Phase 2/3 Study of Darovasertib and Crizotinib Versus Standard Treatment in HLA-A2 Negative Metastatic Uveal Melanoma
- Trial ID
- 2023-506686-66-01
- Protocol
- IDE196-002
- Sponsor
- Ideaya Biosciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **IDE196** (Darovasertib) in combination with **crizotinib** compared to the investigator's choice of treatment in patients with HLA-A2 negative metastatic uveal melanoma. This is assessed through progression-free survival (PFS) per RECIST 1.1 as evaluated by blinded independent central review (BICR) in Phase 2b, and overall survival (OS) in Phase 3. The clinical relevance of this objective lies in determining the potential of IDE196 combined with crizotinib as a first-line therapy, which could offer a new treatment option for this patient population.
Secondary objectives include:
- Comparing IDE196 + crizotinib to investigator’s choice of treatment with respect to objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 as assessed by BICR and investigator.
- Evaluating the safety and tolerability of IDE196 in combination with crizotinib.
- Assessing quality-of-life scores in patients receiving IDE196 + crizotinib versus investigator’s choice of treatment.
Participants
The clinical trial involves a total of **266 participants** diagnosed with **HLA-A2 negative metastatic uveal melanoma**. The study population includes both male and female subjects, aged 18 years and older, with a life expectancy of at least three months. Participants were selected based on their confirmed diagnosis of metastatic uveal melanoma and their HLA-A*02:01 negative status. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants are required to have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. The selection criteria ensure that participants have not received prior systemic therapy in the metastatic or advanced setting, although prior neoadjuvant or adjuvant therapy is permissible under certain conditions. The study aims to determine the optimal dose of the IDE196 and crizotinib combination and to compare its efficacy to the investigator's choice of treatment in terms of progression-free survival and overall survival.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **darovasertib** in combination with **crizotinib** compared to the investigator's choice of treatment in patients with HLA-A2 negative metastatic uveal melanoma. This is a Phase 2/3, randomized, double-blind, controlled trial. The trial aims to determine the optimal dose of the combination therapy in Phase 2a and to compare progression-free survival (PFS) and overall survival (OS) in Phase 2b and Phase 3, respectively. The estimated duration of the trial is from July 2024 to December 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, organ function, and prior treatment history. The screening assessment must be completed within 14 days before the first dose of the study drug. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of adverse events, laboratory tests, and vital signs. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of 12 months for the combination therapy. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to strict ethical guidelines, ensuring informed consent is obtained from all participants before any study-related procedures. The primary endpoints include dose-exposure-response relationships and PFS, while secondary endpoints focus on overall response rate (ORR) and disease control rate (DCR).
Treatment
The clinical trial involves the administration of several experimental and comparator medications. **Ipilimumab** is provided as a **solution for infusion** with a concentration of 5 mg/ml. It is administered intravenously at a dosage of 3 mg/kg, with a maximum total dose of 12 mg/kg over a treatment period of 3 weeks. This medication is not a pediatric formulation and is classified as a protein-based therapeutic agent.
**Darovasertib**, marketed as IDE196 (LXS196), is administered in **tablet** form. The maximum daily dose is 400 mg, with a total dose not exceeding 146 g over a 12-week period. The route of administration is oral, and the formulation is chemical in nature. This medication is also available in a higher dosage form with a maximum daily dose of 600 mg and a total dose of 219 g over the same period.
**Pembrolizumab** is provided as a **concentrate for solution for injection**. It is administered via infusion at a maximum daily dose of 200 mg, with a total dose of 1.74 g over a 6-week period. This protein-based therapeutic agent is not formulated for pediatric use.
**Crizotinib** is available in **hard capsule** form, with a maximum daily dose of 250 mg and a total dose of 91.25 g over a 12-week period. It is administered orally and is a chemical-based medication. An alternative dosage form allows for a maximum daily dose of 400 mg and a total dose of 146 g over the same period.
