Advanced Solid Tumor, Mesothelioma, Malignant
Conditions
Brief summary
This is a first-in-human (FIH), Phase 1a/1b open-label, multicenter, dose escalation and dose expansion study of SW-682 in adult participants with metastatic or unresectable advanced solid tumors with or without Hippo pathway alterations that are refractory to, or have progressed, during or after appropriate prior systemic anticancer therapy, including chemotherapy, immunotherapy, radiation therapy or targeted therapy, or for which no treatment is available, or prior standard of care (SOC) therapy was not tolerated and for which there is no further SOC treatment available. The study includes a Part 1 (Phase 1a) dose escalation phase and a Part 2 (Phase 1b) dose expansion to optimize the dose to be used for further development. All participants will self-administer SW-682 by mouth in 28-day cycles.
Interventions
DRUGSW-682
SW-682 tablet administered orally
DRUGCombination Therapy
Appropriate combination therapy
Sponsors
SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will be conducted in two sequential parts: Part 1 dose escalation and Part 2 dose expansion.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed, metastatic, or unresectable solid cancer that has either not responded to or progressed during or after appropriate prior systemic anticancer therapy including chemotherapy, immunotherapy, radiation therapy, or appropriate targeted therapy, or for which there is no treatment available or prior SOC therapy was not tolerated and for which there is no further SOC treatment available * Part 1: must have one of the following: * Mesothelioma with or without NF2 mutations * Advanced solid tumors with NF2 mutations * Advanced solid tumors with other Hippo pathway mutations or fusions (e.g., FAT1, LATS1/2, YAP fusions; WWTR1-CAMTA1 in EHE). * Part 2: must have the tumor histology and oncogenic mutation or genomic aberration specific to each dose expansion cohort defined below: * Cohort 1: Participants with mesothelioma with or without NF2 mutations * Cohort 2: Participants with advanced solid tumors with NF2 mutations * Cohort 3: Participants with advanced solid tumors with other Hippo pathway mutations identified during Part 1 (Phase 1a) dose escalation * Cohort 4: SW-682 with appropriate combination therapy. * In both parts, participants should have known oncogenic mutation identified by Next Generation Sequencing or local assay * Must have archival tumor tissue or agree to a fresh tumor biopsy at screening * Measurable disease per RECIST 1.1 * Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 * Adequate bone marrow, kidney, hepatic, and coagulation function Key
Exclusion criteria
* Evidence of symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression * Clinically significant cardiac disease or abnormal cardiac parameters * Preexistence or inheritance of a familial renal syndrome * Concomitant non-anti-arrhythmic medications that are known to prolong the QTc interval * Concomitant medicines that are known strong/moderate inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) and/or CYP1A2 within 14 days or 5 half-lives before the first dose of study treatment * Concomitant medicines that are known sensitive substrates of CYP3A4, CYP2C19, CYP2D6, CYP1A2, and/or CYP2B6 within 14 days or 5 half-lives before the first dose of study treatment * Concomitant medicines that are known sensitive substrates of PGP, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT2 * Clinically significant active infection (bacterial, fungal, or viral)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (Part 1 Only) | Up to 24 months | Safety and tolerability endpoint evaluation via incidence of dose limiting toxicities (DLTs), serious adverse events (SAEs), treatment emergent adverse events (TEAE) |
| Maximum Tolerated Dose (Part 1 Only) | Up to 24 months | The maximum tolerated dose (MTD) for SW-682, if any, will be based on safety and tolerability during the first 28 days of treatment in Cycle 1. |
| Recommended Dose for Expansion (Part 1 Only) | Up to 24 months | The recommended dose for expansion (RDE) will be determined based on all safety, tolerability, pharmacokinetics (PK), preliminary antitumor efficacy, and other available data from Part 1 of the study. |
| Objective Response Rate (Part 2 Only) | Up to 24 months | Objective response rate (ORR), defined as the proportion of participants with confirmed CR or PR using RECIST v1.1, mRECIST for mesothelioma, and/or GCIG CA-125 for ovarian cancer, as applicable, assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in plasma and urine concentrations of SW-682 | Up to 24 months | Plasma and urine concentrations of SW-682 and any relevant metabolite(s) will be measured to evaluate systemic exposures and renal elimination. |
| Objective Response Rate (Part 1 Only) | Up to 24 months | Objective response rate (ORR), defined as the proportion of participants with confirmed CR or PR using RECIST v1.1, mRECIST for mesothelioma, and/or GCIG CA-125 for ovarian cancer, as applicable, assessed by the investigator. |
| Disease Control Rate | Up to 24 months | Disease control rate (DCR), defined as the percentage of participants with CR, PR, or stable disease (SD) after starting study treatment. |
| Duration of Response | Up to 24 months | Duration of response (DoR), defined as the time from response (CR + PR using RECIST v1.1, mRECIST and/or (GCIG) criteria for CA-125 response in ovarian cancer, as applicable) to disease progression and/or death, whichever occurs first. |
| Progression-Free Survival | Up to 24 months | Progression-free survival (PFS), defined as the time from the date of the first administration of study treatment to the first documented disease progression per RECIST v1.1, mRECIST, and/or GCIG CA-125, as applicable, or death due to any cause, whichever occurs first. |
Countries
United States
Contacts
CONTACTUS Medical Information
STUDY_DIRECTORMedical Responsible
SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany
Outcome results
None listed