| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Recurrent, Progressive, or Refractory Solid Tumors Harboring MAPK Pathway Aberrations | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | Phase 1b
The Phase 1b objectives will apply to the investigation of DAY101 in combination with other therapies. Additional objectives may be specified according to the related sub-study protocol.
Primary Objective:
• To determine the safety of DAY101 in combination with other therapies.
• To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of DAY101 in combination with other therapies.
Phase 2
The Phase 2 objectives will apply to the investigation of DAY101 as monotherapy and in combination with other therapies. Additional objectives may be specified according to the relevant sub-study protocol.
Primary Objective:
To evaluate the efficacy of DAY101 by RECIST version 1.1 or appropriate tumor response criteria as a monotherapy or in combination with other therapies | |
| E.2.2 | Secondary objectives of the trial | Phase 1b:
• To assess the efficacy of DAY101 in combination with other therapies.
• To characterize the pharmacokinetic (PK) profile of DAY101 in combination with other therapies.
• To characterize pharmacodynamic (PD) effects of DAY101 in combination with other therapies.
Phase 2:
•To assess the safety and tolerability of DAY101 as monotherapy or in combination with othertherapies.
•To assess additional efficacy parameters of DAY101 as monotherapy or in combination with othertherapies.
•To characterize the tumor responses observed with DAY101 as monotherapy or in combination withother targeted therapies.
•To characterize the PK profile of DAY101 in combination with other therapies, according to therelevant sub-study protocol.
•To characterize the PD effects of DAY101 as monotherapy or in combination with other therapies.
•To determine the relationship between PK and PD of DAY101 in combination with other therapies. | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives | Clinical Protocol DAY101-102a (Monotherapy Substudy): A Phase 2, Subprotocol of DAY101 Monotherapy for Patients with Recurrent, Progressive, or Refractory Solid Tumors with Activating BRAF Gene Fusion
| |
| E.3 | Principal inclusion criteria | 1. Signed informed consent by patients ≥18 years of age and, assent for patients ≥ 12 up to < 18 years of age and, unless legally emancipated, his/her parent or legal guardian must be able to understand and willing to provide informed consent concurrently.
2. Patients must have a histologically confirmed diagnosis of tumor with concurrent MAPK pathway alteration as assessed by sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another clinically accepted molecular diagnostic method recognized by local laboratory or regulatory agency (archival tissue < 3 years will be acceptable; otherwise, a fresh sample will be collected at screening)
3. Patients must have radiographically-recurrent or radiographically-progressive disease that is measurable using the appropriate tumor response criteria (e.g. RECIST version 1.1). Imaging must be performed within 28 days prior to the first dose of study drug. Please see sub-studies for additional inclusion criteria.
4. Patients must have progressed after, are intolerant of, or refused standard-of-care treatment prior to documented radiographic progression.
5. Archival tumor tissue preferably less than 3 years old or, if unavailable, freshly acquired tumor tissue for correlative studies is required for all patients, where safe to obtain as determined by the Investigator.
6. Previous chemotherapy and hormone therapy (excluding physiologic replacement) must be completed at least 4 weeks or 5 half-lives, whichever occurs first, prior to initiation of therapy.
7. Previous immunotherapy/monoclonal antibody use must be completed at least 4 weeks or 5 half-lives (whichever is shorter) prior to initiation of therapy. In addition, radiation therapy to the target lesion must be completed at least 6 months prior to initiation of therapy.
8. All associated toxicity from previous therapies must be resolved to ≤ Grade 1 or considered baseline prior to initiation of therapy.
9. If brain metastases are present, they must have been previously treated and be stable by radiographic imaging (must have at least 2 images taken ≥ 4 weeks apart) AND, if receiving corticosteroids, the patient must be neurologically stable by clinical examination and on a stable or a decreasing dose of corticosteroids within 7 days prior to study start.
10. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1. For patients <16 years of age, a Lansky Performance Score > 70.
11. Acceptable end-organ function as demonstrated by the following laboratory values:
• Absolute neutrophil count (ANC) > 1000/μL
• Platelet count > 75,000/μL
• Hemoglobin > 9 g/dL (hemoglobin may not be supported by transfusion, erythropoietin, or other approved hematopoietic growth factors within 2 weeks of the laboratory test)
• Serum bilirubin < 1.5 × upper limit of normal (ULN) or < 2 × ULN if patient is known to have Gilbert’s Disease as the only underlying hepatic disorder
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 × ULN
• Serum creatinine clearance > 60 mL/min/1.73m2 calculated according to CKD-EPI (Appendix I)
12. Thyroid function tests must be consistent with stable thyroid function. Patients on a stable dose of thyroid replacement therapy for a minimum of 3 weeks before starting study drug are eligible.
13. Left ventricular ejection fraction (LVEF) ≥50% or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) within 28 days before the first dose of study drug.
14. Ability to comply with outpatient treatment, laboratory monitoring, required clinic visits, and required imaging studies for the duration of study participation
15. Willingness of male and female patients with reproductive potential to use double highly effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 180 days following the last dose of study drug. Highly effective birth control methods are described in Appendix F.
