest diameter with computed tomography (CT) or magnetic resonance imaging (MRI) (except lymph nodes which must have a short axis ≥15 mm on CT), which is suitable for accurate, repeated measurements. Previously irradiated lesions or a lesion in the field of radiation should not be used as measurable disease unless the lesion(s) has/have demonstrated unequivocal disease progression by RECIST v1.1. Target lesions should not be used for the baseline tumor biopsy, unless there are no other lesions suitable for biopsy and they fulfil requirements outlined in the study protocol.\n- Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n- Subjects must have adequate organ and marrow function within the screening period as defined in the study protocol."}

Exclusion criteria

• {"criterion_text":"- Subject has any prior treatment without adequate washout periods as defined in the study protocol.\n- Subject has uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the subject to give written informed consent.\n- Subject has unresolved treatment-related toxicities from previous anti-cancer therapy of NCI CTCAE Grade ≥2 (with exception of vitiligo or alopecia). a. The following criteria will be only applied to KRAS p.G12Ci-pretreated subjects. The subjects will be ineligible if any 1 of the following criterion was met in the prior KRAS p.G12Ci treatment period: i. Grade 3 or higher ALT and/or AST increased at >2 occurrences ii. Grade 3 or higher cardiac toxicity (ECG QT corrected interval prolonged and ejection fraction decreased) Note: Subjects with other chronic Grade 2 toxicities (e.g., Grade 2 chemotherapy-induced neuropathy) may be eligible per discretion of the Investigator after consultation with the Medical Monitor. Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment may be included only after consultation with the medical Monitor.\n- Subject has active gastrointestinal disease or other condition (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, malabsorption syndrome, or previous significant bowel resection) that could interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g., that would preclude adequate absorption of D3S-001.)\n- Concurrent participation in any clinical research study involving treatment with any investigational drug, radiotherapy, or surgery, except for the non-treatment phases of these studies (e.g., follow-up phase)."}

Primary endpoints

• {"endpoint_text":"- Treatment-emergent AEs, treatment-related Aes","definition_or_measurement_approach":"As stated: assessment of treatment-emergent adverse events and treatment-related adverse events (no additional measurement method specified in the record)."}
• {"endpoint_text":"- Clinically significant changes in vital signs, physical examinations, ECGs, and clinical laboratory test","definition_or_measurement_approach":"As stated: monitoring for clinically significant changes in vital signs, physical exams, ECGs and clinical laboratory tests (no further details provided)."}
• {"endpoint_text":"- The MTD, if applicable, will be based on DLTs","definition_or_measurement_approach":"MTD determination based on dose-limiting toxicities (DLTs) observed during the dose-escalation period."}
• {"endpoint_text":"- The RP2D in the expansion part will be based on emerging data","definition_or_measurement_approach":"RP2D (recommended phase 2 dose) selection in expansion based on emerging safety/tolerability and other data (no further prespecified algorithm provided)."}

Secondary endpoints

• {"endpoint_text":"- PK parameters of D3S-001 including, but not limited to: Cmax, tmax, t1/2, and AUC","definition_or_measurement_approach":"Pharmacokinetic parameters including Cmax, tmax, t1/2 and AUC as measured from plasma concentration-time data."}
• {"endpoint_text":"- PK parameters of D3S-001 including, but not limited to: Cmax, tmax, t1/2, and AUC in the fed versus. fasted states for the food effect assessment","definition_or_measurement_approach":"Comparison of PK parameters (Cmax, tmax, t1/2, AUC) in fed vs fasted states to assess food effect."}
• {"endpoint_text":"- ORR, DOR, DCR, DCR at 24 weeks (CR, PR, or SD ≥24 weeks), and PFS as assessed per RECIST v1.1 by investigators and BICR","definition_or_measurement_approach":"Tumor response and disease control metrics assessed per RECIST v1.1 by investigators and blinded independent central review (BICR); includes ORR, duration of response (DOR), disease control rate (DCR), DCR at 24 weeks, and progression-free survival (PFS)."}

France

Earliest CTIS Part Ii Submission Date

08-03-2024

Latest Decision Or Authorization Date

24-09-2025

Processing Time Days

565

Number Of Sites

4

Number Of Participants

45

Italy

Earliest CTIS Part Ii Submission Date

16-04-2024

Latest Decision Or Authorization Date

18-06-2025

Processing Time Days

428

Number Of Sites

5

Number Of Participants

15

Spain

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

18-06-2025

Processing Time Days

441

Number Of Sites

7

Number Of Participants

30

Germany

Earliest CTIS Part Ii Submission Date

18-04-2024

Latest Decision Or Authorization Date

18-06-2025

Processing Time Days

426

Number Of Sites

3

Number Of Participants

5

Primary sponsor

Full Name

D3 Bio (Wuxi) Co. Ltd.

Organisation Type

Pharmaceutical company

Country Of Registered Address

China

Contract research organisations

Name

Fortrea Inc.

Responsibilities

sponsorDuties codes: [1,12,5,8]

Name

Labcorp Pharmaceutical Research And Development (Shanghai) Co. Ltd.

Responsibilities

Pharmacokinetics (NCA) (sponsorDuties code 15)

Name

Labcorp Central Laboratory Services S.a.r.l.

Responsibilities

Laboratory services (sponsorDuties code 4)

Name

Endpoint Clinical Inc.

Responsibilities

Data management/clinical operations support (sponsorDuties code 3)

Name

Medidata Solutions Inc.

Responsibilities

Clinical data platform/electronic data capture (sponsorDuties code 7)

Third parties

• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"sponsorDuties codes: [1,12,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"China","full_name":"Labcorp Pharmaceutical Research And Development (Shanghai) Co. Ltd.","duties_or_roles":"sponsorDuties code: [15] (value: Pharmacokinetics (NCA))","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"sponsorDuties codes: [4]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"sponsorDuties codes: [3]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"sponsorDuties codes: [7]","organisation_type":"Non-Pharmaceutical company"}