DAROVASERTIB for Metastatic uveal melanoma (HLA-A2 negative)

Inclusion criteria

• {"criterion_text":"- 1. Must be at least 18 years of age.\n- 10. Has a life expectancy of ≥3 months.\n- 11. Has adequate organ function (screening assessment must be obtained within 14 days of the first dose of study treatment): • Absolute neutrophil count ≥1500/mm3 without the use of hematopoietic growth factors • Platelet count ≥100,000/mm3 (must be at least 2 weeks post-platelet transfusion and not receiving platelet-stimulating agents) • Hemoglobin ≥9.0 g/dL (must be at least 2 weeks post-red blood cell transfusion) • Total and direct bilirubin ≤1.5 x the upper limit of normal (ULN). For participants with documented Gilbert’s disease, total bilirubin ≤3.0 mg/dL is allowed • Aspartate transferase (AST) and alanine transferase (ALT) ≤3 x ULN in the absence of documented liver metastases; ≤5 x ULN in the presence of liver metastases • Serum albumin ≥3.0 g/dL • Creatinine clearance ≥45 mL/min by Cockcroft-Gault equation (see Appendix 1, Section 14.1) • Prothrombin time/International Normalized Ratio (INR) or partial thromboplastin time test results at screening ≤1.5 x ULN (this applies only to participants who do not receive therapeutic anticoagulation; participants receiving therapeutic anticoagulation should be on a stable dose for at least 2 weeks prior to the first dose of study drug)\n- 12. Women of childbearing potential who are sexually active with a non-sterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment (see Appendix 5, Section 14.5), and must agree to continue using such precautions for 6 months after the final dose of study treatment; cessation of birth control after this point should be discussed with a responsible physician. Highly effective methods of contraception are described in Appendix 5, Section 14.5.\n- 13. Male participants must be surgically sterile or must agree to use double barrier contraception methods from enrollment through treatment and for 6 months following administration of the last dose of study treatment.\n- 2. Is able to provide written, informed consent before initiation of any study related-procedures, and is able, in the opinion of the Investigator, to comply with all the requirements of the study.\n- 3. Has histological or cytological confirmed UM with metastatic disease\n- 4. HLA-A*02:01 negative\n- 5. Must meet the following criteria related to prior treatment: • No prior systemic therapy in the metastatic or advanced setting including chemotherapy, immunotherapy, or targeted therapy • No prior regional, liver-directed therapy including chemotherapy, radiotherapy, or embolization • Prior ablations or surgical resection of oligometastatic disease are allowed • Prior neoadjuvant or adjuvant therapy is allowed provided administered in the curative setting in participants with localized disease and a minimum of 4 weeks (28 days) has elapsed since the end of neoadjuvant/adjuvant treatment and the start of study treatment o Participants who have received a combination of anti-PD(L)1 plus anti-CTLA-4 as prior neoadjuvant/adjuvant treatment should not receive ipilimumab + nivolumab as investigator’s choice therapy o Participants who have received an anti-PD(L)1 agent as prior neoadjuvant/adjuvant treatment should not receive pembrolizumab as investigator’s choice therapy o Participants who have received a dacarbazine-containing regimen as prior neoadjuvant/adjuvant treatment should not receive dacarbazine as investigator’s choice therapy\n- 6. Has a representative archival metastatic tumor specimen in paraffin blocks with an associated pathology report or a minimum of 16 formalin-fixed paraffin embedded (FFPE) slides is mandatory. If archival tissue block is exhausted or not available, then a tissue biopsy FFPE sample is required unless a biopsy is not medically feasible. Only tissue from a surgical resection or a core needle, punch, or excisional/incisional biopsy sample collection will be accepted. Fine needle aspiration (FNA) samples are not acceptable.\n- 7. Has measurable disease per RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with computer tomography (CT) or magnetic resonance imaging (MRI) scan. An enlarged lymph node must be ≥15 mm in short axis to be a measurable lesion.\n- 8. Able to be safely administered and absorb study therapy\n- 9. Has ECOG performance status 0 or 1."}

