Advanced Solid Cancer, KRAS G12D Mutation
Conditions
Keywords
KRAS G12D Mutation, Advanced Solid Tumors, KRAS G12D Mutated Advanced Solid Tumors, KRAS G12D Mutated Pancreatic Ductal Adenocarcinoma, Pancreatic Cancer, PDAC, Non-Small Cell Lung Cancer, NSCLC, Colorectal Cancer, Colon Cancer, CRC, Appendiceal Carcinoma, Cholangiocarcinoma, Endometrial Cancer, Esophageal Adenocarcinoma, Gallbladder Cancer, Gastric Cancer, Melanoma, Ovarian Cancer, Small Bowel Adenocarcinoma, Thyroid Cancer, advanced cancer, KRAS, G12D mutation, Pancreas cancer
Brief summary
This is a study to evaluate the safety and potential anti-tumor activity of an investigational agent called ARV-806 in Adults with Advanced Cancer having a specific Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. This is an open-label study which means that participants and study staff will know that all participants will receive ARV-806. Researchers think that ARV-806 can work by breaking down a specific protein with a mutation that is present in some tumors, which might help prevent or slow tumors from growing. This will be the first time ARV-806 will be used in people. The investigational drug will be given through a vein. This is called intravenous (IV) infusion. This study will include 2 parts: In Part A (Phase 1), different small groups of participants will receive lower to higher doses of ARV-806. Adults with advanced cancers having a specific KRAS mutation will be included. In Part B (Phase 2), participants will be assigned to receive one of up to 2 dose levels decided by the information from Part A. Part B will include participants with advanced pancreatic ductal cancer having a specific KRAS mutation.
Interventions
DRUGARV-806
Intravenous infusion at assigned dose and dosing schedule
Sponsors
Arvinas Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A: * Histological or cytological diagnosis of unresectable or metastatic solid tumor malignancy, AND * Must have evidence of KRAS G12D mutation in tumor tissue or blood (circulating tumor deoxyribonucleic acid \[ctDNA\]), AND * Must have received prior standard-of-care (SOC) therapy appropriate for their type and stage of disease and have no other available treatment options with curative intent, or, in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy, AND * Must have at least 1 measurable lesion Part B: * Histological or cytological diagnosis of unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12D mutation status confirmed by local testing of tumor tissue using a validated molecular or next-generation sequencing (NGS) testing, AND * Must be willing to provide archival tumor tissue or willing to undergo pretreatment biopsy, AND * Must have received at least one prior standard of care systemic therapy for PDAC (systemic therapy received in the neoadjuvant or adjuvant setting is allowed), AND * Participants must have at least 1 measurable lesion Part A / Part B: * Eastern Cooperative Oncology Group performance status of 0 or 1, * Participants with adequate organ function, * Participants must accept and follow pregnancy prevention guidance.
Exclusion criteria
Part A / Part B: * Active brain metastases * Carcinomatous meningitis * Uncontrolled hypertension despite optimal medical therapy * Prior treatment with a KRAS G12D or a KRAS G12C targeting therapy (pan-KRAS inhibitor/degrader included) * Participants with an inability to comply with listed prohibited treatments * Systemic anticancer therapy within 2 weeks or 5 half-lives (whichever is shorter) or radiation therapy (excluding palliative radiation) within 2 weeks prior to the study intervention treatment. If the last immediate anticancer treatment contained an antibody-based agent(s), then an interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) is required prior to receiving the study intervention treatment. * Standard 12-lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A (Phase 1): Number of dose-limiting toxicities (DLTs) of ARV-806 | 28 days from first ARV-806 administration | Number of participants within a dose escalation cohort with adverse events (AEs) meeting protocol defined dose limiting toxicities during cycle 1 (28 days). |
| Part A (Phase 1): Number of participants with AEs | From the study baseline to at least 28 days after last dose of ARV-806 | AEs as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\]), timing, seriousness, and relationship to study intervention as a measure of safety and tolerability |
| Part B (Phase 2): Overall Response Rate (ORR) | Approximately 2 years | ORR is a parameter measuring the anti-tumor activity of ARV-806. ORR is the percentage of participants for whom the study treatment resulted in a complete response or partial response of the disease under study. It is measured using CT/MRI and RECIST 1.1 criteria per investigator assessment. |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK) of ARV-806 (Part A): Area under the plasma or blood concentration-time profile during a dosing interval (AUCtau) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Area under the plasma or blood concentration time profile from time zero to the time of the last quantifiable concentration (Clast) (AUClast) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Maximum plasma or blood concentration (Cmax) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Minimum observed concentration (Cmin) | Timeframe: At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Plasma or blood clearance (CL) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Time for Cmax (Tmax) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| PK of ARV-806 (Part A): Volume of distribution (Vd) | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| Part A: Overall Response Rate (ORR) | Approximately 2 years |
| Part A: Time to Response (TTR) | Approximately 2 years |
| Part A: Duration of Response (DOR) | Approximately 2 years |
| Part A: Disease Control Rate (DCR) | Approximately 2 years |
| Part B: Number of participants with AEs | From the study baseline to at least 28 days after last dose of ARV-806 |
| Part B: ARV-806 whole blood pre and post dose concentration | At predefined intervals throughout the treatment period, up to approximately 6 months after first dose of ARV-806 |
| Part B: Time to Response (TTR) | Approximately 2 years |
| Part B: Duration of Response (DOR) | Approximately 2 years |
| Part B: Disease Control Rate (DCR) | Approximately 2 years |
Countries
United States
Outcome results
None listed