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Study of the Safety, Pharmacokinetics and Efficacy of EDO-S101, in Patients With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03345485
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
Mundipharma-EDO GmbH

Brief Summary:
Tinostamustine (EDO-S101) is a new chemical entity, an AK-DAC (a first-in-class alkylating deacetylase inhibiting molecule) that, in preclinical studies, has been shown to simultaneously improve access to the DNA strands within cancer cells, break them and block damage repair. This Phase 1/2 study will enroll patients with various advanced solid tumors.

Condition or disease Intervention/treatment Phase
Small-cell Lung Cancer Soft Tissue Sarcoma Triple-negative Breast Cancer Ovarian Cancer Endometrial Cancer Drug: Tinostamustine (EDO-S101) Phase 1 Phase 2

Detailed Description:

The study consists of 2 phases:

  • Phase 1: Dose Escalation until MAD
  • Phase 2: Evaluation of Toxicity and Response Rate in Selected Solid Tumor Cohorts

The study is designed as an open label, Phase 1/2 trial of single agent EDO-S101. The Phase 1 portion of the study is designed to define the MTD by evaluating toxicities during dose escalation until MAD. The Phase 2 portion of the study is designed to evaluate ORR and SD that persists for at least 4 months of the RP2D.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 167 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study to Investigate the Safety, Pharmacokinetics and Efficacy of EDO-S101, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients With Advanced Solid Tumors
Actual Study Start Date : October 6, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: Tinostamustine (EDO-S101)

Phase 1:

Schedule A: Tinostamustine (EDO-S101), IV, 60mg/m2 up to 100mg/m2 Day 1 and 15 of each 28 day cycle

Phase 2:

The RP2D and selected schedule will be further investigated in patients with specific types of solid tumors: relapsed/refractory SCLC, soft tissue sarcoma, triple negative breast cancer, ovarian cancer and endometrial cancer.

Drug: Tinostamustine (EDO-S101)
The study is designed as an open label, Phase 1/2 trial of single agent EDO-S101. The Phase 1 portion of the study is designed to define the MTD by evaluating toxicities during dose escalation until MAD. The Phase 2 portion of the study is designed to evaluate ORR and SD that persists for at least 4 months of the RP2D.




Primary Outcome Measures :
  1. Safety: Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 [ Time Frame: 12 months from beginning phase 1 ]
    Safety: Number of patients experiencing treatment-related adverse events as assessed by CTCAE v4.03.

  2. Objective Response Rate (ORR) and SD that persists for at least 4 months in selected solid tumor cohorts [ Time Frame: 12 months from beginning phase 2 ]
    ORR is defined as proportion of subjects with CR or PR based on RECIST V.1.1


Secondary Outcome Measures :
  1. PK: Maximum Plasma Concentration [Cmax] [ Time Frame: 12 months from beginning phase 1 ]
    Maximum plasma concentration of EDO-S101

  2. PK: Time to reach maximum (peak) plasma concentration following drug administration (Tmax) [ Time Frame: 12 months from beginning phase 1 ]
    Tmax of EDO-S101

  3. PK: Area Under the Curve [AUC] [ Time Frame: 12 months from beginning phase 1 ]
    EDO-S101 AUC in plasma

  4. PK: Elimination half-life [t½] [ Time Frame: 12 months from beginning phase 1 ]
    PK: Half-life [t½] for EDO-S101

  5. Response Rate: Progression Free Survival (PFS) [ Time Frame: 12 months from beginning phase 2 ]
    PFS : Will be measured from the start of treatment with EDO-S101 until the first documentation of disease progression or death due to any cause whichever occurs first

  6. Response Rate: Overall Survival (OS) [ Time Frame: 12 months from beginning phase 2 ]
    OS will be determined as the time from the start of treatment with EDO-S101 until death due to any cause.