**Nivolumab** is provided as a **concentrate for solution for infusion**. It is administered intravenously at a dosage of 1 mg/kg, with a maximum total dose of 4 mg/kg over a 3-week period. This medication is a chemical-based therapeutic agent and is not intended for pediatric use.
**Dacarbazine** is supplied as a **powder for solution for infusion**. It is administered via intravenous infusion at a maximum daily dose of 1000 mg/m², with a total dose of 8670 mg/m² over a 6-week period. This chemical-based medication is not formulated for pediatric use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial includes both experimental and comparator treatments, with the latter serving as a standard-of-care therapy or placebo where applicable. The study aims to evaluate the efficacy and safety of these treatments in the context of metastatic uveal melanoma.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **dose-exposure-response** relationship, plasma concentration profiles, pharmacokinetic parameters, and progression-free survival (PFS), defined as the time from randomization to the first documented date of disease progression or death due to any cause. Overall survival (OS), which is the time from randomization to the date of death due to any cause, is also a primary endpoint.
Secondary endpoints encompass the overall response rate (ORR), defined as the proportion of participants with a complete response (CR) or a partial response (PR) as the best objective response. Additional secondary endpoints include disease control rate (DCR), defined as CR or PR, or stable disease (SD) lasting at least 12 weeks, and duration of response (DOR), which is the time from the first documented evidence of a CR or PR until disease progression or death due to the underlying disease. Time to response and changes from baseline over time and between treatment arms in European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EuroQoL (EQ)-5D-5L scores are also evaluated.
These efficacy parameters will be measured and analyzed at various timepoints throughout the trial, with assessments conducted by blinded independent central review (BICR) using RECIST 1.1 criteria. The trial aims to compare the combination of IDE196 (darovasertib) and crizotinib against the investigator’s choice of treatment in patients with HLA-A2 negative metastatic uveal melanoma, focusing on both progression-free survival and overall survival as key indicators of efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be at least 18 years of age.
- Written, informed consent has been obtained before initiation of any study related-procedures, and the participant is able, in the opinion of the investigator, to comply with all the requirements of the study.
- Has histological or cytological confirmed UM with metastatic disease
- HLA-A*02:01 negative
- 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-programmed cell death ligand 1 (PD-L1) plus anti-cytotoxic T-lymphocyte associated protein 4 (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-L1 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
- 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. • The participants in this study are frontline MUM patients. Participants are eligible for this trial if they are initially diagnosed with MUM or after therapy for localized UM that has subsequently metastasized. In both examples of eligible participants, confirmation of the metastatic pathology is needed to confirm MUM and not a second primary malignancy.
- Has measurable disease per RECIST v1.1, 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.
- Able to be safely administered and absorb study therapy
- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Has a life expectancy of ≥3 months.
- Has adequate organ function (screening assessment must be obtained within 14 days of C1D1): • Absolute neutrophil count (ANC) ≥ 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) • AST and ALT ≤ 3 × ULN in the absence of documented liver metastases; ≤ 5 × ULN in the presence of liver metastases • Total and direct bilirubin ≤ 1.5 × the upper limit of normal (ULN). o If total bilirubin is > 1.5 × ULN, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are within normal limits, direct bilirubin must be ≤ 1.5 × ULN. o For participants with documented Gilbert’s disease, total bilirubin ≤ 3.0 mg/dL is allowed. • Serum albumin ≥ 3.0 g/dL. • Creatinine clearance ≥ 45 mL/min by Cockcroft-Gault equation (see Appendix 1, Section 14.1). Participants with creatinine clearance between 30 and 45 mL/min can be considered for trial enrollment, contingent upon consultation with the Medical Monitor to assess the need for dose modification, ensuring safe administration of the investigational agent. • Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time test results at screening ≤ 1.5 × 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).
- Women of child-bearing potential (WOCBP) 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. Systemically-acting hormonal contraceptives should always be combined with a barrier method (preferably male condom).
