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; Non-Hodgkin's Lymphoma	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 2: Expansion in four Cohorts, in which approximately 12 patients will be enrolled per cohort, for a total of 48 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, four cohorts of patients (with relapsed/refractory multiple myeloma or Waldenström Macroglobulinemia; relapsed/refractory Hodgkin's lymphoma; relapsed/refractory peripheral T-cell lymphoma, or relapsed/refractory non-Hodgkin's lymphoma [except chronic lymphocytic and cutaneous T-cell lymphoma] who have been treated or are refractory to bendamustine); and relapsed/refractory peripheral T-cell lymphoma (PTCL) and T-cell Prolymphocytic leukemia (T-PLL) will be enrolled and treated at the recommended Phase 2 dose (RP2D) based on results of Stage 1. Treatment will occur every 21 days. Patients in each stage of the study are expected to receive a median of four 3-week Cycles of therapy, and the maximum number of treatment Cycles allowed is 6.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	84 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 2018
Estimated Study Completion Date :	May 2019

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	Drug: EDO-S101

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose at optimal infusion time [ Time Frame: 8 months ]
   maximum tolerated dose at optimal infusion time
2. Maximum plasma concentration (Cmax) of EDO-S101 [ Time Frame: 8 months ]
   maximum plasma concentration of EDO-S101 in stage 1
3. Confirm recommended phase 2 dose (RP2D) [ Time Frame: 10 months from beginning of stage 2 ]
   In stage 2, confirm recommended phase 2 dose.
4. Overall response rate [ Time Frame: 10 months from beginning stage 2 ]
   Determine overall response rate
5. EDO-S101 Area under the curve (AUC) [ Time Frame: 8 months ]
   Determine EDO-S101 AUC in plasma

Secondary Outcome Measures :

1. Progression free survival time [ Time Frame: 10 months after beginning stage 2 ]
   Determine the progression free survival time for patients who received the RP2D
2. Overall survival [ Time Frame: 10 months after beginning stage 2 ]
   Determine overall survival time for patients who received the RP2D
3. Maximum plasma concentration of EDO-S101 in patients receiving RP2D [ Time Frame: 10 months after beginning stage 2 ]
   Determine maximum plasma concentration of EDO-S101 in patients receiving the RP2D in stage 2

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. Discontinuation of previous cancer therapies at least four (4) weeks prior to treatment in this study.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
6. Neutrophils >1,000 µL
7. Platelets ≥75,000 µL
8. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤2.5 upper limit of normal (ULN).
9. Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.
10. Creatinine ≤1.5 ULN.
11. Serum potassium within normal range.
12. 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.

Exclusion Criteria:

1. Patients with any central nervous system involvement or CTCL.
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 QTc interval > 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. Chemotherapy, radiotherapy, biologics, and/or other treatment with immunotherapy not completed four (4) weeks prior to first dose of study drug or without complete recovery from all such treatments.
11. Use of other investigational agents from 30 days prior to the Screening Visit through discontinuation of study drug.
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.

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, 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: Michelle A Malanga, MPA 212-326-5731 mm4629@cumc.columbia.edu
Germany
University Hospital of Heidelberg - medical department V	Not yet recruiting
Heidelberg, Germany, 69120
Principal Investigator: Hartmut Goldschmidt, MD
University Hospital of Cologne - Department I of Internal Medicine	Not yet recruiting
Köln, Germany, 50937
Principal Investigator: Von Treskow, 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
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:	April 18, 2018
Last Verified:	April 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; non-Hodgkin's lymphoma

Additional relevant MeSH terms:

Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms; Lymphoma, Non-Hodgkin; Hodgkin Disease; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; 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