Phase 1/2 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
- Conditions
- Malignant solid tumour10027655
- Registration Number
- NL-OMON50797
- Lead Sponsor
- Mundipharma
- Brief Summary
Trial never started
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 15
General Inclusion Criteria:
• Signed informed consent.
• Patients age >=18 years at signing of the informed consent.
• Life expectancy > 3 months
• Histologically confirmed diagnosis of advanced or metastatic solid
tumors, disease should have progressed following at least 1 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:
(1) Residual neurological symptoms <= Grade 1
(2) 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
(3) Follow-up imaging studies show 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.
• Eastern Cooperative Oncology Group (ECOG) performance status <=2
(Section 13.1).
• Absolute neutrophil count (ANC) (polymorphonuclear [PMN] cells 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.
• Serum potassium and magnesium at least at above the lowest limit of normal
(LLN) range, before every IMP administration. If it is below LLN,
supplementation is permissible.
• Female study participants of child-bearing potential and their partners, and
male study participants who intend to be sexually active with a woman of
child-bearing potential, must be willing to use at least TWO highly effective
forms of contraception
Female study participants of child-bearing potential must continue using
contraception for at least six months after the last administration of the IMP.
Male study participants who are sexually active with a woman of child-bearing
potential should also use a condom during treatment and for at least ninety
(90) days after the last administration of IMP.
Cohort-specific eligibility criteria phase 2 portion of the trial in addition
to the general inclusion/exclusion criteria for listed above (refer to
protocol page 19-21).
Cohort 1 Patient Population: Relapsed/Refractory Small-cell Lung Cancer (SCLC)
Cohort 2 Patient Population: Relapsed/Refractory Soft Tissue Sarcoma
Cohort 3 Patient Population: Relapsed/Refractory Triple Negative Breast Cancer
(RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED)
Cohort 4 Patient Population: Relapsed/Refractory Ovarian Cancer
Cohort 5 Patient Population: Relapsed/Refractory Endometrial Cancer
(RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED)
To be eligible to participate in the trial, a patient cannot meet any of the
following exclusion criteria:
• Patients with primary CNS cancer.
• Patients with QTc interval (Fridericia*s formula) >450 ms.
• Patients who are on treatment with drugs known to prolong the QT/QTc
interval. Refer to CredibleMeds list of drugs with known risk of Torsade des
pointes (TdP): http://crediblemeds.org/new-drug-list.
• Patients who are being treated with valproic acid for any of its indication
(epilepsy, mood disorder)
• Any serious medical condition that interferes with adherence to trial
procedures.
• Prior history of another solid tumor malignancy diagnosed within the last 3
years of trial 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 women.
• New York Heart Association (NYHA) stage III/IV congestive heart failure
(Section 13.2). The following arrhythmias: atrial fibrillation/flutter with
poor rate control, documented sustained ventricular tachycardia (defined
as >30 seconds or requiring cardioversion before
30 seconds have elapsed) or TdP.
• 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 or previous anticancer therapies
within 28 days prior to the first dose of tinostamustine, provided the patient
has recovered from any related toxicities >=Grade 1.
• Steroid treatment within 7 days prior to trial treatment. Patients that
require intermittent use of bronchodilators, topical steroids, or local steroid
injections will not be excluded from the trial. Patients who have been
stabilized to 10 mg prednisolone orally (PO) once daily (QD) (or equivalent),
daily (or less) at least 7 days prior to trial drug administration are allowed.
Cohort-specific eligibility criteria phase 2 portion of the trial in addition
to the general inclusion/exclusion criteria for listed above (refer to
protocol page 19-21).
Cohort 1 Patient Population: Relapsed/Refractory Small-cell Lung Cancer (SCLC)
Cohort 2 Patient Population: Relapsed/Refractory Soft Tissue Sarcoma
Cohort 3 Patient Population: Relapsed/Refractory Triple Negative Breast Cancer
(RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED)
Cohort 4 Patient Population: Relapsed/Refractory Ovarian Cancer
Cohort 5 Patient Population: Relapsed/Refractory Endometrial Cancer
(RECRUITMENT INTO THIS COHORT HAS NOW BEEN HALTED)
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Phase 2: Evaluation of Toxicity and Response Rate in Selected Solid Tumor<br /><br>Cohorts<br /><br><br /><br>• To determine the objective response rate (ORR) [complete response (CR)<br /><br>plus partial response (PR)] of any duration, plus the rate of patients with<br /><br>stable disease (SD) of at least<br /><br>4 months duration at a dose of 80 mg/m2 administered over 1 hour on Day 1 and<br /><br>15 of each<br /><br>4-week treatment cycle.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Phase 2: Evaluation of Toxicity and Response Rate in Selected Solid Tumor<br /><br>Cohorts<br /><br><br /><br>• To evaluate safety and tolerability of 80 mg/m2 of tinostamustine<br /><br>administered over 1 hour on Day 1 and 15 of each 4-week treatment cycle.<br /><br><br /><br>• To determine the progression-free survival (PFS) time for patients who<br /><br>received 80 mg/m2 of tinostamustine administered over 1 hour on Day 1 and 15 of<br /><br>each 4-week treatment cycle.<br /><br><br /><br>• To determine the overall survival (OS) for patients who received 80 mg/m2 of<br /><br>tinostamustine administered over 1 hour on Day 1 and 15 of each 4-week<br /><br>treatment cycle.<br /><br><br /><br>• To determine duration of response.<br /><br><br /><br>• To establish the trough PK profiles of tinostamustine.<br /><br><br /><br>Exploratory Objective<br /><br><br /><br>• To correlate the extent of gene expression changes in tumor samples<br /><br>with anti-tumor activity. </p><br>