Study of the Safety, Pharmacokinetics and Efficacy of Tinostamustine in Patients With Advanced Solid Tumors.

NCT03345485 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: EDO-S101-10022020-004246-11
• Study Type: interventional
• Target: 71
• Locations: 5 countries
• Sites: 13

Brief Summary

Tinostamustine (EDO-S101) is a first-in-class alkylating deacetylase inhibitor designed to improve drug access to deoxyribonucleic acid (DNA) strands, induce DNA damage and counteract its repair in cancer cells. The main purpose of this study is to assess the safety, tolerability and efficacy of Tinostamustine in subjects with advanced solid tumours. Subjects will be given Tinostamustine via intravenous infusion on Days 1 and 15 of a 4-week cycle, the dose and infusion time will vary depending on the phase of the study.

Conditions

Small Cell Lung Cancer; Soft Tissue Sarcoma; Triple-negative Breast Cancer; Ovarian Cancer; Endometrial Cancer

Keywords

Phase 1 (P1); Solid Tumor; Small Cell Lung Cancer (SCLC); Breast Cancer; Ovarian Cancer (OC); Soft Tissue Sarcoma (STS); Relapsed/Refractory; Triple Negative; Gastrointestinal stromal tumors (GIST); Epithelial cancer; Peritoneal cancer; Fallopian tube cancer; Metastatic; Advanced; Endometrial Cancer (EC); Phase 2 (P2); Corrected QT interval (QTc); System Organ Class (SOC); Preferred Term (PT); Day 1 (D1); Day 15 (D15); Treatment-Emergent Adverse Events (TEAEs); Investigational Medicinal Product (IMP); Polymorphonuclear cell (PMN); Progressive Response (PR); Stable disease (SD); Maximum administered dose (MAD); Dose-limiting toxicity (DLT)

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE V4.03 on Phase 1

  All TEAEs was reported from the first dose of study drug through the time of study drug discontinuation (at any time or Day 28 of the last treatment Cycle). All treatment-related TEAEs was followed until resolution or stabilization. For the purpose of regulatory reporting requirements, causal relationships of definite, probable, and possible was considered treatment-related. Number of patients experiencing treatment-related adverse events (TEAE) as assessed by CTCAE v4.03. (June 2010).

  From each patient's time of first dose administration to discontinuation of study drug (at any time or D28 of the last treatment cycle), up to 6 months.

• Clinical Benefit Response Rate in Selected Solid Tumor Cohorts on Phase 2

  The Clinical Benefit Response Rate is calculated as the number of patients with Clinical Benefit Response divided by number of patients in the FAS (in the respective cohort). Clinical Benefit Response is defined as patients achieving stable disease with a duration of at least 12 weeks (84 days). Summary subjects analysed were 36.

  From start treatment and assessed after every 2 cycles until determination of stable disease and follow up for up to 84 days.

• Highest Change From Baseline in QTcF in Sub-studies

  QTcF: corrected QT interval \[QTc\] using Fridericia's formula) and other electrocardiogram (ECG) parameters in subjects with solid tumours who have progressed after at least 1 line of therapy and for whom no other standard therapy with proven clinical benefit is available. Within each cycle a Change from baseline (CfB) is calculated for QTcF relative to the baseline value of day 1 of the cycle. QTcF CfB= QTcF Post-dose value - QTcF pre-dose value of D1 ECG Parameters: 4-hours ECG holter monitoring in C1 and ECGs during EDO-S101 administration. Continuous variables the mean and standard deviation are presented together with the total number of observations and the number of missing and non-missing values.

  From cycle 1 and at every cycle on treatment days D1 and D15, assessed pre-dose and post-start of infusion at 30 and 80mins (Substudy 2 - up to 6 months) and 30, 60, 90, 120 and 180mins (substudy 1 - up to 6 months).

Secondary Outcomes (11)

• Treatment-related Adverse Events on Phase 2 and Sub Studies

  From each patient's time of informed consent to discontinuation of study drug (at any time or D28 of the last treatment cycle), up to 8 months

• Progression Free Survival (PFS) Time for Phase 2 and Sub Studies

  From patient's first dose until first documented progression/start of subsequent anti-cancer therapy/death from any cause, whichever came first, up to 26 months.

• Overall Survival (OS) Time for Phase 2 and Sub Studies

  From patient's first dose until first documented progression/start of subsequent anti-cancer therapy/death from any cause, whichever came first, up to 42 months.

• Maximum Duration of Response (DoR) Time for Phase 2 and Sub Studies

  From patient's first overall response of CR or PR, until disease progression/subsequent anti-cancer therapy/death from any cause, up to 24 months.

• Objective Response Rate (ORR) and the Clinical Benefit Rate (CBR) That Persists for at Least Four (4) Months in Selected Solid Tumor Cohorts on Sub Studies

  From start of treatment, assessed every 2 cycles, until first documented complete CR, PR or SD, up to 6 months. If SD, assessment continued every 2 cycles until CR/PR/death (up to 6 months)

Study Arms (13)

Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (30 min) cohort 1

EXPERIMENTAL

Drug: Tinostamustine 60mg/m2 over 30min

Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (30 min) cohort 2

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 30min

Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (30 min) cohort 3

EXPERIMENTAL

Drug: Tinostamustine 100mg/m2 over 30min

Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (60 min) cohort 4

EXPERIMENTAL

Drug: Tinostamustine 60mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (60 min) cohort 5

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (60 min) cohort 6

EXPERIMENTAL

Drug: Tinostamustine 100mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) cohort