- Male participants must be surgically sterile or must agree to use double-barrier contraception methods from enrollment through treatment and for 3 months following administration of the last dose of study treatment.
Exclusion Criteria
- 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.
- 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 or HIV should be discussed with the Sponsor Medical Monitor.
- 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).
- 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.
- 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.
- Receives treatment with medications that cannot be discontinued prior to study entry and that are considered to be any of the following (see Table 18): • Other antineoplastic therapies (not including palliative radiotherapy) or investigational therapies other than IDE196 • Known risk for QT prolongation, except for the specific use of oral ondansetron for the management of nausea and vomiting (Note: intravenous [IV] formulations of ondansetron are to be used with caution.) • Narrow therapeutic index sensitive substrates of P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP) • 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
- Females who are pregnant or breastfeeding
- History of severe hypersensitivity reactions (e.g., anaphylaxis) to other biologic drugs or monoclonal antibodies
- Impaired cardiac function or clinically significant cardiac diseases, including any of the following: • A history or presence of ventricular tachyarrhythmia • Presence 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 • Has had angina pectoris or acute myocardial infarction ≤ 6 months prior to study treatment • Has congestive heart failure requiring treatment. For New York Heart Association Class 1, inclusion can be considered with discussion and agreement with the Sponsor Medical Monitor • Has other clinically significant heart disease (e.g., uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen, symptomatic bradycardia) • Has a drug eluting stent for cardiovascular purposes placed ≤ 2 months prior to study treatment • Corrected QT interval using Fridericia’s formula (QTcF) (see Appendix 2, Section 14.2): o QTcF > 470 msec on baseline 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 Sponsor 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]
- Has an allergy to mammalian meat products or gelatin.
- 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 (e.g., severe active autoimmune disease requiring potent immunosuppression) and must be discussed with the Sponsor Medical Monitor.
- 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.
- History of stroke within the last 6 months of the first dose of study drug.
- 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
- 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.
- 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 (e.g., opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions (DDI) should be taken into consideration.
- Active adrenal insufficiency (e.g., not stable on replacement therapy), active colitis, or active inflammatory bowel disease.
- 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.
- History of syncope (except due to an acute medical condition [e.g., hemorrhage] within 6 months of the first dose of study treatment and is not likely to reoccur). 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. Participants at high risk of falls should be considered ineligible.
- Active infection requiring systemic antibiotic therapy. Participants requiring systemic antibiotics for infection must have completed therapy at least one week prior to the first dose of study drug.
- 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, including institutionalization on the basis of an official or court order.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jul 2024 | 10 |
 France | Not Recruiting | 01 Jul 2024 | 30 |
 Germany | Not Recruiting | 01 Jul 2024 | 42 |
 Italy | Not Recruiting | 01 Jul 2024 | 20 |
 The Netherlands | Not Recruiting | 01 Jul 2024 | — |
 Poland | Not Recruiting | 01 Jul 2024 | 20 |
 Spain | Not Recruiting | 01 Jul 2024 | 24 |
| Netherlands | — | — | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DACARBAZINE | Comparator | — | INTRAVENIOUS INFUSION | 1000 | 6 | SUB06882MIG |
IPILIMUMAB | Comparator | — | INFUSION | 3 | 3 | SUB29397 |
IDE196LXS196 | Test | TABLET | ORAL | 600 | 12 | PRD10390878 |
NIVOLUMAB | Comparator | — | INFUSION | 1 | 3 | SUB122750 |
CRIZOTINIB | Test | — | ORAL | 400 | 12 | SUB32267 |
CRIZOTINIB | Test | — | ORAL | 250 | 12 | SUB32267 |
PEMBROLIZUMAB | Comparator | — | INFUSION | 200 | 6 | SUB167136 |
IDE196LXS196 | Test | TABLET | ORAL | 400 | 12 | PRD10390877 |