Phase 2 EL219 Versus Liposomal Amphotericin B or Voriconazole for Early Antifungal Therapy

Elion Therapeutics, Inc.

Status and phase: Enrolling; Phase 2

Conditions: Invasive Mould Infection

Treatments: Drug: Active Comparator- IV Antifungal (LAmB or voriconazole); Drug: EL219

Study type: Interventional

Funder types: Industry

Identifiers

NCT07215273

EL219.IV.2.04

Details and patient eligibility

About

The purpose of this study is to determine if EL219 is safe and effective compared to liposomal amphotericin B (LAmB) or voricanozole for early treatment of invasive mould infections

Full description

A Phase 2, multicenter, randomized, double-blind Study of Safety and Efficacy of EL219 versus Comparator (LAmB or voriconazole) for early antifungal therapy of suspected or confirmed Invasive Mould Infections (IMI)

Enrollment: 60 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Participants who meet ALL the following inclusion criteria will be eligible to participate in the study:

1. Willing and able to provide written informed consent.

2. 18 years and older, of any gender, race, or ethnicity

3. Are at risk for invasive fungal infections (IFIs), by virtue of acquired or inherited immunocompromising condition including but not limited to the following:

   1. Receipt of a blood or marrow transplant (BMT) from an allogeneic donor
   2. Active hematologic malignancy.
   3. Recent neutropenia with absolute neutrophil count <500 cells/mm3 >10 days
   4. Receipt of corticosteroids at mean minimum doses of 0.3 mg/kg/day prednisone equivalent for >3 weeks.
   5. Receipt of other recognized T-cell immunosuppressants, such as cyclosporin, tumor necrosis factor alpha (TNF-α) blockers, or specific monoclonal antibodies during the last 3 months.
   6. Inherited severe immunodeficiency

4. Has suspected or confirmed mould infection (IMI) supported by one or both of the following:

   1. Results of an assay having regulatory clearance in Europe or the United States (Conformité Européene [CE] mark or United States Food and Drug Administration [US FDA] 510k clearance), demonstrating positivity at validated cut-off that is suggestive of IMI. Diagnostic tests must have regulatory approval in the region in which the diagnostic is performed and are inclusive of Platelia serum or bronchoalveolar lavage (BAL) galactomannan, serum or BAL polymerase chain reaction (PCR), serum or BAL Aspergillus antigen lateral flow assays (LFAs; IMMY, OLM Diagnostics, or TECO®), or urine MycoMEIA®-Aspergillus assay
   2. Abnormal findings on chest computed tomography (CT) scan without alternative microbiologic diagnosis Note: If CT of the chest is used to establish eligibility it must be performed within 7 days prior to randomization.

5. Must have IV access in place or to be placed prior to beginning IV study therapy.

6. Must be willing to adhere to dosing, study visit schedule, and mandatory diagnostic procedures.

7. Female participants must meet 1 of the following criteria:

   1. A woman of childbearing potential (WOCBP) must agree to use a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) for at least 30 days prior to screening and agree to remain on a highly effective method until 2 months after study drug administration.
   2. A female of non-childbearing potential must be surgically sterile (i.e., have undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation/occlusion without reversal surgery) or in a menopausal state (at least 2 years without menses), or confirmation of menopause by follicle-stimulating hormone (FSH) levels (≥40 mIU/mL).

8. A WOCBP must have a negative pregnancy test (highly sensitive serum β-human chorionic gonadotropin or a urine test) during both the current hospitalization AND on Day -1 before study drug administration.

9. Females must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of at least 2 months after study drug administration.

10. Male participants must be vasectomized or agree to abstain from intercourse or if engaging in sexual activity that has risk of pregnancy, must agree to use a double barrier method (e.g. condom and spermicide) and agree not to donate sperm during the study and for at least 120 days after study drug administration.

Exclusion criteria

Participants must NOT meet any of the following exclusion criteria:

1. Participant has received prior antifungal treatment (azole or echinocandin prophylaxis permitted) for >96 hours prior to randomization.

2. Active, microbiologically confirmed systemic bacterial infection with ongoing receipt of antibacterial therapy. Antibacterial prophylaxis and secondary therapy is allowed, providing that follow-up cultures have been without growth for >2 days.