Exclusion criteria

• {"criterion_text":"- 1. Has received previous treatment with a PKC inhibitor (including prior treatment with IDE196), an inhibitor directly targeting MET, or an inhibitor directly targeting GNAQ/11.\n- 10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the participant has a history of HBV or HCV infection. NOTE: participants with suspected hepatitis should be discussed with the Sponsor Medical Monitor.\n- 11. Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary).\n- 12. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass.\n- 13. Use of hematopoietic colony-stimulating factors (CSF) (eg, granulocyte [G]-CSF, granulocyte-macrophage [GM]-CSF, macrophage [M]-CSF) within2 weeks prior to start of study drug. An erythroid-stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the participant is not red blood cell transfusion dependent.\n- 14. Receives treatment with medications that cannot be discontinued prior to study entry and that are considered to be any of the following (see Table 19): • Known risk for QT prolongation, except for the specific use of oral 5-HT3 Receptor Antagonists (eg., granisetron, ondansetron or dolansetron) for the management of nausea and vomiting (note: intravenous formulations are prohibited) • Known to be strong inducers or inhibitors of cytochrome P (CYP)3A4/5 • Known to be substrates of CYP3A4/5 with a narrow therapeutic index • Known to be sensitive substrates to P-gp, BCRP, OAT3, MATE-1 and MATE-2K\n- 15. Females who are pregnant or breastfeeding\n- 16. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies.\n- 17. Impaired cardiac function or clinically significant cardiac diseases, including any of the following: •\tA history or presence of ventricular tachyarrhythmia •\tPresence of unstable atrial fibrillation (ventricular response >100 beats per minute [bpm]); participants with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria •\tHas had angina pectoris or acute myocardial infarction ≤6 months prior to study treatment •\tHas congestive heart failure requiring treatment. For New York Heart Association Class 1, inclusion can be considered with discussion and agreement with the Medical Monitor •\tHas other clinically significant heart disease (eg, uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen, symptomatic bradycardia) •\tHas a drug eluting stent for cardiovascular purposes placed ≤2 months prior to study treatment •\tCorrected QT interval using Fridericia’s method (QTcF) (see Appendix 2, Section 14.2): -\tQTcF >470 msec on baseline electrocardiogram (ECG) (mean of baseline values). If electrolytes are abnormal, they may be corrected, and baseline ECGs should be repeated. In addition, participants with asymptomatic persistent heart rate <55 bpm must be discussed with the Medical Monitor for inclusion NOTE: for participants with a significantly prolonged QRS complex (>110 msec) due to a bundle branch block or an intraventricular conduction delay, an “adjusted” QTcF for the QRS widening will be used to evaluate study eligibility. “Adjusted QTcF” = measured QTcF – [measured QRS – 90 msec]\n- 18. Has an allergy to mammalian meat products or gelatin.\n- 19. Contraindication for treatment with investigator’s choice alternatives (dacarbazine, ipilimumab + nivolumab, and pembrolizumab) as per applicable labelling. Participants may have a contraindication to one or two of the choices if he/she is a candidate for dosing with at least one investigator’s choice and meets all other study eligibility criteria. Choice of dacarbazine should only be made in the setting where treatment with immunotherapy is deemed likely to result in irreversible serious (or life threatening) AEs (eg. severe active autoimmune disease requiring potent immunosuppression) and must be discussed with the Medical Monitor.\n- 2. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.\n- 20. Has any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the Investigator, would make the participant inappropriate for entry into the study.\n- 3. Has AEs from prior anti-cancer therapy that have not resolved to Grade ≤1 except for alopecia or anemia: • Any ongoing diarrhea requires discussion with the Sponsor Medical Monitor • Endocrinopathies resulting from previous immunotherapy are considered part of medical history and not an AE • Stable Grade 2 neuropathy is allowed\n- 4. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require doses of corticosteroids within the prior 3 weeks to study Day 1. Participants with brain metastases are eligible if lesions have been treated with localized therapy and there is no evidence of progression for at least 4 weeks by MRI prior to the first dose of study drug.\n- 5. Known acquired immunodeficiency syndrome (AIDS)-related illness. NOTE: human immunodeficiency virus (HIV) seropositive participants who are healthy and low risk for AIDS related outcomes could be considered eligible. Eligibility criteria for HIV positive participants should be evaluated and discussed with Sponsor Medical Monitor and will be based on current and past cluster of differentiation 4 (CD4) and T cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions should be taken into consideration.\n- 6. Active adrenal insufficiency (eg. not stable on replacement therapy), active colitis, or active inflammatory bowel disease.\n- 7. History of interstitial lung disease, active pneumonitis, or history of pneumonitis from prior therapies requiring corticosteroid treatment. However, history of grade 1 only pneumonitis OR prior radiation pneumonitis can be discussed with the Medical Monitor for consideration of inclusion.\n- 8. History of syncope (except due to an acute medical condition [eg, hemorrhage] that is not likely to reoccur and with permission of the medical monitor) within 6 months of the first dose of study treatment. Any history of potential syncope should be clarified and verified if possible. All participants with prior history of syncope should be discussed with the Sponsor Medical Monitor.\n- 9. Active infection requiring systemic antibiotic therapy. Participants requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug."}

