Inclusion Criteria

• Participant(s) or parent(s) or legal guardian(s), is (are) willing and able to provide written informed consent for the study prior to the performance of any study-specific procedures.
• Lansky (< 16 yo) or Karnofsky (≥ 16 yo) performance status of ≥ 50.
• The participant must have a clinical diagnosis of PROS or a malformation within the ISSVA 2018 classification.
• One or more documented activating PIK3CA mutation(s) that are targeted by selective PI3Kα inhibitors in lesional tissue and/or cellfree DNA from the lesion or blood per local assessment as defined by:
  • H1047X, E542X, E545X, R88Q, R93X, G118D, N345X, C420R, E453X, Q546X, E726K, M1043I, or G1049R (where “X” represents any amino acid change)
  • Other potentially activating PIK3CA mutations may be considered but must be approved by the Sponsor prior to enrollment.

Note for Parts 1 and 2: Due to a high incidence (>80%) of PIK3CA mutation, participants with PROS or lymphatic malformation (LM) may enroll without a documented PIK3CA mutation as long as no other genetic driver has been documented.

• Must be a candidate for investigational therapy, as defined as:
  • Participant must not be a candidate for local therapy (i.e., sclerotherapy or surgery).
  • Disease that is refractory to standard medical therapy; participant has declined standard or local therapy with documentation of the rationale for refusal or is intolerant to standard or local medical therapy.
  • Severe, symptomatic, and/or progressive disease with potentially life-threatening complications that warrant medical treatment, including but not limited to airway compromise, swallowing impairment/aspiration, speech delay, vision or hearing compromise, ascites, effusions, organ damage, or compromise of nervous or limb function, amputation, significant cosmetic disfigurement, coagulopathy, severe pain, or serious infection (particularly if complications are recurrent or progressive).
• [For Parts 1 and 2]: Agree to provide archived lesional fluid and/or tissue or be willing to undergo pretreatment lesional biopsy (if considered safe and medically feasible) to assess PIK3CA status. If the participant does not have available archived lesion fluid or tissue or biopsy is not possible, he or she may be eligible for the study upon consultation with the Sponsor.
• [For Part 3]: Submit lesional fluid and/or tissue (archived or newly obtained biopsy if considered safe and medically feasible) prior to study drug initiation for determination of PIK3CA mutation.
• Must have at least one target lesion amenable for volumetric assessment, as assessed by central review, which is actively growing and/or directly leading to symptoms:
  • Lesions that have been subject to prior local therapy (i.e., sclerotherapy or surgery) must have grown significantly since the last procedure to be considered a target lesion.
  • Lesions that previously responded to systemic therapy must have worsened significantly by radiographic assessment to be considered a target lesion (as one example, a ≥ 20% increase in volumetric assessment, if performed, would be considered substantial)
  • [Part 2 only]: The SRC may elect to open a cohort of participants without target lesions.
• Adequate organ function defined as:
  • Platelet count ≥ 75×109 /L
  • Absolute neutrophil count (ANC) of ≥ 1×109 /L
  • Hemoglobin ≥ 9 g/dL (red blood cell transfusion and erythropoietin may be used to reach 9 g/dL but must have been administered at least 2 weeks prior to the first dose of study drug)
  • Total bilirubin < 1.5×ULN; <3×ULN with direct bilirubin > 1.5×ULN in the presence of Gilbert’s disease
  • Estimated or measured creatinine clearance ≥ 60 mL/min. Calculated creatinine clearance should be done with the Chronic Kidney Disease Epidemiology Collaboration formula for adults and Schwartz formula for pediatric participants.

