Advanced Solid Tumor
Conditions
Brief summary
A Phase 1/2a open-label, multicenter, dose escalation and expansion study of mirdametinib in combination with BGB-3245 in adult participants with histologically confirmed, advanced (American Joint Committee on Cancer (AJCC) Stage III or IV) metastatic or unresectable solid cancer that is refractory to or has progressed during or after at least 1 line of appropriate prior systemic anti-cancer therapy including chemotherapy, immunotherapy, or appropriate targeted therapy, or for which there is no treatment available, or prior standard of care therapy was not tolerated.
Detailed description
The study will be conducted in two sequential parts: Part 1 dose escalation (Phase 1) and Part 2 dose expansion (Phase 2a). Participants will receive mirdametinib and brimarafenib administered by mouth every day on a continuous schedule. Mirdametinib will be dosed twice a day (BID) and brimarafenib will be dosed once a day (QD). One treatment cycle will be 28 days. Part 1 of the study will assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary evidence of anti-tumor efficacy. Part 1 will also identify the MTD and the RP2D for the combination of mirdametinib with brimarafenib. Part 2 will confirm the safety, tolerability, efficacy, PK, and PDx for the combination of mirdametinib and brimarafenib. It will follow a parallel design and include one or more dose expansion cohorts, where each participant would be treated with the combination of mirdametinib and brimarafenib at the RP2D. It will begin after the RP2D for the combination of mirdametinib and brimarafenib is identified in Part 1. Part 2 may start either in parallel with, or after, the conduct and analysis of the PDx Expansion Cohort in Part 1. Participants who experience a TEAE requiring treatment modification will be managed according to the applicable guidelines in the protocol.
Interventions
DRUGMirdametinib 2mg
Mirdametinib 2mg administered orally
DRUGBGB-3245 5mg
BGB-3245 5mg administered orally
DRUGMirdametinib 3mg
Mirdametinib 3mg administered orally
DRUGMirdametinib 4mg
Mirdametinib 4mg administered orally
DRUGBGB-3245 10mg
BGB-3245 10mg administered orally
DRUGBGB-3245 20mg
BGB-3245 20mg administered orally
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 (Phase 1) and Part 2 dose expansion (Phase 2a).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Able to provide informed consent * At least 18 years of age on day of signing ICF * Advanced, metastatic or unresectable solid cancer that has not responded to or progressed during or after at least 1 line of appropriate therapy or for which there is no treatment available or prior therapy was not tolerated. * Part 1: oncogenic mutation or other genomic aberration of the MAPK pathway * Part 2: oncogenic mutation or genomic aberration defined below: * Cohort A: cutaneous melanoma harboring NRAS mutations. * Cohort B: non-small cell lung cancer (NSCLC) harboring a KRAS mutation. * Cohort C: NSCLC or cutaneous melanoma harboring BRAF Class II or Class III mutations or BRAF Fusion mutation. * 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 ≤ 2 * Adequate organ function and no transfusion within 14 days of first dose Key
Exclusion criteria
* Central Nervous System metastases, leptomeningeal carcinomatosis or untreated spinal cord compression * History of glaucoma * Active parathyroid disorder or history of malignancy associated hypercalcemia * Clinically significant cardiac disease within the past 6 months of signing ICF * History of toxicity from another RAF, MEK, ERK inhibitor requiring discontinuation of treatment from these agents * Severe or uncontrolled systemic disease * Inability to swallow oral medications * Clinically significant active infection (HIV, Hepatitis B or Hepatitis C) * History of or ongoing Immune Thrombocytopenia (ITP), Von Willebrand disease and/or other past or present bleeding disorders * Underlying medical conditions in investigator's opinion to be unfavorable to be a part of the study * Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose or anticipates need for major surgery while on study * Systemic anti-cancer therapy within 2 weeks or 5 half-lives before first dose * Concomitant systemic or glucocorticoid therapy within 2 weeks before first dose * Concomitant medicines that are strong CYP3A4 inhibitors or inducers within 2 weeks or 5 half-lives before first dose * Live vaccine within 4 weeks before first dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events | All adverse events were collected from the time of signing ICF until 30 days after the last dose of study treatment (an average of 3.48 months and up to 16.76 months). | Safety and tolerability endpoint evaluation via incidence of treatment emergent Adverse Events (TEAEs). TEAE severities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. AEs were coded using MedDRA Version 27.1. |