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Triple Negative breast Cancer (TNBC) cohort

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 60min

Tinostamustine (EDO-S101) - Sub study 1 (SS1)

EXPERIMENTAL

Drug: Tinostamustine 60mg/m2 over 60min

Tinostamustine (EDO-S101) - Sub study 2 (SS2)

EXPERIMENTAL

Drug: Tinostamustine 80mg/m2 over 80min

Interventions

Tinostamustine 60mg/m2 over 30min DRUG

Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (30 min) cohort 1

Tinostamustine 80mg/m2 over 30min DRUG

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (30 min) cohort 2

Tinostamustine 100mg/m2 over 30min DRUG

Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 30 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (30 min) cohort 3

Tinostamustine 60mg/m2 over 60min DRUG

Tinostamustine as a single agent was administered at doses of 60mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Phase 1 - 60mg/m2 (60 min) cohort 4; Tinostamustine (EDO-S101) - Sub study 1 (SS1)

Tinostamustine 80mg/m2 over 60min DRUG

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101.

Tinostamustine (EDO-S101) - Phase 1 - 80mg/m2 (60 min) cohort 5; Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Endometrial Cancer (EC) cohort; Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Ovarian Cancer (OC) cohort; Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Small Cell Lung Cancer (SCLC) cohort; Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Soft Tissue Sarcoma (STS) cohort; Tinostamustine (EDO-S101) - Phase 2 Relapsed/refractory Triple Negative breast Cancer (TNBC) cohort

Tinostamustine 100mg/m2 over 60min DRUG

Tinostamustine as a single agent was administered at doses of 100mg/m2 by intravenous infusion over 60 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Phase 1 - 100mg/m2 (60 min) cohort 6

Tinostamustine 80mg/m2 over 80min DRUG

Tinostamustine as a single agent was administered at doses of 80mg/m2 by intravenous infusion over 80 minutes on Days (D) 1 and 15 of each 28-day cycle.

Also known as: EDO-S101

Tinostamustine (EDO-S101) - Sub study 2 (SS2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Patient willing and able to sign the informed consent.
• Patients age ≥18 years at signing the informed consent.
• Life expectancy \> 3 months.
• 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 or recommended based on the investigator's individual risk-benefit assessment for the patient.
• Patients with secondary metastasis to the central nervous system (CNS) are eligible if they have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to trial day 1 and they meet all of the following criteria:
• Residual neurological symptoms ≤Grade 1.
• No glucocorticoids requirement or patients may be receiving low doses of glucocorticoids providing the dose has been stable for at least 2 weeks prior to starting the trial medication.
• Follow-up imaging studies show no progression of treated lesions and no new lesions.
• Evaluable disease; measurable on imaging as assessed by RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Absolute neutrophil count (ANC) (polymorphonuclear cells \[PMN\] plus bands) \>1,000/ μL.
• Platelets ≥100,000 μL. Platelet transfusions within the 14 days before Day 1 of Cycle 1 is prohibited.
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3 upper limit of normal (ULN). In cases with liver involvement ALT/ AST ≤ 5× ULN.
• Total bilirubin ≤1.5 mg/dL unless elevated due to known Gilbert's syndrome.
• Creatinine ≤1.5 ULN.

Sponsors & Collaborators

• Mundipharma Research Limited: lead

Study Sites (13)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

New York University

New York, New York, 10016, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75251, United States

Location

Juravinski Cancer Centre

Hamilton, Ontario, on, L8V 1C3, Canada

Location

McGill University

Montreal, Quebec, H4A 3J1, Canada

Location

BC Cancer-Vancouver

Vancouver, Vancouver, BC, V5Z 1M9, Canada

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

Istituto Europeo di Oncologia

Milan, MI 20141, Italy

Location

Erasmus MC Kanker Instituut

Rotterdam, 3015, Netherlands

Location

Hospital Universitario La Paz

Madrid, Fuencarral-El Pardo, 28046, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Horta-Guinardó, 08035, Spain

Location

MeSH Terms

Conditions

Small Cell Lung Carcinoma; Sarcoma; Triple Negative Breast Neoplasms; Ovarian Neoplasms; Endometrial Neoplasms; Breast Neoplasms; Recurrence; Gastrointestinal Stromal Tumors; Fallopian Tube Neoplasms; Neoplasm Metastasis

Interventions

tinostamustine

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Uterine Neoplasms; Uterine Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Connective Tissue; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Fallopian Tube Diseases; Neoplastic Processes

Results Point of Contact

• Title: Mónica Araujo - Senior Programmer, Data Management
• Organization: Mundipharma Research Limited

monica.araujo@mundipharma-rd.eu

+447922223436

Study Officials

• Shivaani Kummar, MD

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

• Ana Oaknin, MD

  Head of Gynaecologic Cancer Program, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In phase 1 (dose escalation phase) of the study, subjects were allocated sequentially. In phase 2, subjects were allocated in parallel to the various arms (cohorts) based on their cancer specifics. In the substudies 1 and 2, subjects were allocated into a single group in each substudy. Overall, the study model is described as Sequential as the study proceeded in phases.

Study Record Dates

• First Submitted: October 24, 2017
• First Posted: November 17, 2017
• Study Start: November 8, 2017
• Primary Completion: July 27, 2022
• Study Completion: March 29, 2023
• Last Updated: October 21, 2024
• Results First Posted: October 21, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Available on request through Enquiries@napp.co.uk
• Access Criteria: Available on request through Enquiries@napp.co.uk

Locations

NL (1); ES (2); US (5); CA (3); IT (2)