Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: Study of EDO-S101, A First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies

Summary: This study evaluates the efficacy, safety and pharmacokinetics of EDO-S101 in patients with relapsed/refractory hematologic malignancies. All patients will receive EDO-S101.

Detailed description: EDO-S101 is a new chemical entity, a first-in-class fusion molecule of an alkylator, bendamustine and a histone-deacetylase inhibitor (HDACi), vorinostat. It is anticipated that EDO-S101 may have activity in various hematological malignancies and solid tumors. This phase 1 study will enroll patients with various hematological malignancies.
  The study consists of 2 stages:
  -  Stage 1: Dose Escalation to determine Maximum Tolerated Dose (MTD) at the optimal infusion time and the pharmacokinetic (PK) profiles; is expected to enroll between 21 and 48 patients. Stage 1 has now been completed.
  -  Stage 2: Expansion in five Cohorts, in which approximately 6-16 patients will be enrolled per cohort, for a maximum of 65 patients.
  In Stage 1, EDO-S101 doses will be escalated following the standard 3+3 design. The decision to escalate to the next dose level will occur after all cohort patients have completed 3 weeks (21 days) of observation and have been evaluated for safety and toxicity.The starting dose is a 1 hour infusion of 20 mg/m2, and the maximum dose level is 150 mg/m2. Reduced infusion times of 45 minutes and 30 minutes will also be assessed once the maximum tolerated dose at a 1-hour infusion is determined.
  In Stage 2, five cohorts of patients (with relapsed/refractory multiple myeloma (MM); relapsed/refractory Hodgkin's lymphoma; relapsed/refractory peripheral T-cell lymphoma (PTCL); relapsed/refractory cutaneous T-cell lymphoma (CTCL); and relapsed/refractory T-cell Prolymphocytic leukemia (T-PLL) will be enrolled and treated at the recommended Phase 2 dose (RP2D) based on results of Stage 1. For MM patients, treatment will occur on Day 1 and Day 15 of a 28 day cycle. For lymphoma patients, treatment will occur on Day 1 of a 21 day cycle. Patients in each stage of the study are expected to receive a median of four Cycles of therapy, and the maximum number of treatment Cycles allowed is 12.

Eligibility: Inclusion Criteria:
  1. Execute an informed consent.
  2. Patients age ≥18 years at signing the informed consent.
  3. Diagnosis of relapsed or refractory lymphoid malignancy for which there are no available therapies.
  4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
  5. Neutrophils >1,000 µL
  6. Platelets ≥75,000 µL
  7. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of normal (ULN).
  8. Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.
  9. Creatinine ≤1.5 ULN.
  10. Serum potassium within normal range (potassium supplementation is permissable).
  11. If female of child-bearing potential (i.e. not postmenopausal or surgically sterile), must be willing to abstain from sexual intercourse or employ an effective barrier or medical method of contraception during the study drug administration and follow-up periods. If male, must be sterile or willing to abstain from sexual intercourse or employ a barrier method of contraception during the study treatment and follow-up periods.
  Specific Eligibility Criteria for Each Patient Cohort in Stage 2 Phase of the Study Cohort 1: relapsed/refractory multiple myeloma
  1. At least one line and a maximum of four prior standard systemic therapies and no other standard therapy available with proven clinical benefit.
  Cohort 2: relapsed/refractory Hodgkin's lymphoma 1. At least three lines of prior therapy and no other standard therapy available with proven clinical benefit.
  Cohort 3: relapsed/refractory peripheral T-cell lymphoma (PTCL)
  1. Only PTCL patients with histologically or cytologically confirmed PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) or anaplastic large-cell lymphoma (ALCL).
  2. At least one line of prior combination therapy and no other standard therapy available with proven clinical benefit.
  Cohort 4: relapsed/refractory cutaneous T-cell lymphoma (CTCL), subtypes mycosis fungoides (MF) and Sézary syndrome (SS)
  1. Only CTCL patients with histologically or cytologically confirmed MF or SS with stage IIb to IVb disease based on modified ISCL/EORTC staging.
  2. At least one line and a maximum of four prior standard systemic therapies and no other standard therapy available with proven clinical benefit.
  Cohort 5: relapsed/refractory T-cell Prolymphocytic leukemia (T-PLL)
  1. A maximum of two lines of prior therapy and no other standard therapy available with proven clinical benefit. Patients ineligible for treatment with alemtuzumab can be included.
  Exclusion Criteria:
  1. Patients with any central nervous system involvement.
  2. Diagnosis of acute leukemia or any patient that has been treated with fludarabine.
  3. Allogeneic stem cell transplant patients and any patient who has relapsed within 100 days of stem cell infusion following an autologous bone marrow transplant.
  4. Patients with corrected QT (QTc) interval (Fridericia's formula) > 450 msec.
  5. Patients who are on treatment with drugs known to prolong the QT/QTc interval.
  6. Any serious medical condition that interferes with adherence to study procedures.
  7. Patients with a history of a second malignancy diagnosed within three (3) years of study enrollment excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  8. Pregnant or breast feeding females.
  9. New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias not adequately controlled, active infections, or other significant co-morbidities [e.g. active central nervous system metastases and/or carcinomatous meningitis, active infection requiring systemic therapy, history of human immunodeficiency virus (HIV) infection, or active Hepatitis B or Hepatitis C.
  10. Previous cancer therapies within four (4) weeks or 5 half-lives, whichever is shorter, of dosing unless the patient has recovered to eligibility levels prior to treatment in this study.
  11. Use of other investigational agents within 30 days or 5 half-lives prior to the first dose of study drug unless patient has recovered from any related toxicities ≥ Grade 1.
  12. Steroid treatment within seven (7) days prior to study treatment. Patients that require intermittent use of bronchodilators, topical steroids or local steroid injections will not be excluded from the study. Patients who have been stabilized to 10 mg PO QD or less seven (7) days prior to study drug administration are allowed.
  13. Patients on Valproic Acid for any indication (epilepsy, mood disorder) must be excluded from the trial or must stop using the medication and have a wash out period of 3.5 days prior to first dose of EDO-S101 (C1D1).

Relevance to patient case: not relevant