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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

General Phase 1 and 2 Inclusion Criteria:

  1. Signed informed consent.
  2. Patients age ≥18 years at signing the informed consent.
  3. Histologically confirmed diagnosis of advanced or metastatic solid tumors, disease should have progressed following at least one line of therapy and no other standard therapy with proven clinical benefit is available
  4. Patients with secondary metastasis to the CNS are eligible if they have met certain criteria.
  5. Evaluable disease; either measurable on imaging or with informative tumor marker.
  6. Discontinuation of previous cancer therapies at least three (3) weeks or 5 half-lives, whichever is shorter.
  7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  8. Neutrophils ≥1,500 μL.
  9. Platelets ≥100,000 μL.
  10. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3 upper limit of normal (ULN). In cases with liver involvement ALT/ AST ≤ 5× ULN.
  11. Total bilirubin ≤1.5 mg/dL unless elevated due to known Gilbert's syndrome.
  12. Creatinine ≤1.5 ULN.
  13. Serum potassium within normal range.
  14. 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 for at least 6 months following last treatment. If male, must be sterile or willing to abstain from sexual intercourse or employ a barrier method of contraception during the study treatment and for at least 6 months following last treatment.

General Phase 1 and 2 Exclusion Criteria:

  1. Patients with primary central nervous system (CNS) cancer.
  2. Patients with QTc interval >450 msec for male and >470 msec for female.
  3. Patients who are on treatment with drugs known to prolong the QT/QTc interval.
  4. Patients who are being treated with Valproic Acid for any of its indication (epilepsy, mood disorder) must be excluded or must stop using the medication.
  5. Any serious medical condition that interferes with adherence to study procedures.
  6. Prior history of solid tumor malignancy diagnosed within the last three (3) years of study enrollment excluding adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer, in situ breast cancer, in situ prostate cancer (patients must have shown no evidence of active disease for 2 years prior to enrollment)
  7. Pregnant or breast feeding females.
  8. New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias not adequately controlled, or other significant co-morbidities [e.g. active infection requiring systemic therapy, history of human immunodeficiency virus (HIV) infection, or active Hepatitis B or Hepatitis C].
  9. Use of other investigational agents within 30 days or 5 half-lives prior to the first dose of study drug. As long as patient has recovered from any related toxicities ≥ Grade 1.
  10. 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 Prednisolone PO QD (or equivalent), daily (or less) at least seven (7) days prior to study drug administration are allowed.

Phase 2 Tumor-specific Eligibility Criteria

Phase 2 patients must meet the cohort-specific inclusion/exclusion criteria in addition to the general inclusion/exclusion criteria for Phase 1 and Phase 2 study listed above.

Cohort 1: Patient Population: Relapsed/Refractory SCLC

  1. Histologically or cytologically confirmed limited or extensive disease stage of SCLC. The disease should be progressing during or relapsing after the previous treatment.
  2. At least one line of prior combination and no other standard therapy with proven clinical benefit is available.
  3. At least 3 weeks or 5 half-lives, whichever is shorter, should have elapsed since prior treatment as long as the patient recovered from any related toxicities to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
  4. Prior radiotherapy is acceptable provided the patient has recovered from any radiotherapy related acute toxicities.
  5. Presence of measurable disease as defined by the RECIST version 1.1

Cohort 2: Patient Population: Relapsed/Refractory Soft Tissue Sarcoma

  1. Histologically confirmed diagnosis of advanced, unresectable, or metastatic soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy excluding: neuroblastoma, embryonal rhabdomyosarcoma, or Kaposi sarcoma.
  2. Must have received at least one prior line chemotherapy regimen and no other standard therapy with proven clinical benefit is available. For GIST-patients: must have received at least two lines of tyrosine kinase inhibitors or do not respond to or for which tyrosine kinase inhibitor therapy is not suitable.
  3. The disease should be progressing/relapsed during or after the previous treatment. At least 3 weeks should have elapsed since prior chemotherapy or 5 half-lives, whichever is shorter, as long as the patient recovered from any related toxicities to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
  4. Presence of measurable disease as defined by RECIST version 1.1

Cohort 3: Patient Population: Relapsed/Refractory Triple Negative Breast Cancer

  1. Histologically or cytologically confirmed locally advanced or metastatic Triple Negative Breast Cancer.
  2. Must have received at least one line of chemotherapy and no other standard therapy with proven clinical benefit is available. At least 3 weeks should have elapsed since prior chemotherapy or 5 half-lives, whichever is shorter, as long as the patient recovered from acute toxicity of previous therapies to ≤ grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
  3. Prior radiotherapy is acceptable provided it was applied within 4 four weeks (2 weeks for palliative, limited field radiation therapy) prior to starting treatment on this trial and the patient recovered from any radiotherapy related acute toxicities.
  4. The disease should be progressing/relapsed during or after the previous treatment.
  5. Presence of measurable disease as defined by RECIST version 1.1

Cohort 4: Patient Population: Relapsed/Refractory Ovarian Cancer

  1. Histologically or cytologically confirmed advanced ovarian cancer: epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer (excluding borderline ovarian cancer) that is resistant or refractory to platinum therapy and no other standard therapy with proven clinical benefit is available.

