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

Study Overview
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Brief Summary
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Tinostamustine (EDO-S101) is a new chemical entity, an AK-DAC (a first-in-class alkylating deacetylase inhibiting molecule), that in pre-clinical 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.

Detailed Description
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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.

Official Title
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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

Conditions
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Small-cell Lung Cancer, Soft Tissue Sarcoma, Triple-negative Breast Cancer, Ovarian Cancer, Endometrial Cancer

Intervention / Treatment
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* Drug: Tinostamustine (EDO-S101)


Participation Criteria
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Eligibility Criteria
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General Phase 1 and 2 Inclusion Criteria: Signed informed consent. Patients age ≥18 years at signing the informed consent. 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 as-sessment for the patient. Patients with secondary metastasis to the CNS are eligible if they have met certain criteria. Evaluable disease; either measurable on imaging or with informative tumor marker. Discontinuation of previous cancer therapies at least three (3) weeks or 5 half-lives, whichever is shorter. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Neutrophils ≥1,500 μL. Platelets ≥100,000 μL. 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. Serum potassium within normal range. 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: Patients with primary central nervous system (CNS) cancer. Patients with QTc interval >450 msec for male and >470 msec for female. Patients who are on treatment with drugs known to prolong the QT/QTc interval. 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. Any serious medical condition that interferes with adherence to study procedures. 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) Pregnant or breast feeding females. 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]. 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. 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 Histologically or cytologically confirmed limited or extensive disease stage of SCLC. The disease should be progressing during or relapsing after the previous treatment. At least one line of prior combination 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. 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). Prior radiotherapy is acceptable provided the patient has recovered from any radiotherapy related acute toxicities. Presence of measurable disease as defined by the RECIST version 1.1 Cohort 2: Patient Population: Relapsed/Refractory Soft Tissue Sarcoma 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. Must have received at least one prior line chemotherapy regimen 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. 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. 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). Presence of measurable disease as defined by RECIST version 1.1 Cohort 3: Patient Population: Relapsed/Refractory Triple Negative Breast Cancer Histologically or cytologically confirmed locally advanced or metastatic Triple Negative Breast Cancer. Proven HER2 negative by immunohistochemistry (IHC) or in situ hybridization (ISH) per ASCO-CAP guidelines. Must have received at least one line of chemotherapy 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. 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). 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. The disease should be progressing/relapsed during or after the previous treatment. Presence of measurable disease as defined by RECIST version 1.1 Cohort 4: Patient Population: Relapsed/Refractory Ovarian Cancer 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 or recommended based on the investigator's individual risk-benefit assessment for the patient. 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. 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. 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). Presence of measurable disease as defined by RECIST version 1.1 Cohort 5: Relapsed/Refractory Endometrial Cancer Histologically or cytologically confirmed locally advanced or metastatic endometrial cancer. Must have received at least one line of chemotherapy 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. 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). 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. The disease should be progressing/relapsed during or after the previous treatment. Presence of measurable disease as defined by RECIST version 1.1.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tinostamustine (EDO-S101)<br>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)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of participants with treatment-related adverse events as assessed by CTCAE V4.03 | Safety: Number of patients experiencing treatment-related adverse events as assessed by CTCAE v4.03. | 12 months from beginning phase 1 | 
| Objective Response Rate (ORR) and SD that persists for at least 4 months in selected solid tumor cohorts | ORR is defined as proportion of subjects with CR or PR based on RECIST V.1.1 | 12 months from beginning phase 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: Maximum Plasma Concentration [Cmax] | Maximum plasma concentration of EDO-S101 | 12 months from beginning phase 1 | 
| PK: Time to reach maximum (peak) plasma concentration following drug administration (Tmax) | Tmax of EDO-S101 | 12 months from beginning phase 1 | 
| PK: Area Under the Curve [AUC] | EDO-S101 AUC in plasma | 12 months from beginning phase 1 | 
| PK: Elimination half-life [t½] | PK: Half-life [t½] for EDO-S101 | 12 months from beginning phase 1 | 
| Response Rate: Progression Free Survival (PFS) | 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 | 12 months from beginning phase 2 | 
| Response Rate: Overall Survival (OS) | OS will be determined as the time from the start of treatment with EDO-S101 until death due to any cause. | 12 months from beginning phase 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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