3. Participants with 1 or more of the following laboratory abnormalities as defined by the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v5.0:

   1. Alanine aminotransferase (ALT) ≥5 × upper limit of normal (ULN).
   2. Total serum bilirubin ≥5 × ULN (excluding Gilbert's Syndrome).
   3. Serum creatinine ≥2 mg/dL or creatinine clearance (CrCL) ≤30 mL/minute.

4. Known cirrhosis of the liver, diagnosed according to country or Medical Society-specific guidelines and documented in the medical records prior to screening.

5. Known New York Heart Association (NYHA) Class III or Class IV heart failure.

6. Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin) or forced expiratory volume in 1 second (FEV1) ≤65% of predicted value, or oxygen (O2) saturation ≤82% on room air.

7. Receiving either hemodialysis or peritoneal dialysis.

8. Personal or family history of long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF; >470 msec in males and >490 msec in females).

9. If the Investigator chooses voriconazole as Comparator therapy, current or projected use of the following medications or drug classes known to interact with voriconazole: terfenadine, astemizole, cisapride, pimozide, quinidine, sirolimus, rifampin, phenytoin, carbamazepine, flucloxacillin, eplerenone, fineronone, voclosporin, ritonavir or other protease inhibitors, efavirenz, venetoclax or other non-nucleoside reductase inhibitors, rifabutin, naloxegol, tolvaptan, ivabradine, lurasidone, St. John's Wort, ergot alkaloids, or long-acting barbiturates.

10. If the Investigator chooses voriconazole as Comparator therapy, history of hereditary problems with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

11. Known hypersensitivity to EL219 Powder for Injection, polyenes, or known hypersensitivity to voriconazole if the Investigator chooses voriconazole as Comparator therapy.

12. History of severe allergic response to mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine and/or polyethylene glycol (PEG)-containing products.

13. Previous participation in any study using an investigational drug within 5 half-lives of the drug, or intention to use investigational drug before completion of the Day 56 Safety Follow-Up. Concurrent participation in another trial may be allowed (e.g., interventional trial with a previously approved study drug[s] or observational trial). In such cases, the Medical Monitor should be consulted prior to enrolling a potential participant.

14. Prior recipient of orthotopic lung transplant.

15. Imminent transition to hospice or withdrawn care such as with refractory malignancy or multiorgan failure.

16. Female participants who are pregnant or lactating or planning to become pregnant within 2 months following study drug administration.

17. The Principal Investigator (PI) determines the participant should not participate in the study.

18. Considered unlikely to follow up for required days due to logistic concerns (i.e., home location relative to study site).

19. Persons committed to an institution by virtue of an order issued either by the judicial or the administrative authorities or are in a dependent relationship with the Sponsor or the Investigator.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 2 patient groups

EL219

Experimental group

Description:

Participants randomized to EL219 will receive a single loading dose of EL219 at 2 mg/kg via IV infusion on Day 1, and 1.5 mg/kg IV infusions on Days 8, 15, 22, 29, and 36. All dosing calculations for EL219 will be based on total body weight (TBW). To maintain the blind, placebo IV infusions will be administered to participants randomized to EL219 arm daily (corresponding to Liposomal Amphotericin B (LAmB) dosing); or 2x daily (corresponding to voriconazole dosing depending on the Investigator's choice of Comparator).

Treatment:

Drug: EL219

Antifungal Comparator

Active Comparator group

Description:

Comparator arm (CMPTR) will receive LAmB 3mg/kg once daily IV infusions for min.14 days \& up to 42 days. Participants w/suspected or diagnosed mucormycosis may be dosed at 5mg/kg. Voriconazole (Vori) 6mg/kg BID IV loading dose on Day 1 followed by 4mg/kg IV BID thereafter. Dosing calculations for LAmB \& vori are based on TBW. Participants may switch from CMPTR to optional SOC antifungals (PI discretion) if any of these occur: Toxicity; serum creatinine 2×baseline (bsln) level or 50% reduction in GFR, Hypokalemia or hypomagnesemia not controlled with IV supplementation, increase in ALT to 3×bsln and/or total bili 3×bsln, intractable IRR •Imminent hosp discharge requiring switch from CMPTR •Intolerable clinical s/s consistent w/known drug-related effect •Dx by C\&S testing suggesting IMI not appropriately treated w/1 or both CMPTR drug Vori trough level \<2.0 or \>5.5mg/L for whom vori was selected as the randomized CMPTR

Treatment:

Drug: Active Comparator- IV Antifungal (LAmB or voriconazole)