| Maximum Tolerated Dose (Part 1 Only) | Up to 18 months | The maximum tolerated dose (MTD) for mirdametinib and BGB-3245 administered as a combination, if any, will be based on safety and tolerability during the first 28 days of treatment in Cycle 1. |
| Recommended Phase 2 Dose [RP2D] (Part 1 Only) | Up to 24 months | The recommended phase 2 dose (RP2D) for mirdametinib and BGB-3245 administered as a combination will be determined based on safety, tolerability, PK, preliminary anti-tumor efficacy, and other available data. |
| Objective Response Rate (Part 2 Only) | Up to 24 months | Preliminary anti-tumor efficacy for the RP2D of mirdametinib and BGB-3245 administered as a combination as assessed by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Objective Response Rate (ORR) defined as the proportion of participants with complete response (CR) + partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (Part 1 Only) | From participants' date of first dose of study treatment through end of treatment, an average of 3.5 months | Preliminary anti-tumor efficacy of mirdametinib and BGB-3245 administered as a combination as assessed by CT or MRI. ORR defined as the proportion of participants with Complete Response (CR) + Partial Response (PR) using RECIST v1.1. Responses were as reported by the investigators. |
| Duration of Response Rate | Up to 36 months | Duration of response rate in participants treated with the combination of mirdametinib and BGB-3245, defined as the time from response (CR + PR using RECIST v1.1) to disease progression and/or death. |
| Change in Plasma Concentrations of Mirdametinib and BGB-3245 | Up to 24 months | To determine the PK of mirdametinib and BGB-3245 administered as a combination in the eligible participant population. Plasma concentrations of mirdametinib and BGB-3245 will be measured to evaluate systemic exposures (AUC, Cmax, Ctrough, and other PK parameters as data allow). |
Countries
Australia, United States
Participant flow
Recruitment details
Participants were enrolled in each Part 1 cohort following safety committee review. Study was terminated after Part 1 Cohort 5 was completed due to intolerance of the combination and no apparent early signs of efficacy. No participants were enrolled in Part 2 of the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 41 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| History of Prior Cancer Surgery - Complete Resection No | 0 Participants |
| History of Prior Cancer Surgery - Complete Resection Yes | 5 Participants |
| History of Prior Cancer Surgery - Indication Diagnostic | 0 Participants |
| History of Prior Cancer Surgery - Indication Missing | 1 Participants |
| History of Prior Cancer Surgery - Indication Therapeutic | 3 Participants |
| Lesion Location Bone | 1 Participants |
| Lesion Location Liver | 2 Participants |
| Lesion Location Lung | 1 Participants |
| Lesion Location Lymph Node | 6 Participants |
| Lesion Location Other Site | 1 Participants |
| Lesion Location Other Soft Tissue | 0 Participants |
| Number of Prior Lines of Cancer Therapy 1 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 2 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 3 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 4 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 5 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 6 | 0 Participants |
| Number of Prior Lines of Cancer Therapy 7 | 1 Participants |
| Number of Prior Lines of Cancer Therapy 9 | 1 Participants |
| Prior Anti-Cancer Therapy No | 0 Participants |
| Prior Anti-Cancer Therapy Yes | 23 Participants |
| Prior Radiotherapy No | 2 Participants |
| Prior Radiotherapy Yes | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
| Time Since First Metastatic Disease | 68.3 months |
| Time Since Initial Diagnosis | 68.8 months |
| Type of Cancer Diagnosis Colorectal Cancer | 0 Participants |
| Type of Cancer Diagnosis Melanoma | 2 Participants |
| Type of Cancer Diagnosis Non-small Cell Lung Carcinoma | 1 Participants |
| Type of Cancer Diagnosis Other | 5 Participants |
| Type of Cancer Diagnosis Ovarian Cancer | 1 Participants |
| Type of Cancer Diagnosis Pancreatic Cancer | 2 Participants |
| Type of Mutation BRAF | 7 Participants |
| Type of Mutation HRAS | 0 Participants |
| Type of Mutation KRAS | 6 Participants |
| Type of Mutation NRAS | 1 Participants |
| Type of Mutation Other | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 7 | 0 / 6 | 1 / 4 | 1 / 3 | 3 / 23 |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 5 / 6 | 4 / 4 | 3 / 3 | 22 / 23 |
| serious Total, serious adverse events | 2 / 3 | 3 / 7 | 5 / 6 | 3 / 4 | 3 / 3 | 16 / 23 |
Outcome results
None listed