16. Male patients must agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug.
In addition to those outlined in Study Protocol DAY101-102 (Master Protocol), the following additional inclusion criteria must be met to be eligible for enrollment in this study:
2a. Patients must have a histologically confirmed diagnosis of melanoma or other solid tumor with an activating BRAF fusion, CRAF/RAF1 fusion, or CRAF/RAF1 amplifications as assessed by sequencing, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or another sponsor-accepted method | |
| E.4 | Principal exclusion criteria | 1. Prior receipt of any BRAF-, MEK-, or MAPK-directed inhibitor therapy, except for tumor types and indications where such therapy has been approved by the FDA or applicable regulatory authorities.
2. Known presence of concurrent activating alterations. Examples include, but are not limited, to the following: EGFR, ALK, MET, ROS, FGFR, RET, NTRK, EGFR, PIK3A, IDH1/2, EGFR, and cKIT. Genetic profile of tumor under study, if available, will be reviewed by the Sponsor to confirm eligibility.
3. Current enrollment in any other investigational treatment study
4. Patients with current evidence or a history of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at screening or baseline who would be considered a risk factor for CSR or RVO
5. Patients who have an unstable neurological condition, despite adequate treatment (e.g., uncontrolled seizures)
6. Evidence of current uncontrolled cardiovascular conditions, including but not limited to clinically significant cardiac arrythmias, congestive heart failure, angina, myocardial infarction, or cerebrovascular accident (CVA), within the past 6 months
7. Mean resting QT calculated using Fridericia’s formula (QTcF) interval > 470 ms based on triplicate electrocardiogram (ECG) average; or family or personal history of long or short QT syndrome; Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of screening
8. Concomitant treatment with strong CYP2C8 inhibitor and/or inducers within 14 days before initiation of therapy. See sub-study protocol for details on prohibited medications with DAY101.
9. Concomitant treatment with medications that are sensitive substrates of CYP2C8 and CYP2C9 or predominantly transported by a breast cancer resistance protein (BCRP) (See sub-study protocol for details on prohibited medications with DAY101. Additional restricted medications may apply depending on the combination partner. Refer to the eligibility criteria for each sub-study for additional restrictions specific to the combination that may apply.)
10. Unable to swallow investigational product or has refractory nausea and vomiting, malabsorption, external biliary diversion, or any significant small bowel resection that may interfere with adequate absorption of investigational product
11. Major surgery within 28 days of Day 1 (does not include central venous access or ventriculoperitoneal shunts).
12. Active, uncontrolled systemic bacterial, viral, or fungal infection.
13. History of any major disease that might interfere with safe protocol participation, as determined by the Investigator (e.g., allogeneic bone marrow transplantation, organ transplantation, or interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis).
14. Patients with subclinical pneumonitis who have received immunotherapy previously can be included if his/her condition is stable without any medical intervention.
15. History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens Johnsons syndrome (SJS), or hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product(s)
16. History of second malignancy within 3 years prior to study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, or superficial bladder cancer
17. Female patients who are pregnant or currently breastfeeding
18. Other unspecified reasons that, in the opinion of the Investigator, make the patient unsuitable for enrollment | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Phase 1b:
• Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5
• Change from baseline in targeted vital signs
• Change from baseline in targeted clinical laboratory test results
• Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5
• Change from baseline in targeted vital signs
• Change from baseline in targeted clinical laboratory test results
• Incidence of dose-limiting toxicities (DLTs)
Phase 2:
Overall response rate (ORR) as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or PR according to the appropriate response assessment criteria for the disease setting as assessed by the Investigator. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | Phase 1b:
• ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) according to the appropriate tumor response criteria as assessed by Investigator
• DOR in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earlier]
• Duration of progression-free survival (PFS) following initiation of study treatment to disease progression, death, or date of analysis, whichever occurs earlier
• Duration of overall survival (OS) following initiation of study treatment to time of death
• Time to response (TTR) in patients with best overall response of CR or PR as determined by treating Investigator [from initiation of study treatment to date of first response]
• Comparing the DOR in patients with CR or PR as determine by treating Investigator with the DOR observed with the immediate prior line of anticancer treatment
• Plasma concentration of DAY101 at specified time points in order to define PK parameters
• Measured by downstream MAPK pathway signaling, including pERK and other relevant pathway signaling using appropriate assay(s) on tumor biopsies obtained at baseline and on Cycle 1 Day 1 and Cycle 2 Day 1 (± 3 days)
Phase2:
• Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5
• Change from baseline in targeted vital signs
• Change from baseline in targeted clinical laboratory test result
• ORR as assessed by the proportion of patients with the best overall confirmed response of complete response (CR) or PR according to the appropriate tumor response criteria as assessed by Investigator
• DOR in patients with best overall response of CR or PR as determined by the treating Investigator [from time of first tumor response to progression or date of data analysis, whichever occurs earlier]
• Duration of progression-free survival (PFS) following initiation of study treatment to disease progression, death, date of analysis, whichever occurs earlier
• Duration of OS following initiation of study treatment to time of death
• Time to response (TTR) in patients with best overall response of CR or PR as determined by treating Investigator [from initiation of study treatment to date of first response]
• Comparing the DOR in patients with CR or PR as determine by treating Investigator with the DOR observed with the immediate prior line of anticancer treatment]
• Measure plasma concentration of DAY101 at specified time points in order to define population PK parameters
• Measured by downstream MAPK pathway signaling and other relevant pathway signaling using appropriate assay(s) on tumor biopsies obtained at baseline and while on-treatment
• Measured by the relationship between PK and PD biomarkers | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description | | Phase 1b will only apply to sub-studies of DAY101 in combination with other therapies | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Belgium | | France | | Korea, Republic of | | Spain | | United States | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