Primary endpoints

• {"endpoint_text":"- PFS, defined as the time from randomization to the first documented date of disease progression or death due to any cause, whichever occurs first;","definition_or_measurement_approach":"Time from randomization to first documented date of disease progression or death due to any cause; PFS assessed per RECIST 1.1 by blinded independent central review (BICR) (as specified in main objective)."}
• {"endpoint_text":"- OS, defined as the time from randomization to date of death due to any cause","definition_or_measurement_approach":"Time from randomization to date of death from any cause (overall survival)."}

Secondary endpoints

• {"endpoint_text":"- TEAEs, laboratory test abnormalities, ECG and vital sign changes","definition_or_measurement_approach":"Safety assessed by treatment-emergent adverse events (TEAEs), laboratory abnormalities, ECGs and vital signs; AEs to be graded per NCI CTCAE v5.0 or later."}
• {"endpoint_text":"- Study intervention discontinuation due to AEs","definition_or_measurement_approach":"Measurement: count and description of participants who discontinue study intervention because of adverse events."}
• {"endpoint_text":"- Dose-exposure-response (safety and efficacy) relationship","definition_or_measurement_approach":"Assessment of relationship between administered dose, systemic exposure and safety/efficacy outcomes (PK/PD analyses)."}
• {"endpoint_text":"- Plasma concentration profiles and PK parameters including but not limited to Cmax, Ctrough, Tmax, AUC0-t, T1/2, Racc","definition_or_measurement_approach":"Pharmacokinetic sampling to derive plasma concentration profiles and PK parameters (Cmax, Ctrough, Tmax, AUC0-t, T1/2, accumulation ratio Racc)."}
• {"endpoint_text":"- PFS, defined as the time from randomization to the first documented date of disease progression or death due to any cause, whichever occurs first","definition_or_measurement_approach":"As above: PFS per RECIST 1.1 (used also as secondary assessment by Investigator in addition to BICR)."}
• {"endpoint_text":"- ORR, defined as the proportion of participants with a CR or a PR as best response","definition_or_measurement_approach":"Objective response rate (ORR) per RECIST 1.1; proportion with complete response (CR) or partial response (PR) as best overall response."}
• {"endpoint_text":"- Disease control rate (DCR) (defined as CR or PR, or stable disease [SD] ≥12 weeks)","definition_or_measurement_approach":"DCR defined as CR or PR or SD lasting ≥12 weeks per RECIST 1.1."}
• {"endpoint_text":"- Best objective response (BOR)","definition_or_measurement_approach":"Best overall objective response per RECIST 1.1 (BOR)."}
• {"endpoint_text":"- Duration of response (DOR), defined as the time from the first documented evidence of a CR or PR until disease progression or death due to any cause, whichever occurs first","definition_or_measurement_approach":"Time from first documented CR/PR to disease progression or death; measured per RECIST 1.1."}
• {"endpoint_text":"- Time to response","definition_or_measurement_approach":"Time from randomization to first documented objective response (CR or PR)."}
• {"endpoint_text":"- Change from baseline over time and between treatment strategies in EORTC QLQ-C30 and EuroQoL (EQ)-5D-5L scores","definition_or_measurement_approach":"Patient-reported outcomes: change from baseline in EORTC QLQ-C30 and EQ-5D-5L scores over time and between arms."}

Belgium

Earliest CTIS Part Ii Submission Date

06-10-2023

Latest Decision Or Authorization Date

31-01-2024

Processing Time Days

117

Number Of Sites

1

Number Of Participants

10

France

Latest Decision Or Authorization Date

18-12-2023

Germany

Latest Decision Or Authorization Date

23-01-2024

Italy

Latest Decision Or Authorization Date

11-01-2024

Spain

Latest Decision Or Authorization Date

23-01-2024

Netherlands

Latest Decision Or Authorization Date

19-01-2024

Poland

Latest Decision Or Authorization Date

19-01-2024

Primary sponsor

Full Name

Ideaya Biosciences Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

United Biosource Corporation S.L.

Responsibilities

sponsorDuties codes: [1,12,2,5] (roles per CTIS record)

Name

Suvoda LLC

Responsibilities

sponsorDuties codes: [14,3] (roles per CTIS record)

Name

Labcorp Central Laboratory Services LP

Responsibilities

cfDNA blood and tissue testing PK/PD testing

Third parties

• {"country":"Spain","full_name":"United Biosource Corporation S.L.","duties_or_roles":"sponsorDuties codes: [1,12,2,5]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"sponsorDuties codes: [14,3]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"cfDNA blood and tissue testing PK/PD testing","organisation_type":"Pharmaceutical company"}