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

Study Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
Hematological Malignancies; Multiple Myeloma; Hodgkin's Lymphoma; Peripheral T-cell Lymphoma; Cutaneous T Cell Lymphoma; T-cell Prolymphocytic Leukemia	Drug: EDO-S101	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	111 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1 Study to Investigate the Safety, Pharmacokinetic Profiles and the Efficacy of EDO-S101, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies
Study Start Date :	March 2016
Estimated Primary Completion Date :	December 2020
Estimated Study Completion Date :	May 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: EDO-S101; EDO-S101, IV, 20mg/m2 up to 150mg/m2 Day1 of each 21 day cycle-Stage 1; EDO-S101,IV, 40mg/m2 up to 60mg/m2 on Day 1 and Day 15 of 28 day cycle in multiple myeloma patients and IV, 40mg/m2 up to 100mg/m2 on Day 1 of 21 day cycle in lymphoma patients-Stage 2	Drug: EDO-S101

Outcome Measures

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Primary Outcome Measures :

1. Classification of each stage 2 cohort as to interest or no interest based upon overall response rate [ Time Frame: 10-20 months from beginning stage 2 ]
   Determine overall response rate by cohort
2. Overall response rate [ Time Frame: 10-20 months from beginning of stage 2 ]
   Determine overall response rate
3. Clinical benefit rate by cohort [ Time Frame: 10-20 months from beginning of stage 2 ]
   Determine clinical benefit rate by cohort
4. Safety of selected doses in expanded population [ Time Frame: 36 months from beginning stage 2 ]
   Number of participants with treatment-related adverse events as assessed by CTCAE V4.03

Secondary Outcome Measures :

1. Time to overall response [ Time Frame: 10-20 months after beginning stage 2 ]
   Determine time to overall response by cohort
2. Time to complete response [ Time Frame: 10-20 months after beginning stage 2 ]
   Determine time to complete response by cohort
3. Duration of response [ Time Frame: 10-20 months after beginning stage 2 ]
   Determine duration of response by cohort
4. Progression free survival (PFS) [ Time Frame: 32-36 months after beginning stage 2 ]
   Determine time to progression free survival by cohort
5. Overall Survival (OS) [ Time Frame: 32-36 months after beginning stage 2 ]
   Determine the overall survival time by cohort
6. PK trough profiles [ Time Frame: 10-20 months after beginning stage 2 ]
   Determine the trough PK profiles for EDO-S101

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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).