Exclusion Criteria

• Participant or parent(s) or legal guardian(s), as appropriate, is (are) unwilling or unable to provide or understand written informed consent and comply with any study procedures and restrictions.
• Participant with other known pathogenic somatic or germline mutations known to drive PROS or endothelial overgrowth, including, but not limited to, TIE2 (TEK), BRAF, KRAS, HRAS, NRAS, GNAQ, GNA11, GNA14, IDH1/2, and PTEN.
• Type 1 or 2 diabetes requiring antihyperglycemic medication or fasting plasma glucose ≥ 140 mg/dL and glycosylated hemoglobin (HbA1c) ≥ 7.0%
• History of hypersensitivity to PI3K inhibitors.
• Any of the following cardiac criteria:
  • Mean resting corrected QT interval using Fridericia’s formula (QTcF) > 470 msec obtained from 3 consecutive electrocardiograms (ECGs); any clinically important abnormalities in rhythm, conduction, or morphology with resting ECG (e.g., complete left-bundle branch block, 3rd-degree heart block); or clinically significant, uncontrolled arrhythmia including bradyarrhythmias that may cause QT prolongation (e.g., Type II 2nd-degree heart block).
  • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death, and use of concomitant medications that prolong QT/QTc interval.
  • Clinically significant, uncontrolled cardiovascular disease including congestive heart failure Grade 3 and Grade 4 according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months, and uncontrolled hypertension (Grade 3 or higher). An echocardiogram (ECHO) or multigated acquisition scan (MUGA) may be performed to rule out cardiac ejection fraction outside institutional range of normal in patients who are at risk for highoutput cardiac failure.
• Received disease-directed therapy prior to first dose of study drug:
  • Systemic therapy within 5 half-lives of the drug or 14 days, whichever is longer and received antibody within 28 days.
  • Local therapy including radiation, surgery, or other procedures within 28 days; lesion(s) must have demonstrated progression after the procedure.

Note: If the participant has rapid progressive disease from prior therapy, RLY-2608 may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the participant with prior Sponsor approval.

• Received neutrophil growth factor support within 14 days of the first dose of RLY-2608.
• Requires treatment with a prohibited medication (as listed in the protocol) that cannot be discontinued at least 2 weeks or 5 half-lives before the start of study drug administration, whichever is shorter. If the patient has rapidly progressing disease, this criterion may be waived if considered by the Investigator to be safe and in the best interest of the participant with approval of the Sponsor.
• Had a major surgical procedure within 28 days of the first dose of RLY-2608 (procedures such as central venous catheter placement and tumor needle biopsy are not considered major surgical procedures). The Investigator should discuss other minor surgeries with the Sponsor.
• History of malignancy that has been diagnosed or required therapy within the past year. Note: The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate or breast cancer, curatively treated localized thyroid cancer, curatively treated localized cervical cancer, and completely resected carcinoma in situ of any site.
• Females of childbearing age (postmenarche) who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception or from donating oocyte during the study drug administration period and for at least 199 days after the last dose of study drug. Males who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception or from donating sperm during the administration period and for at least 109 days after the last dose of study. Acceptable methods of contraception are listed in the protocol.
• Pregnancy, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the first dose of study drug. β-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Females of nonchildbearing potential (i.e., are premenarche or postmenopausal for more than 1 year or have had bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do not require a serum β-hCG test.
• Currently breastfeeding.
• Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the participant; could alter the absorption, distribution, metabolism, or excretion of the RLY-2608; or could impair the assessment of study results.
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection unless meeting the following criteria:
  • Participant with HIV infection is eligible if:
    • Documented CD4+T-cell (CD4+) counts ≥ 350 cells/μL and undetectable HIV RNA within 4 weeks of starting study treatment, and
    • No acquired immunodeficiency syndrome defining opportunistic infections within the past 12 months prior to study enrollment, and
    • On established anti-retroviral therapy for at least 4 weeks prior to study enrollment.
  • Participant with HBV infection is eligible if:
    • Documented HBV DNA <1000 IU/mL within 4 weeks of starting study treatment and
    • Chronic HBV infection (detectable HBV DNA) or serologic evidence of resolved infection (Hepatitis B surface antigen (HBsAg)-negative, anti-HBc positive) must be treated with anti-HBV therapy for at least 4 weeks prior to study enrollment.
  • Participant with HCV infection is eligible if:
    • HCV Ab positive and documented HCV RNA negative within 4 weeks of study enrollment due to completion of prior antiviral treatment or natural resolution of infection.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/09/2024. Questions regarding updates should be directed to the study team contact.