MC# 18-22 - A Phase I/II Study to Investigate the Safety, Pharmacokinetics and Efficacy of Tinostamustine, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Patients with Advanced Solid Tumors. Sub-study to Characterize the Effects of Tinostamustine at a Dose of 80 mg/m2 Administered during a 80-minute Infusion on Cardiac Repolarization in Patients with Advanced Solid Tumors
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Agent(s): Tinostamustine
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Disease Type(s): Solid Tumor
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Phase(s): I, II
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Drug Classification(s): Targeted Therapy
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Molecular Target(s): HDAC
Mechanism of Action
Tinostamustine is a novel drug that improves access to the DNA strands within cancer cells, breaks them and then counteracts damage repair.
Purpose
In this study, the sponsor and investigators want to learn:
- How much Tinostamustine can be given with an acceptable level of side effects
- The effects of Tinostamustine (good and bad)
- How fast Tinostamustine is removed from your body
- If research tests can be used in the future to predict who will benefit from Tinostamustine
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
- Patients with secondary metastasis to the CNS are eligible if they have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study 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 two weeks prior to starting the study medication.
- Follow-up MRI shows no progression of treated lesions and no new lesions
- Evaluable disease; either measurable on imaging or with informative tumor marker as assessed by RECIST version 1.1 or other relevant response assessment for tumor type.
- Discontinuation of previous cancer therapies at least three (3) weeks or 5 half-lives, whichever is shorter, as long as the patient has recovered to eligibility levels prior to treatment in this study.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
- Neutrophils >1,000 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.
Exclusion Criteria
- Patients with primary central nervous system (CNS) cancer.
- Patients with QTc interval (Fridericia’s formula) > 450 msec in male and > 470 msec in 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 and have a wash out period of 3.3 days prior to first dose of study drug treatment in this study.
- 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.
Location
- Dallas, TX - Mary Crowley Cancer Research - Medical City
