A Phase I/II, Open Label, Dose-escalation, and Dose-expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of D3S 001 Monotherapy or Combination Therapy in Subjects with Advanced Solid Tumors with a KRAS P.G12C Mutation
Study Identifier:
D3S-001-100
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
Recruiting
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Study Summary
This is a first-in-human (FIH), multicenter, open-label, dose-escalation, and dose-expansion Phase 1/2 clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of D3S-001 or combination therapy in subjects with advanced KRAS p.G12C mutant solid tumors. D3S-001 will be taken daily by oral administration in 21-day treatment cycles. To evaluate the safety and tolerability of D3S-001 in subjects with KRAS p.G12C mutant solid tumors; to determine MTD (if applicable) and RP2D. To correlated ctDNA dynamics with clinical efficacy. Mutant allele frequencies (MAF) were analyzed by NGS (Guardant360 or BNR OncoCompass) on liquid biopsy at baseline, C1D8, C4D1 and end-of-treatment (EOT). The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy. To present findings in G12Ci resistant NSCLC patients (pts) from the ongoing Phase 2 trial To evaluate the safety and tolerability of D3S-001 as monotherapy (Part 1, Part 2 and Part 4a) and as combination therapy (Part 3) in adult subjects with KRAS p.G12C mutant solid tumors. Determine the MTD, if applicable, and the RP2D.
The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy (Guardant360® CDx or OncoCompass® Target).
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
Inclusion criteria
- Subject must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor which is progressing. Subject must have documented KRAS p.G12C mutation identified within the last 5 years by a local test on tumor tissue or blood. Subject must have measurable disease per RECIST v1.1. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subject must have adequate organ and marrow function within the screening period. Subjects were able to understand and voluntarily signed an informed consent form (ICF) and adhered to study restrictions. Subjects must be ≥18 years of age at the time of signing the informed consent form. Subjects must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is progressing. Subjects must provide documentation of the KRAS p.G12C mutation, which can be locally detected in tumor tissue or blood within the past 5 years. KRAS p.G12C tested locally must comply with local regulations, be performed using a verified and well-validated assay, and, for research centers in the United States, must be accredited under the Clinical Laboratory Improvement Act Amendments or the College of American Pathologists laboratory for testing. Research centers outside the U.S. require testing in an equivalently accredited laboratory. Subjects must have measurable lesions as defined by RECIST v1.1, i.e., at least 1 lesion that can be accurately measured by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline with a longest diameter ≥10 mm (unless it is a lymph node, the short axis must be ≥15 mm on CT) and suitable for accurate and repeatable measurements. Lesions that have previously received radiotherapy or lesions within the radiotherapy field should not be used as measurable lesions unless definitive disease progression has been demonstrated according to RECIST v1.1. Target lesions should not be used for baseline tumor biopsy unless there are no other lesions suitable for biopsy and meet the requirements outlined in Protocol Appendix 7 (Section 10.7). Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Subjects must have adequate organ and bone marrow function as defined in Table 6 of the protocol during the screening period. Pts of locally advanced or metastatic NSCLC with historically confirmed KRAS G12C mutation were eligible for inclusion if they had radiologically or clinically documented PD following TX of 1 prior KRAS G12Ci achieving CR/PR or SD for >= 6 months.
- Pts with locally advanced or metastatic KRAS G12C-mutated NSCLC were eligible. All pts must had received at least one prior line of systemic treatment, including IO and/or platinum doublet chemotherapy. For G12Ci-refractory pts, they were required to have radiologically or clinically documented PD following a KRAS G12Ci.
Exclusion criteria
- Subject has any prior treatment with other treatments without adequate washout periods as defined in the protocol.
- 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.
- Subject has unresolved treatment-related toxicities from previous anticancer therapy of NCI CTCAE Grade >or= 2 (with exception of vitiligo or alopecia).
- Subject has active gastrointestinal disease or other that could interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy.
- Concurrent participation in any clinical research study involving treatment with any investigational drug, radiotherapy, or surgery, except for the nontreatment phases of these studies (e.g., follow-up phase).
- Other protocol inclusion/exclusion criteria may apply
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Recruiting
Condition(s) Treated at Site
Gene Mutations
Location
START Lisbon
Lisbon, Portugal, 1649-035
Investigator
Andre Mansinho
Status
Recruitment on Hold
Condition(s) Treated at Site
Gene Mutations