    1. Platinum-resistant ovarian cancer is defined as disease that responded to primary platinum therapy and then progressed within 6 months or disease that progressed during or within six months of completing a subsequent platinum therapy.
    2. Primary platinum refractory disease is defined as disease that has not responded to a platinum-based regimen or experienced disease recurrence within 3 months of completing a first-line platinum-based regimen.
  2. The disease should be progressing/relapsed during or after the previous treatment. At least 3 weeks should have elapsed since prior chemotherapy or 5 half-lives, whichever is shorter, as long as the patient recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
  3. Presence of measurable disease as defined by RECIST version 1.1

Cohort 5: Relapsed/Refractory Endometrial Cancer

  1. Histologically or cytologically confirmed locally advanced or metastatic endometrial cancer.
  2. Must have received at least one line of chemotherapy and no other standard therapy with proven clinical benefit is available. At least 3 weeks should have elapsed since prior chemotherapy or 5 half-lives, whichever is shorter, as long as the patient recovered from acute toxicity of previous therapies to ≤ Grade 1 (or ≤ Grade 2 for any symptomatic neuropathy or endocrinopathies).
  3. Prior radiotherapy is acceptable provided it was administered at least 4 weeks (2 weeks for palliative, limited field radiation therapy) prior to starting treatment on this trial and recovered from any radiotherapy related acute toxicities.
  4. The disease should be progressing/relapsed during or after the previous treatment.
  5. Presence of measurable disease as defined by RECIST version 1.1.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03345485


Contacts
Contact: David Browning 615-975-7776 David.browning@edoncology.com

Locations
United States, Arizona
Mayo Clinic Cancer Center Withdrawn
Phoenix, Arizona, United States, 85054
United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Alain Mita, MD    310-423-0721    Alain.Mita@cshs.org   
Principal Investigator: Alain Mita, MD         
Stanford University Medical Center Recruiting
Palo Alto, California, United States, 94304
Contact: Shivaani Kummar, MD    650-724-9084    skummar@stanford.edu   
Principal Investigator: Shivaani Kummar, MD         
United States, District of Columbia
Georgetown University Not yet recruiting
Washington, District of Columbia, United States, 20007
Contact: Filipa Lynce, MD         
Principal Investigator: Filipa Lynce, MD         
United States, Illinois
Northwestern University Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Young K Chae, MD         
Principal Investigator: Young K Chae, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Rashmi Chugh, MD         
Principal Investigator: Rashmi Chugh, MD         
United States, New York
New York Univesity Not yet recruiting
New York, New York, United States, 10016
Contact: Daniel Cho, MD         
Principal Investigator: Daniel Cho, MD         
United States, Texas
Mary Crowley Cancer Research Not yet recruiting
Dallas, Texas, United States, 75251
Contact: James Strauss, MD         
Principal Investigator: James Strauss, MD         
Canada, Ontario
Princess Margaret Cancer Center Not yet recruiting
Toronto, Ontario, Canada, M5G 1Z5
Contact: Razak Albiruni, MD         
Principal Investigator: Razak Albiruni, MD         
Canada, Quebec
McGill University Not yet recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Scott Owen, MD         
Principal Investigator: Scott Owen, MD         
Sponsors and Collaborators
Mundipharma-EDO GmbH
Investigators
Principal Investigator: Shivaani Kummar, MD Stanford University

Additional Information:
Responsible Party: Mundipharma-EDO GmbH
ClinicalTrials.gov Identifier: NCT03345485     History of Changes
Other Study ID Numbers: EDO-S101-1002
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mundipharma-EDO GmbH:
Phase 1 clinical trial
Solid Tumor
Small Cell Lung Cancer
Breast Cancer
Ovarian Cancer
Soft Tissue Sarcoma
Relapsed/Refractory
Triple Negative
GIST
Epithelial cancer
Peritoneal cancer
Fallopian tube cancer
Metastatic
Advanced
Endometrial
Phase 2 clinical trial

Additional relevant MeSH terms:
Sarcoma
Ovarian Neoplasms
Small Cell Lung Carcinoma
Endometrial Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Uterine Neoplasms
Uterine Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases