A Phase 1/2, First-in-Human, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of RNK08954 in Patients With Advanced Solid Tumors With a KRAS G12D Mutation TRIAD1 (Trial of RNK08954 In KRAS G12D Mutation)
Overview
- Phase
- Phase 1
- Intervention
- RNK08954-01
- Conditions
- KRAS G12D Mutation
- Sponsor
- Ranok Therapeutics (Hangzhou) Co., Ltd.
- Enrollment
- 152
- Locations
- 6
- Primary Endpoint
- Treatment-emergent adverse events (TEAEs).
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
Brief Summary
This is a first in human (FIH), Phase 1/2 open-label multi-center, dose escalation and expansion study to evaluate the safety, tolerability and pharmacokinetics of RNK08954 to determine the optimal dose and recommended dose for expansion and evaluate clinical activity in patients with advanced solid tumors with KRAS G12D mutation.
This is a 2-part study: dose exploration/indication expansion and dose optimization ( to identify a dose that preserves clinical benefit with optimal tolerability).
Detailed Description
In Phase 1a, enrolled subjects will receive oral RNK08954 daily after one subject completes a Lead-in Pharmacokinetic (PK) guided single-patient cohort. The dose escalation cohorts will start with one patient per cohort for the first dose levels, then will enroll a minimum of 3 patients per dose level. Five dose levels will be explored and a total of 42 patients are projected for enrollment. Phase 1b- Multiple Indications Cohorts will open once the optimal dose has been determined in Phase 1a, and will consist of 3 cohorts including colorectal cancer, pancreatic adenocarcinoma and other indications. Approximately 20 patients will be assigned to each of the 3 cohorts for a total of 60 patients. All enrollment will be concurrent. Enrolled subjects will receive oral RNK08954 daily. Phase 2 Dose Optimization Study will enroll subjects who will receive two different doses of oral RNK08954 daily to compare two different doses and further characterize the optimal dose.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must be 18 years of age or older.
- •Must have pathologically documented locally advanced or metastatic malignancy harboring KRAS G12D mutations identified through deoxyribonucleic acid (DNA) sequencing of tumor tissues or circulating deoxyribonucleic acid (ctDNA) performed locally.
- •Must have received prior standard therapy appropriate for their tumor type, or in the opinion of the investigator, would be unlikely to derive further clinically meaningful benefit from appropriate standard of care therapy.
- •Must have measurable lesion(s) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by Computed tomography (CT) scan with contrast (magnetic resonance imaging (MRI), if the patient is allergic to contrast media).
- •Measurable disease may be in the field of prior irradiation; however, at least 3 weeks must have elapsed between the completion of radiation therapy and the baseline scan documenting disease status.
- •Bone disease is considered radiologically measurable only if there is at least a 50% lytic component.
- •NOTE: Bone disease consisting of only blastic lesion is not considered measurable.
- •NOTE: in Phase 1a, patients must have measurable or evaluable disease.
- •Archival or fresh tumor tissue must be available for evaluating relevant biomarkers. Formalin-fixed paraffin-embedded (FFPE)block preferred, or a minimum of 3 unstained FFPE slides of one archived block is required.
- •NOTE: cytology samples from fine needle aspirates or brushing biopsies are not sufficient.
Exclusion Criteria
- •A patient is not eligible to participate in the study if any of the following criteria are met:
- •Concurrent anticancer therapy \[chemotherapy, monoclonal antibodies, targeted therapy, hormonal therapy or investigational agents\] within the lesser of 28 days or 5 half-lives before study Day
- •NOTE: Patient must agree not to participate in any other interventional clinical studies during their participation in this trial while on study treatment.
- •NOTE: patients receiving hormonal ablation therapy for breast cancer or hormone refractory prostate cancer are allowed.
- •NOTE: Patients taking part in surveys or observational studies are eligible to participate in this study.
- •Significant acute decline in clinical status including:
- •Decline in ECOG PS to \>1 between baseline visit and within 72 hours prior to starting study treatment.
- •Weight loss of ≥10% during screening.
- •Presence of active or symptomatic untreated central nervous system (CNS) metastases.
- •NOTE: Patients with asymptomatic or stable CNS metastases are eligible, provided that the CNS metastases are radiologically and clinically stable for at least 2 weeks prior to enrollment, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
Arms & Interventions
RNK08954
Dose-escalation of RNK08954 oral dose therapy once daily.
Intervention: RNK08954-01
Outcomes
Primary Outcomes
Treatment-emergent adverse events (TEAEs).
Time Frame: 12-15 months
To evaluate the safety and tolerability of RNK08954 in adult patients with KRAS G12D mutant solid tumors in approximately 42 subjects
Optimal Biological Dose (OBD).
Time Frame: 12-15 months
To determine the Recommended Dose for Expansion (RDE) of RNK08954 monotherapy in adult patients with KRAS G12D mutant solid tumors.
Secondary Outcomes
- Dose limiting toxicities (DLT)(12-15 months)
- Objective response rate (ORR)(12-15 months)
- Overall survival (OS), 1-year survival rate.(12-15 months)
- .Evaluate Area under the plasma concentration (AUC0-72) in the fasted and fed states.(12-15 months)