Contacts and Locations

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Locations

United States, Arizona
Mayo Clinic	Recruiting
Phoenix, Arizona, United States, 85054
Contact: Leif Bergsagel, MD 480-301-8335 bergsagel.leif@mayo.edu
Principal Investigator: Leif Bergsagel, MD
United States, Florida
Mayo Clinic Cancer Center	Recruiting
Jacksonville, Florida, United States, 32224
Contact: Han W Tun, MD 904-953-7290 tun.han@mayo.edu
Contact: Kathleen M Burke, RN 904 953 6174 burke.kathleen@mayo.edu
Principal Investigator: Han W. Tun, MD
United States, Minnesota
Mayo Clinic Cancer Center	Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Wei Ding, MD 507-284-2511 Ding.Wei@mayo.edu
Contact: Joeliann M Quarve 507-538-4846 Quarve.Joeliann@mayo.edu
Principal Investigator: Wei Ding, MD
United States, New York
Columbia University Medical Center	Recruiting
New York, New York, United States, 10019
Contact: Owen A O'Connor, MD,PhD 212-326-5720 oo2130@cumc.columbia.edu
Contact: Freddy Laffredo 212-326-5733 fl2156@cumc.columbia.edu
United States, Texas
The University of Texas MDACC	Not yet recruiting
Houston, Texas, United States, 77030
Contact: Gautam Borthakur, MD 713-563-1586 GBorthak@mdanderson.org
Contact: Carol Bivins 713-794-4460 cbibins@mdanderson.org
Principal Investigator: Gautam Borthakur, MD
France
CHU de Caen	Not yet recruiting
Caen, France, CS 3001
Contact: Ghandi L Damaj, MD 00 33 231 06 25 36 damag-gl@chu-caen.fr
Contact: Emilie Marin 00 33 231 27 20 72 marin.e@chu-caen.fr
Principal Investigator: Ghandi L Damaj, MD
CHU Hotel Dieu	Not yet recruiting
Nantes, France, 44093
Contact: Philippe Moreau, MD 00 33 240 08 32 71 philippe.moreau@chu-nantes.fr
Principal Investigator: Philippe Moreau, MD
Centre hospitalier Lyon Sud	Not yet recruiting
Pierre Bénite, France, 69495
Contact: Gilles Salles, MD 00 33 478 86 43 07 gilles.salles@chu-lyon.fr
Contact: Virginie Tronchon 00 33 478 84 43 35 virginie.tronchon@chu-lyon.fr
Principal Investigator: Gilles Salles, MD
Italy
Institute of Hematology "L. A. Seràgnoli", University of Bologna	Recruiting
Bologna, Italy, 40138
Contact: Luigi Zinzani, MD +39 0512143680 pierluigi.zinzani@unibo.it
Principal Investigator: Luigi Zinzani, MD
National Cancer Institute, Fondazione 'G. Pascale'	Recruiting
Naples, Italy, I-80131
Contact: Antonio Pinto, MD +39 081 5903 382 apinto.int.napoli@tin.it
Principal Investigator: Antonio Pinto, MD
Netherlands
VU medisch centrum	Not yet recruiting
Amsterdam, Netherlands, 1081 HV
Contact: Josée Zijlstra, MD +31 20 4442604 J.Zijlstra@vumc.nl
Contact: Maaike Leidekker +31 20 4442639 m.leidekker@vumc.nl
Principal Investigator: Josée Zijlstra, MD
Erasmus MC	Not yet recruiting
Rotterdam, Netherlands, 3015 GD
Contact: Pieternella Lugtenburg, MD +31 10 7033123 p.lugtenburg@erasmusmc.nl
Principal Investigator: Pieternella Lugtenburg, MD
Spain
Institut Català d'Oncologia de Barcelona	Not yet recruiting
Hospitalet de Llobregat, Barcelona, Spain, 08908
Contact: Ana S Balari, MD +34 93 260 72 10 asureda@iconcologia.net
Principal Investigator: Ana S Balari, MD
Hospital Universitario de Salamanca	Not yet recruiting
Salamanca, Spain, 37007
Contact: Maria V Mateos, MD +34 678438203 mvmateos@usal.es
Principal Investigator: Maria V Mateos, MD
Hospital Universitario Marqués de Valdecilla	Not yet recruiting
Santander, Spain, 39008
Contact: Enrique Ocio, MD +34 649-391848 ocioem@unican.es
Principal Investigator: Enrique Ocio, MD
Switzerland
Kantonsspital St.Gallen	Recruiting
St.Gallen, Switzerland, 9007
Contact: Christoph Driessen, MD 41 71 494 11 62 christoph.driessen@kssg.ch
Principal Investigator: Christoph Driessen, MD

Sponsors and Collaborators

Mundipharma-EDO GmbH

Investigators

Principal Investigator:	Owen A O'Connor, MD,PhD	Columbia University

More Information

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Responsible Party:	Mundipharma-EDO GmbH
ClinicalTrials.gov Identifier:	NCT02576496 History of Changes
Other Study ID Numbers:	EDO-S101-1001
First Posted:	October 15, 2015
Last Update Posted:	January 10, 2019
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	relevant patient listing data of de-identified patients may be reviewed

Keywords provided by Mundipharma-EDO GmbH:

phase 1 clinical trial; multiple myeloma; Hodgkin's lymphoma	peripheral T-cell lymphoma; cutaneous T-cell lymphoma; T-cell Prolymphocytic Leukemia

Additional relevant MeSH terms:

Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms; Hodgkin Disease; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, T-Cell, Cutaneous; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases	Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia; Leukemia, T-Cell